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Wen R, Huang R, Xu K, Yi X. Insights into the role of histone lysine demethylases in bone homeostasis and skeletal diseases: A review. Int J Biol Macromol 2025; 306:141807. [PMID: 40054804 DOI: 10.1016/j.ijbiomac.2025.141807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 03/03/2025] [Accepted: 03/04/2025] [Indexed: 05/11/2025]
Abstract
Histone lysine demethylases (KDMs), as important epigenetic regulators, are involved in various biological processes such as energy metabolism, apoptosis, and autophagy. Recent research shows that KDMs activate or silence downstream target genes by removing lysine residues from histone tails, and participate in the regulation of bone marrow mesenchymal stem cells (BM-MSCs), osteoblasts (OB), osteoclasts (OC), chondrocytes and other skeletal cell development, differentiation and formation. Moreover, several members of the KDM family affect the occurrence and development of bone diseases such as osteoporosis (OP), osteoarthritis (OA), osteosarcoma (OS), by regulating target genes. Specific regulation mechanisms of KDMs suggest new strategies for bone disease treatment and prevention. Despite the unique function and importance of KDMs in the skeletal system, previous studies have never systematically summarized their specific role, molecular mechanism, and clinical treatment in bone physiology and pathology. Therefore, this review summarises the expression pattern, intracellular signal transduction, and mechanism of action of the KDM family in several bone physiological and pathological conditions, aiming to highlight the important role of KDMs in bone diseases and provide a reference for the future treatment of bone diseases.
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Affiliation(s)
- Ruiming Wen
- School of Sports Health, Shenyang Sport University, Shenyang, Liaoning, China
| | - Ruiqi Huang
- School of Sports Health, Shenyang Sport University, Shenyang, Liaoning, China; School of Physical Education, Liaoning Normal University, Dalian, Liaoning, China
| | - Ke Xu
- School of Sports Health, Shenyang Sport University, Shenyang, Liaoning, China
| | - Xuejie Yi
- School of Sports Health, Shenyang Sport University, Shenyang, Liaoning, China.
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Triwardhani A, Alida A, Winoto ER, Pramusita A, Putranti NAR, Ariadi KS, Pribadi OB, Anwar AA, Purnamasari AE, Mappananrang RA, Situmorang PC, Riawan W, Noor TNEBTA, Nugraha AP, Nugraha AP. Moringa oleifera L. Nanosuspension Extract Administration Affects Heat Shock Protein-10 and -70 under Orthodontics Mechanical Force In Vivo. Eur J Dent 2025; 19:523-530. [PMID: 39788532 PMCID: PMC12020578 DOI: 10.1055/s-0044-1791937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2025] Open
Abstract
OBJECTIVE The mechanical stimulation known as orthodontic mechanical force (OMF) causes biological reactions in orthodontic tooth movement (OTM). Heat shock protein-70 (HSP-70) needs pro-inflammatory cytokines to trigger bone resorption in OTM; nevertheless, heat shock protein-10 (HSP-10), a "Alarmin" cytokine, should control these pro-inflammatory cytokines to get the best alveolar bone remodeling (ABR). Moringa oleifera L. nanosuspension extract (MONE) has anti-inflammatory, antioxidant, and ABR-stimulating properties. The aim of the study was to examine in vivo HSP-10 and HSP-70 expressions under OMF following MONE application in Wistar rats (Rattus norvegicus). MATERIAL AND METHODS A total of 36 Wistar rats (R. norvegicus) were split up into eight groups: one for treatment (OMF + MONE) and one for control (OMF + MONE administration for days 1, 7, 14, and 21). By employing nickel-titanium coil springs and using 10 g of light force per millimeter to implant the orthodontic device, the OMF was completed. According to the day of observation, all of the samples were sacrificed. To perform an immunohistochemistry investigation, the premaxilla of the sample was isolated. Tukey's Honest Significant Different (HSD) test (p < 0.05) was performed after an Analysis of Variance (ANOVA) analysis of the data. RESULTS In both the OMF and MONE groups, HSP-70 peaked on day 14 and began to fall on day 21. HSP-10 peaked on day 21, but along with MONE, it also began to progressively decline on days 14 and 21, with significant differences (p < 0.05). CONCLUSION According to immunohistochemistry evidence, postadministration of MONE markedly elevated HSP-10 but lowered HSP-70 expression in the alveolar bone of Wistar rats under OMF.
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Affiliation(s)
- Ari Triwardhani
- Department of Orthodontic, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Alida Alida
- Department of Orthodontic, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Ervina Restiwulan Winoto
- Department of Orthodontic, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Adya Pramusita
- Department of Orthodontic, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia
| | | | - Kristian Satrio Ariadi
- Department of Orthodontic, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Okso Brillian Pribadi
- Department of Orthodontic, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia
| | | | | | | | - Putri Cahaya Situmorang
- Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Sumatera Utara, Medan, Indonesia
| | - Wibi Riawan
- Department of Molecular Biochemistry, Faculty of Medicine, Universitas Brawijaya, Malang, East Java, Indonesia
| | | | | | - Alexander Patera Nugraha
- Department of Orthodontic, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia
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Dong X, Liu H, Yuan D, Gulati K, Liu Y. Re-engineering bone: pathogenesis, diagnosis and emerging therapies for osteoporosis. J Mater Chem B 2025; 13:4938-4963. [PMID: 40192254 DOI: 10.1039/d4tb02628d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2025]
Abstract
Osteoporosis, a multifaceted metabolic bone disease, is becoming increasingly prevalent and poses a significant burden on global healthcare systems. Given the limitations of traditional treatments such as pharmacotherapy, tissue engineering has emerged as a promising alternative for osteoporosis management. This review begins by exploring the pathogenesis of osteoporosis, with a focus on the abnormal metabolic, cellular, and molecular signalling microenvironments that drive the disease. We also examine commonly used clinical diagnostic techniques, discussing their strengths and limitations. Notably, this review evaluates various advanced tissue engineering strategies for osteoporosis treatment. Delivery systems, including injectable hydrogels and nanomaterials, are detailed alongside bone tissue engineering materials such as bioactive ceramics, bone cements, and polymers. Additionally, biologically active substances, including exosomes and cytokines, and emerging therapies that leverage small-molecule drugs are explored. Through a comprehensive analysis of the advantages and limitations of current biomaterials and therapeutic approaches, this review provides insights into future directions for tissue engineering-based solutions. By synthesizing current advancements, it aims to inspire innovative perspectives for the clinical management of osteoporosis.
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Affiliation(s)
- Xinyi Dong
- Central Laboratory, Peking University School and Hospital of Stomatology, Beijing 100081, China.
- National Center for Stomatology & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices Beijing Key Laboratory of Digital Stomatology & Translational Research Center for Oro-craniofacial Stem Cells and Systemic Health, Beijing 100081, China
| | - Hao Liu
- Central Laboratory, Peking University School and Hospital of Stomatology, Beijing 100081, China.
- National Center for Stomatology & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices Beijing Key Laboratory of Digital Stomatology & Translational Research Center for Oro-craniofacial Stem Cells and Systemic Health, Beijing 100081, China
| | - Dian Yuan
- Hubei University of Science and Technology, School of Dentistry and Optometry, Xianning 430030, China
| | - Karan Gulati
- School of Dentistry, The University of Queensland, Herston, QLD, 4006, Australia.
- Centre for Orofacial Regeneration, Reconstruction and Rehabilitation (COR3), Herston, QLD 4006, Australia
| | - Yan Liu
- Central Laboratory, Peking University School and Hospital of Stomatology, Beijing 100081, China.
- Centre for Orofacial Regeneration, Reconstruction and Rehabilitation (COR3), Herston, QLD 4006, Australia
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing 100081, China
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Zhao R, Fu J, Jiang Y, Wu L, Yan Z, Liu Y. Maltol promotes osteoclastogenesis and exacerbates periodontitis via TRAF6/JNK/Nfatc1 pathway. Biochem Biophys Res Commun 2025; 770:151855. [PMID: 40373380 DOI: 10.1016/j.bbrc.2025.151855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2025] [Revised: 04/09/2025] [Accepted: 04/18/2025] [Indexed: 05/17/2025]
Abstract
OBJECTIVE The aim of this study was to investigate the role of maltol in osteoclast differentiation and its mechanism, and to provide evidence for the effect of common sweeteners on periodontal tissue destruction and the prevention of periodontitis. METHODS BMMNCs were treated with maltol, M-CSF and RANKL to observe their osteoclast potential. The differentiation of osteoclasts was observed by TRAP staining, Western blotting and RT-PCR analysis. Further investigations into the relevant signaling pathways were carried out. In vivo, periodontitis was established by ligating the maxillary second molars of mice with silk thread (n = 8 in each group). After that, we evaluated the effect of maltol on bone resorption by oral gavage. RESULTS Maltol significantly promoted osteoclast differentiation of rankl stimulated BMMNCs. This is mediated by modulation of the tumor necrosis factor receptor-related factor 6 (TRAF6)/C-Jun n-terminal kinase (JNK)/activated T cell nuclear factor 1 (Nfatc1) signaling pathway. In addition, maltol can significantly promote bone resorption in animal models of periodontitis. CONCLUSIONS Maltol promotes OC differentiation of bone marrow mesenchymal stem cells induced by rankl through TRAF/JNK pathway and upregulates NFATc1 expression. Maltol promotes bone resorption by promoting osteoclast differentiation in experimental periodontitis model of mice.
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Affiliation(s)
- Rui Zhao
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, 100070, PR China
| | - Jingfei Fu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, 100070, PR China
| | - Yiyang Jiang
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, 100070, PR China
| | - Lili Wu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, 100070, PR China
| | - Ziqi Yan
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, 100070, PR China
| | - Yi Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, 100070, PR China.
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Zeng Y, Zhao B, Gong J, Zhang Q, Yang F. MiRNA-mRNA network in osteoporotic fractures proposes the functional mechanism of hsa-miR-32-3p/TNFSF11 axis. J Orthop Surg Res 2025; 20:426. [PMID: 40301936 PMCID: PMC12039004 DOI: 10.1186/s13018-025-05836-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Accepted: 04/22/2025] [Indexed: 05/01/2025] Open
Abstract
BACKGROUND AND AIMS This study aimed to construct a miRNA-mRNA network in OF and explored the effect of the hsa-miR-32-3p/TNFSF11 axis on osteoclast function. METHODS GSE70318 and GSE74209 datasets were used to filter the differentially expressed miRNAs in OF. Then, the targets of these miRNAs intersected with the disease genes of OF. The target genes were annotated using GO terms and KEGG pathway enrichment analysis. The network for miRNA-gene-top 30 GO terms/top 20 pathways was drawn. Sankey diagrams were drawn for Parathyroid hormone synthesis, secretion, and action pathway (hsa04928) and ossification (GO:0001503) related to osteoporotic fracture. The hsa-miR-32-3p/TNFSF11 axis was selected for expression and functional verification. RESULTS A total of 21 differentially expressed miRNAs in OF were obtained by analyzing GSE70318 and GSE74209 datasets. A total of 36 genes were related to OF among the miRNA-targets. The genes were enriched in GO terms and KEGG pathways related to OF. Parathyroid hormone synthesis, secretion, and action pathway (hsa04928) and ossification proposed that the hsa-miR-32-3p/TNFSF11 axis may be involved in OF. The expression level of hsa-miR-32-3p was decreased in patients with low bone mineral density (BMD) and fracture, while the expression level of TNFSF11 mRNA was increased. Hsa-miR-32-3p complementarily bound with TNFSF11. Hsa-miR-32-3p inhibited osteoclast activation, while TNFSF11 promoted osteoclast activation. CONCLUSIONS The miRNA-mRNA network in OF proposed the TNFSF11 as a downstream target of hsa-miR-32-3p. The hsa-miR-32-3p/TNFSF11 axis was involved in the regulation of osteoclast activity. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Yukai Zeng
- School of Biomedical Engineering, Capital Medical University, Beijing, 100069, China
- Department of Orthopedic Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China
| | - Bo Zhao
- Department of Orthopedic 2, Zhongxian People's Hospital of Chongqing, Chongqing, 404300, China
| | - Jiawei Gong
- Department of Spinal Surgery, Traditional Chinese Medicine Hospital of Kunshan, Suzhou, 215300, China
| | - Qingfeng Zhang
- Spine Department, Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing, 100029, China
| | - Fei Yang
- Department of Orthopaedics, Zibo Central Hospital, No. 54, Gongqingtuan West Road, Zhangdian District, Zibo, Shandong, 255036, China.
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Chen N, Danalache M, Liang C, Alexander D, Umrath F. Mechanosignaling in Osteoporosis: When Cells Feel the Force. Int J Mol Sci 2025; 26:4007. [PMID: 40362247 PMCID: PMC12071322 DOI: 10.3390/ijms26094007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 04/15/2025] [Accepted: 04/21/2025] [Indexed: 05/15/2025] Open
Abstract
Bone is a highly mechanosensitive tissue, where mechanical signaling plays a central role in maintaining skeletal homeostasis. Mechanotransduction regulates the balance between bone formation and resorption through coordinated interactions among bone cells. Key mechanosensing structures-including the extracellular/pericellular matrix (ECM/PCM), integrins, ion channels, connexins, and primary cilia, translate mechanical cues into biochemical signals that drive bone adaptation. Disruptions in mechanotransduction are increasingly recognized as an important factor in osteoporosis. Under pathological conditions, impaired mechanical signaling reduces bone formation and accelerates bone resorption, leading to skeletal fragility. Defects in mechanotransduction disrupt key pathways involved in bone metabolism, further exacerbating bone loss. Therefore, targeting mechanotransduction presents a promising pharmacological strategy for osteoporosis treatment. Recent advances have focused on developing drugs that enhance bone mechanosensitivity by modulating key mechanotransduction pathways, including integrins, ion channels, connexins, and Wnt signaling. A deeper understanding of mechanosignaling mechanisms may pave the way for novel therapeutic approaches aimed at restoring bone mass, mechanical integrity, and mechanosensitive bone adaptation.
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Affiliation(s)
- Nuo Chen
- Department of Orthopedic Surgery, University Hospital Tübingen, 72072 Tübingen, Germany; (N.C.)
| | - Marina Danalache
- Department of Orthopedic Surgery, University Hospital Tübingen, 72072 Tübingen, Germany; (N.C.)
| | - Chen Liang
- Department of Orthopedic Surgery, University Hospital Tübingen, 72072 Tübingen, Germany; (N.C.)
| | - Dorothea Alexander
- Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, 72076 Tübingen, Germany;
| | - Felix Umrath
- Department of Orthopedic Surgery, University Hospital Tübingen, 72072 Tübingen, Germany; (N.C.)
- Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, 72076 Tübingen, Germany;
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7
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Ren F, Zheng S, Luo H, Yu X, Li X, Song S, Bu W, Sun H. Fibroblast derived C3 promotes the progression of experimental periodontitis through macrophage M1 polarization and osteoclast differentiation. Int J Oral Sci 2025; 17:30. [PMID: 40240339 PMCID: PMC12003657 DOI: 10.1038/s41368-025-00361-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 02/20/2025] [Accepted: 03/05/2025] [Indexed: 04/18/2025] Open
Abstract
Complement C3 plays a critical role in periodontitis. However, its source, role and underlying mechanisms remain unclear. In our study, by analyzing single-cell sequencing data from mouse model of periodontitis, we identified that C3 is primarily derived from periodontal fibroblasts. Subsequently, we demonstrated that C3a has a detrimental effect in ligature-induced periodontitis. C3ar-/- mice exhibited significantly less destruction of periodontal support tissues compared to wild-type mice, characterized by mild gingival tissue damage and reduced alveolar bone loss. This reduction was associated with decreased production of pro-inflammatory mediators and reduced osteoclast infiltration in the periodontal tissues. Mechanistic studies suggested that C3a could promote macrophage polarization and osteoclast differentiation. Finally, by analyzing single-cell sequencing data from the periodontal tissues of patients with periodontitis, we found that the results observed in mice were consistent with human data. Therefore, our findings clearly demonstrate the destructive role of fibroblast-derived C3 in ligature-induced periodontitis, driven by macrophage M1 polarization and osteoclast differentiation. These data strongly support the feasibility of C3a-targeted interventions for the treatment of human periodontitis.
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Affiliation(s)
- Feilong Ren
- Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Shize Zheng
- Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Huanyu Luo
- Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Xiaoyi Yu
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory Oral Biomedical Engineering, Jilin University, Changchun, China
| | - Xianjing Li
- Hospital of Stomatology, Jilin University, Changchun, China
| | - Shaoyi Song
- Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Wenhuan Bu
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun, China.
- Jilin Provincial Key Laboratory Oral Biomedical Engineering, Jilin University, Changchun, China.
| | - Hongchen Sun
- Hospital of Stomatology, Jilin University, Changchun, China.
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun, China.
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8
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Fan Y, Yu Y, Yan P. The protective effects of tectoridin on bone fractures against oxidative stress via the inhibition of NF-κB and apoptotic pathways in ovariectomized rats. Toxicol Appl Pharmacol 2025; 500:117345. [PMID: 40246203 DOI: 10.1016/j.taap.2025.117345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 04/10/2025] [Accepted: 04/10/2025] [Indexed: 04/19/2025]
Abstract
Oxidative stress and inflammation lead to high bone turnover, contributing to osteoporosis caused by estrogen deficiency in postmenopausal women. Tectoridin, an isoflavonoid with antioxidant and anti-inflammatory properties, was evaluated for its protective effects in ovariectomized (OVX) rats, a model of postmenopausal osteoporosis. Five groups of female rats (n = 6) were established: normal, OVX control, OVX treated with tectoridin at 10 and 20 mg/kg bw, and OVX treated with estrogen, over a four-week period. Tectoridin treatment resulted in reduced body weight and improved femur weight and thickness. Serum E2, calcium, and phosphate levels increased, while alkaline phosphatase (ALP) levels decreased after treatment. Additionally, tectoridin altered lipid profiles by decreasing total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL), while increasing high-density lipoprotein (HDL). The treatment elevated serum bone-specific alkaline phosphatase (BALP) and procollagen type I N-terminal propeptide (PINP) levels, and decreased levels of bone resorption markers CTX-1 and NTx. Tectoridin upregulated osteogenic markers Runx2, Osx, and BMP2, suggesting enhanced bone properties. Moreover, it reduced lipid peroxidation and increased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities, indicating reduced oxidative stress. Tectoridin also inhibited inflammatory proteins and exhibited anti-apoptotic effects on Bax/Caspase3 and Bcl2 expression. This study highlights the potential of tectoridin in modulating oxidative stress, inflammation, and improving bone remodeling in OVX rats, making it a candidate for managing postmenopausal osteoporosis.
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Affiliation(s)
- Yanwei Fan
- Department of Orthopedics, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yaokun Yu
- Department of Orthopedics, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Peng Yan
- Department of Orthopedics, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
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Yin JX, Huang YY, Nguyen MT, Si XM, Huang YQ, Chen W, Zhang HY. Tibial adaptations to dietary 25-hydroxyvitamin D 3 supplementation under two distinct vitamin regimens in young ducks. Poult Sci 2025; 104:105145. [PMID: 40245539 PMCID: PMC12032329 DOI: 10.1016/j.psj.2025.105145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 03/31/2025] [Accepted: 04/06/2025] [Indexed: 04/19/2025] Open
Abstract
Tibia disorders in modern ducks are frequently associated with rapid weight gain and compromised bone quality, which is defined as the structural and material properties of bone tissue that determines its strength and fracture resistance. These factors significantly increase the risk of fractures and chronic pain. Studies suggest that 25-hydroxycholecalciferol (25-OH-D3), a vitamin D3 metabolite, effectively addresses bone disorders, potentially depending on dietary vitamin regimens, which are determined by the amount and ratio of vitamins in the diet. This study used a 2 × 2 factorial design to evaluate the effects of two vitamin regimens (regular and high) with or without exogenous 25-OH-D3 (0.069 mg/kg) on leg health and tibia quality in meat ducks (1-14 d). The high-vitamin regimen contained greater amounts of all vitamins except biotin and significantly enhanced ash content, tibial microstructure, fracture load, and reduced tibial dyschondroplasia (TD) scores (P < 0.05) compared to the regular regimen, despite no impact on growth performance or tibia length, weight, and diameter (P > 0.05). Additionally, dietary 25-OH-D3 supplementation increased weight gain (P < 0.05), improved bone quality, and strengthened bone formation and resorption processes. Notably, under the regular vitamin regimen, 25-OH-D3 reduced TD scores and enhanced weight gain, tibia mechanical properties, and the serum content of procollagen type I N-terminal propeptide (PN1P) that a marker of bone formation (all P < 0.05). However, these effects were diminished in ducks fed the high-vitamin diet. There were some interactions that were noticed regarding serum 25-OH-D3 content, trabecular area, tibia fracture load, and PN1P levels in the present study (P < 0.05). In conclusion, the biochemical effects of 25-OH-D3 were influenced by the baseline levels of dietary vitamins, a high-vitamin diet or treatment with 25-OH-D3 in a regular vitamin diet improved bone quality and reduced tibial dyschondroplasia by enhancing bone formation.
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Affiliation(s)
- J X Yin
- College of Animal Science and Technology, Henan Agricultural University, Henan, 450046, China
| | - Y Y Huang
- College of Animal Science and Technology, Henan Agricultural University, Henan, 450046, China
| | - Minh Tu Nguyen
- Department of Agriculture and Forestry, Hue University, Hue, 49000, Vietnam
| | - X M Si
- College of Animal Science and Technology, Henan Agricultural University, Henan, 450046, China
| | - Y Q Huang
- College of Animal Science and Technology, Henan Agricultural University, Henan, 450046, China
| | - W Chen
- College of Animal Science and Technology, Henan Agricultural University, Henan, 450046, China
| | - H Y Zhang
- College of Animal Science and Technology, Henan Agricultural University, Henan, 450046, China; Laboratory for Animal Nutrition and Animal Product Quality, Department of Animal Sciences and Aquatic Ecology, Ghent University, Ghent, 9000, Belgium.
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10
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Lin Y, Jiang S, Yao Y, Li H, Jin H, Yang G, Ji B, Li Y. Posttranslational Modification in Bone Homeostasis and Osteoporosis. MedComm (Beijing) 2025; 6:e70159. [PMID: 40170748 PMCID: PMC11959162 DOI: 10.1002/mco2.70159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 02/28/2025] [Accepted: 03/06/2025] [Indexed: 04/03/2025] Open
Abstract
Bone is responsible for providing mechanical protection, attachment sites for muscles, hematopoiesis micssroenvironment, and maintaining balance between calcium and phosphorate. As a highly active and dynamically regulated organ, the balance between formation and resorption of bone is crucial in bone development, damaged bone repair, and mineral homeostasis, while dysregulation in bone remodeling impairs bone structure and strength, leading to deficiency in bone function and skeletal disorder, such as osteoporosis. Osteoporosis refers to compromised bone mass and higher susceptibility of fracture, resulting from several risk factors deteriorating the balanced system between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. This balanced system is strictly regulated by translational modification, such as phosphorylation, methylation, acetylation, ubiquitination, sumoylation, glycosylation, ADP-ribosylation, S-palmitoylation, citrullination, and so on. This review specifically describes the updating researches concerning bone formation and bone resorption mediated by posttranslational modification. We highlight dysregulated posttranslational modification in osteoblast and osteoclast differentiation. We also emphasize involvement of posttranslational modification in osteoporosis development, so as to elucidate the underlying molecular basis of osteoporosis. Then, we point out translational potential of PTMs as therapeutic targets. This review will deepen our understanding between posttranslational modification and osteoporosis, and identify novel targets for clinical treatment and identify future directions.
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Affiliation(s)
- Yuzhe Lin
- Department of OrthopedicsXiangya HospitalCentral South UniversityChangshaChina
- Xiangya School of Medicine Central South UniversityChangshaChina
| | - Shide Jiang
- The Central Hospital of YongzhouYongzhouChina
| | - Yuming Yao
- Department of OrthopedicsXiangya HospitalCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric DisordersXiangya HospitalCentral South UniversityChangshaChina
| | - Hengzhen Li
- Department of OrthopedicsXiangya HospitalCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric DisordersXiangya HospitalCentral South UniversityChangshaChina
| | - Hongfu Jin
- Department of OrthopedicsXiangya HospitalCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric DisordersXiangya HospitalCentral South UniversityChangshaChina
| | - Guang Yang
- Department of OrthopedicsXiangya HospitalCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric DisordersXiangya HospitalCentral South UniversityChangshaChina
| | - Bingzhou Ji
- Department of OrthopedicsXiangya HospitalCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric DisordersXiangya HospitalCentral South UniversityChangshaChina
| | - Yusheng Li
- Department of OrthopedicsXiangya HospitalCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric DisordersXiangya HospitalCentral South UniversityChangshaChina
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Ding X, Yang J, Wei Y, Wang M, Peng Z, He R, Li X, Zhao D, Leng X, Dong H. The Nexus Between Traditional Chinese Medicine and Immunoporosis: Implications in the Treatment and Management of Osteoporosis. Phytother Res 2025; 39:1826-1846. [PMID: 39625224 DOI: 10.1002/ptr.8397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 05/21/2024] [Accepted: 11/06/2024] [Indexed: 01/06/2025]
Abstract
Osteoporosis (OP) is a globally prevalent bone disease characterized by reduced bone mass and heightened fracture risk, posing a significant health and economic challenge to aging societies worldwide. Osteoimmunology-an emerging field of study-investigates the intricate relationship between the skeletal and the immune systems, providing insights into the immune system's impact on bone health and disease progression. Recent research has demonstrated the essential roles played by various immune cells (T cells, B cells, macrophages, dendritic cells, mast cells, granulocytes, and innate lymphoid cells) in regulating bone metabolism, homeostasis, formation, and remodeling through interactions with osteoclasts (OC) and osteoblasts (OB). These findings underscore that osteoimmunology provides an essential theoretical framework for understanding the pathogenesis of various skeletal disorders, including OP. Traditional Chinese medicine (TCM) and its active ingredients have significant clinical value in OP treatment. Unfortunately, despite their striking multieffect pathways in the pharmacological field, current research has not yet summarized them in a comprehensive and detailed manner with respect to their interventional roles in immune bone diseases, especially OP. Consequently, this review addresses recent studies on the mechanisms by which immune cells and their communication molecules contribute to OP development. Additionally, it explores the potential therapeutic benefits of TCM and its active components in treating OP from the perspective of osteoimmunology. The objective is to provide a comprehensive framework that enhances the understanding of the therapeutic mechanisms of TCM in treating immune-related bone diseases and to facilitate the development of novel therapeutic strategies.
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Affiliation(s)
- Xiaolei Ding
- Affiliated Hospital of Changchun University of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Jie Yang
- Affiliated Hospital of Changchun University of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Yuchi Wei
- Affiliated Hospital of Changchun University of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Mingyue Wang
- Affiliated Hospital of Changchun University of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Zeyu Peng
- Affiliated Hospital of Changchun University of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Rong He
- Affiliated Hospital of Changchun University of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Xiangyan Li
- Northeast Asia Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Daqing Zhao
- Northeast Asia Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Xiangyang Leng
- Affiliated Hospital of Changchun University of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Haisi Dong
- Northeast Asia Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
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Zhao W, Qian J, Li J, Su T, Deng X, Fu Y, Liang X, Cui H. From death to birth: how osteocyte death promotes osteoclast formation. Front Immunol 2025; 16:1551542. [PMID: 40165960 PMCID: PMC11955613 DOI: 10.3389/fimmu.2025.1551542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Accepted: 02/28/2025] [Indexed: 04/02/2025] Open
Abstract
Bone remodeling is a dynamic and continuous process involving three components: bone formation mediated by osteoblasts, bone resorption mediated by osteoclasts, and bone formation-resorption balancing regulated by osteocytes. Excessive osteocyte death is found in various bone diseases, such as postmenopausal osteoporosis (PMOP), and osteoclasts are found increased and activated at osteocyte death sites. Currently, apart from apoptosis and necrosis as previously established, more forms of cell death are reported, including necroptosis, ferroptosis and pyroptosis. These forms of cell death play important role in the development of inflammatory diseases and bone diseases. Increasing studies have revealed that various forms of osteocyte death promote osteoclast formation via different mechanism, including actively secreting pro-inflammatory and pro-osteoclastogenic cytokines, such as tumor necrosis factor alpha (TNF-α) and receptor activator of nuclear factor-kappa B ligand (RANKL), or passively releasing pro-inflammatory damage associated molecule patterns (DAMPs), such as high mobility group box 1 (HMGB1). This review summarizes the established and potential mechanisms by which various forms of osteocyte death regulate osteoclast formation, aiming to provide better understanding of bone disease development and therapeutic target.
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Affiliation(s)
- Weijie Zhao
- Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Emergency Surgery, Key Laboratory of Hainan Trauma and Disaster Rescue, The First Affiliated Hospital, Hainan Medical University, Haikou, China
| | - Jiale Qian
- Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Emergency Surgery, Key Laboratory of Hainan Trauma and Disaster Rescue, The First Affiliated Hospital, Hainan Medical University, Haikou, China
| | - Ji Li
- Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Emergency Surgery, Key Laboratory of Hainan Trauma and Disaster Rescue, The First Affiliated Hospital, Hainan Medical University, Haikou, China
| | - Tian Su
- Key Laboratory of Emergency and Trauma, Ministry of Education, Key Laboratory of Haikou Trauma, Key Laboratory of Hainan Trauma and Disaster Rescue, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, China
- Engineering Research Center for Hainan Bio-Smart Materials and Bio-Medical Devices, Key Laboratory of Hainan Functional Materials and Molecular Imaging, College of Emergency and Trauma, College of pharmacy, Hainan Medical University, Haikou, China
| | - Xiaozhong Deng
- Department of Pain Treatment, Nanxi Shan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Yonghua Fu
- Department of Hand and Foot Microsurgery, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Xuelong Liang
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Hongwang Cui
- Key Laboratory of Emergency and Trauma of Ministry of Education, Department of Emergency Surgery, Key Laboratory of Hainan Trauma and Disaster Rescue, The First Affiliated Hospital, Hainan Medical University, Haikou, China
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13
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Santos AGD, Spigariol KS, Santos LM, Holzhausen M, Sipert CR. Immunomodulatory effects of apical papilla cells on periodontal ligament fibroblasts stimulated with Escherichia coli lipopolysaccharide: an in vitro study. J Appl Oral Sci 2025; 33:e20240338. [PMID: 40105577 PMCID: PMC11869941 DOI: 10.1590/1678-7757-2024-0338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 11/25/2024] [Accepted: 01/17/2025] [Indexed: 03/20/2025] Open
Abstract
BACKGROUND The role of human Stem Cells from the Apical Papilla (SCAP) in tissue regeneration has been described, but their impact on modulating the apical inflammatory process by other surrounding cell populations, such as periodontal ligament fibroblasts (PLFs), is unclear. Therefore, we investigated the role of SCAP in the activation of PLFs in vitro. METHODS Primary SCAP culture was used to obtain conditioned media (CM). A primary human PLF culture was established and stimulated with increasing concentrations of Escherichia coli lipopolysaccharide (LPS) (0.01, 0.1, and 1 µg/mL). At the 24 h time-point, an MTT viability assay was performed, and interleukin (IL)-6 and chemokine (CC-motif) ligand 2 (CCL2) levels were quantified by enzyme-linked immunosorbent assay. Then, PLFs were stimulated with LPS in the presence of SCAP-CM (1:5 dilution) for cell viability assessment and cytokine detection. The following groups were tested: PLF activated with LPS at concentrations of 0.01 and 1 µg/mL with or without SCAP-CM; a group with PLF stimulated by SCAP-CM alone; and a control group (proliferation medium only). The experiments were conducted in triplicate and sextuplicate. Statistical analyses were performed using analysis of variance followed by Tukey's post-hoc test, with statistical significance established at 5% (p=0.05). RESULTS The MTT assay showed no cytotoxicity of LPS or SCAP-CM on PLFs (p>0.05). The production of CCL2 and IL-6 significantly increased in the presence of SCAP-CM regardless of the presence of LPS (p<0.0001). CONCLUSION SCAP-CM significantly enhanced the release of proinflammatory cytokines by PLFs in vitro.
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Affiliation(s)
| | | | - Letícia Martins Santos
- Universidade de São Paulo, Faculdade de Odontologia, Departamento de Biomateriais e Biologia Oral, São Paulo, SP, Brasil
| | - Marinella Holzhausen
- Universidade de São Paulo, Faculdade de Odontologia, Divisão de Periodontia, Departamento de Estomatologia, São Paulo, SP, Brasil
| | - Carla Renata Sipert
- Universidade de São Paulo, Faculdade de Odontologia, Departamento de Dentística, São Paulo, SP, Brasil
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Zhao Y, An Y, Wu F, Liu L, Tay FR, Jiao Y, Wang J. Regulation of immune microenvironments by polyetheretherketone surface topography for improving osseointegration. J Nanobiotechnology 2025; 23:199. [PMID: 40069791 PMCID: PMC11895393 DOI: 10.1186/s12951-025-03272-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Accepted: 02/24/2025] [Indexed: 03/15/2025] Open
Abstract
Optimizing the immune microenvironment is essential for successful implant osseointegration. In this study, four different nano/microstructures were fabricated on polyetheretherketone (PEEK) substrates by varying the agitation speed during sulfonation to influence osteoimmunomodulation and implant integration. The results indicate that nano/microstructures with minimal dimensions (SP450) inhibit actin polymerization by reducing calcium influx through PIEZO1, activating the anti-inflammatory M2 macrophage phenotype. Among the tested specimens, SP450 exhibited the lowest expression levels of tumor necrosis factor-α and interleukin-1β while releasing the highest levels of anti-inflammatory factors, including interleukin-4 and interleukin-10. This optimized immune environment promotes the osteogenesis of MC3T3-E1 pre-osteoblasts and enhances the osseointegration of PEEK implants. Transcriptomic analysis and validation experiment further revealed that SP450 inhibits osteoclastic differentiation by down-regulating transforming growth factor-β2 and suppressing the NF-κB signaling pathway. These findings suggest that manipulating the surface topography of PEEK implants is an effective strategy for enhancing osseointegration with promising clinical applications.
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Affiliation(s)
- Yuqing Zhao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, PR China
| | - Yanxin An
- Department of General Surgery, The First Affiliated Hospital of Xi'an Medical University, Xi'an, 710077, PR China
| | - Fan Wu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, PR China
| | - Lipeng Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, PR China
| | - Franklin R Tay
- The Graduate School, Augusta University, Augusta, GA, 30912, USA
| | - Yang Jiao
- Department of Stomatology, The Seventh Medical Center of PLA General Hospital, Beijing, 100700, PR China.
| | - Jing Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, PR China.
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15
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Wu B, Dong Q, Zhang Q, Jin F, Weng J. Protective effects of Catalpol to attenuate TNF- α and collagen-induced inflammation in vitro HFLS-RA cells and in vivo mice models for the treatment of rheumatoid arthritis. Clin Rheumatol 2025; 44:1041-1056. [PMID: 39907970 DOI: 10.1007/s10067-024-07261-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 11/06/2024] [Accepted: 12/02/2024] [Indexed: 02/06/2025]
Abstract
BACKGROUND/RATIONALE Rheumatoid Arthritis (RA) is a prolonged autoimmune condition marked by persistent inflammation, causing joint damage and bone erosion. Catalpol (CAT), an iridoid glycoside, offers anti-inflammatory benefits, warranting its study in RA models. OBJECTIVE To investigate the anti-inflammatory effects of CAT in RA by evaluating its impact on cellular and animal RA models. METHODS In vitro biological actions of CAT were investigated by the methods of cell viability, proliferation, migration, invasion, apoptosis, ROS generation, double luciferase reporter assay for NF-κB-p65 activity, Nitrite release detection, and RT-qPCR for gene expression in Tumor Necrosis Factor-alpha (TNF-α)-induced Human Fibroblast-Like Synoviocytes from RA patients (HFLS-RA) (cellular RA model). Arthritis severity, joint cellular structure, gene expression, inflammatory factors, and joint inflammation studies were investigated in mice with collagen-induced arthritis (CIA) (animal RA model). KEY RESULTS CAT treatment groups showed significant improvements (P < 0.001) in cell viability, migration, invasion, and apoptosis compared to the TNF-α-induced group. ROS generation and the activity of NF-κB-p65 were significantly reduced (P < 0.001). Nitrite release was decreased (P < 0.01, P < 0.001) in CAT-treatment groups. Pro-inflammatory and bone-metabolizing cytokine gene expression was markedly downregulated (P < 0.05, P < 0.001) in the cellular RA model. CIA mice treated with CAT exhibited significantly reduced arthritis severity, paw edema, and arthritis index (P < 0.05, P < 0.01). Joint pathology scores showed improvement (P < 0.001) in CAT-treatment groups. In the animal RA model, bone-metabolizing and inflammatory cytokine gene expression was significantly reduced in CAT-treatment groups (P < 0.01, P < 0.001). CONCLUSION CAT effectively reduces RA's inflammation and bone metabolism issues, suggesting its potential as a therapeutic agent for RA treatments. Key Points • Plant-derived Catalpol compound is an effective choice for rheumatoid arthritis treatment due to its anti-inflammatory potential. • CAT's effects were tested on TNF-α-induced HFLS-RA cells and in CIA mice, assessing cell viability, apoptosis, ROS generation, arthritis severity, inflammatory factors, and joint inflammation studies. • The administration of CAT could greatly enhance cell health and reduce inflammation markers and arthritis symptoms. • Observed significant reduction of RA inflammation and bone issues, confirming CAT as a therapeutic agent in RA treatment.
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Affiliation(s)
- Bin Wu
- Department of Orthopaedics, The Second Affiliated Hospital of Jiaxing University, Jiaxing, 314000, Zhejiang, China
| | - Qinyan Dong
- Department of Orthopaedics, The Second Affiliated Hospital of Jiaxing University, Jiaxing, 314000, Zhejiang, China
| | - Qin Zhang
- Department of Orthopaedics, The Second Affiliated Hospital of Jiaxing University, Jiaxing, 314000, Zhejiang, China
| | - Fangqin Jin
- Department of Orthopaedics, The Second Affiliated Hospital of Jiaxing University, Jiaxing, 314000, Zhejiang, China
| | - Jiangping Weng
- Department of Orthopaedics, The Second Affiliated Hospital of Jiaxing University, Jiaxing, 314000, Zhejiang, China.
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16
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Al-Lami RSS, Al-Hilfy JHY. Role of Interleukins-8, -17 and -22 in Iraqi postmenopausal women with Osteoporosis. Cytokine 2025; 187:156853. [PMID: 39787824 DOI: 10.1016/j.cyto.2024.156853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 12/23/2024] [Accepted: 12/31/2024] [Indexed: 01/12/2025]
Abstract
OBJECTIVES Osteoporosis (OP) is a systemic skeletal disease characterized by low bone mineral density and deterioration of bone architecture, resulting in bone strength reduction and increased fracture susceptibility. Estrogen deficiency in post-menopausal women is possibly responsible for the instability between bone formation and resorption, which is managed by specific osteoclastogenic cytokines that may be leading to resorption. This study aims to estimation of the concentrations of interleukins -8, -17, -22, beside to certain parameters in blood serum and explained their roles in the development of osteoporosis pathogenicity in postmenopausal women. MATERIALS AND METHODS A case-control study included 108 Iraqi postmenopausal women participants their ages ranged between 45 and 70 years. All participants subjected to the DEXA scan, 58 samples were osteoporotic patients, whereas 50 were healthy controls. Blood samples collected from all participants in order to assess the levels of interleukins -8, -17, -22, CBC, CRP, RF, and ACPA. RESULTS The concentrations of IL-8, -17, -22, ESR, PLT, CRP, RF and ACPA exhibited a positive correlation with OP development. Conversely, WBC and HGB concentrations showed a negative association with osteoporosis. CONCLUSION A remarkable relationship was obtained between the values of IL-8, 17, -22, CRP, RF, ACPA, ESR, PLT and osteoporosis but in contrary with WBCs and HGB. IL-8, -17, and - 22 can be linked to specific inflammatory diseases associated with the postmenopausal period, may act as one of the main biomarkers for osteoporosis due to their ability to stimulate osteoclastogenesis and bone resorption, and may be considered potential prognostic factors for osteoporosis.
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Affiliation(s)
- Reem Salim Sultan Al-Lami
- Department of Biology, College of Science, University of Baghdad, Baghdad, Iraq; Department of Biology, College of Science for women, University of Baghdad, Baghdad, Iraq.
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Wang H, Guan Y, Lin L, Qiang Z, Huo Y, Zhu L, Yan B, Shao S, Liu W, Yang J. DEC1 deficiency promotes osteoclastic activity by augmenting NFATc1 signaling via transactivation and the Ca 2+/calcineurin pathway. Biochem Pharmacol 2025; 233:116754. [PMID: 39824467 DOI: 10.1016/j.bcp.2025.116754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 11/30/2024] [Accepted: 01/13/2025] [Indexed: 01/20/2025]
Abstract
We have previously demonstrated that DEC1 promotes osteoblast differentiation. This study aims to evaluate the impact of DEC1 knockout on osteopenic activities, such as osteoclast differentiation and the expression of bone-degrading genes. To gain mechanistic insights, we employed both in vivo and in vitro experiments, utilizing cellular and molecular approaches, including osteoclast differentiation assays and RNA-seq in combination with ChIP-seq. Our results showed that NFATc1, a master regulator of osteoclast differentiation, and PPP3CB, a member of the calcineurin family, were significantly upregulated in DEC1-/- mice. In vitro experiments revealed that osteoclast differentiation significantly increased both the number and size of osteoclasts in DEC1-/- bone marrow macrophages (BMMs) compared to DEC1+/+ BMMs. Additionally, NFATc1 expression was notably higher in DEC1-/- BMMs than in DEC1+/+ BMMs. Overexpression of DEC1 reduced NFATc1 promoter activity, while knockout increased it. Furthermore, intracellular free Ca2+ levels and calcineurin activity were elevated (∼150 %) in DEC1-/- BMMs compared to DEC1+/+ BMMs. Importantly, the use of calcineurin inhibitors and calcium channel blockers effectively abolished the increased osteoclast differentiation observed in DEC1-/- BMMs. In summary, DEC1 deficiency promotes osteoclast differentiation by enhancing NFATc1 signaling through transcriptional regulation and the Ca2+/calcineurin pathway. Clinically, the mRNA levels of DEC1 were reduced by up to 75 % in patients with osteoporosis. The findings of this study establish that inducing DEC1 expression, alongside attenuators of the Ca2+/calcineurin pathway, offers a molecular basis for preventing and treating osteoporosis associated with DEC1 deficiency.
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Affiliation(s)
- Haobin Wang
- Department of Pharmacology, Nanjing Medical University, Nanjing 211166, PR China
| | - Yu Guan
- Department of Pharmacology, Nanjing Medical University, Nanjing 211166, PR China
| | - Lan Lin
- Department of Pharmacology, Nanjing Medical University, Nanjing 211166, PR China
| | - Zhiyi Qiang
- Department of Pharmacology, Nanjing Medical University, Nanjing 211166, PR China
| | - Ying Huo
- Department of Pharmacology, Nanjing Medical University, Nanjing 211166, PR China
| | - Ling Zhu
- Department of Pharmacology, Nanjing Medical University, Nanjing 211166, PR China
| | - Bingfang Yan
- James L. Winkle College of Pharmacy University of Cincinnati, Cincinnati, OH 45229, USA
| | - Shulin Shao
- Nanjing Pukou District Traditional Chinese Medicine Hospital, Nanjing 210000, PR China
| | - Wei Liu
- Department of Pharmacology, Nanjing Medical University, Nanjing 211166, PR China
| | - Jian Yang
- Department of Pharmacology, Nanjing Medical University, Nanjing 211166, PR China.
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18
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Zhang K, Liu Y, Lu Y, Liu G, Shen X. Involvement of icaritin in the regulation of osteocyte exosomal microRNAs. J Orthop Surg Res 2025; 20:164. [PMID: 39953581 PMCID: PMC11827220 DOI: 10.1186/s13018-025-05583-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 02/06/2025] [Indexed: 02/17/2025] Open
Abstract
OBJECTIVE To explore the effects of Icaritin (ICA) on the regulation of osteocyte exosomal miRNAs and to promote the understanding of the potential molecular mechanisms involved in bone repair by ICA. METHODS MLO-Y4 cells were treat with PBS or 10 µM ICA for 24 h and the supernatant was collected. Exosomes were isolated and purified according to standard methods, and identified by transmission electron microscopy, nanoparticle tracking analysis and protein blotting. Exosomal miRNAs were analysed by RNA sequencing. RESULTS Osteocyte exosomes were successfully isolated and characterised. MiRNA sequencing showed that two known exosomal miRNAs (miR-128-3p, miR-30a-5p) were significantly up-regulated and two were significantly down-regulated (miR-5112, miR-1285) after ICA intervention. CONCLUSION Based on the findings, ICA regulates several miRNAs of osteocytes, which deepen our understanding of the therapeutic effects and mechanisms of ICA on skeletal diseases. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE Osteocytes are the most abundant cell type in bone tissue, of which the impact on bone homeostasis is still not clear. This study explored the impact of icaritin on osteocytes and their derived exosomes. By doing so, we hope to contribute to the understanding the therapeutic potential of ICA and osteocytes in maintaining bone health and treating conditions such as osteoporosis.
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Affiliation(s)
- Kaijia Zhang
- Suzhou TCM Hospital, Nanjing University of Chinese Medicine, Suzhou, 215003, P. R. China
| | - Yujiang Liu
- Suzhou TCM Hospital, Nanjing University of Chinese Medicine, Suzhou, 215003, P. R. China
| | - Yue Lu
- Suzhou TCM Hospital, Nanjing University of Chinese Medicine, Suzhou, 215003, P. R. China
| | - Gongwen Liu
- Suzhou TCM Hospital, Nanjing University of Chinese Medicine, Suzhou, 215003, P. R. China
| | - Xiaofeng Shen
- Suzhou TCM Hospital, Nanjing University of Chinese Medicine, Suzhou, 215003, P. R. China.
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Zhao F, Han H, Wang J, Wang J, Zhai J, Zhu G. Oversecretion of CCL3 by Irradiation-Induced Senescent Osteocytes Mediates Bone Homeostasis Imbalance. Cells 2025; 14:249. [PMID: 39996722 PMCID: PMC11853822 DOI: 10.3390/cells14040249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 01/26/2025] [Accepted: 02/07/2025] [Indexed: 02/26/2025] Open
Abstract
Various stressors such as ionizing radiation (IR), chemotherapeutic agents, oxidative stress, and inflammatory responses can trigger the stress-induced premature senescence (SIPS) of cells in the bone microenvironment, including osteocytes. However, little is known about the mechanisms underlying the senescent cellular regulation of the differentiation potential and bone homeostasis. Here, we report a secretory change in senescent osteocytes activated by IR, its subsequent impact on osteogenic and osteoclastic differentiation, and the inflammatory cascade response. It was observed that osteocytes exhibited altered biological function, persistent and incomplete DNA damage repair, and characteristic senescence phenotypes after exposure to IR in vitro. Meanwhile, a concomitant increase in the CC chemokine ligand 3 (CCL3), a key component of the senescence-associated secretory phenotype (SASP), was observed in the IR-induced senescent osteocytes, which could further downregulate the osteogenic differentiation and enhance the osteoclastic differentiation in cell supernatant co-culture experiments. Notably, the enhancement of the PI3K/Akt/NF-κB signaling pathway in IR-induced senescent osteocytes appears to be an essential driver of the imbalance between the osteogenic and osteoclastic differentiation potentials. Taken together, these data suggest a novel role of CCL3 in IR-induced bone homeostatic imbalance through SASP cascade secretion, mediated by the PI3K/Akt/NF-κB signaling pathway.
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Affiliation(s)
| | | | | | | | | | - Guoying Zhu
- Institute of Radiation Medicine, Fudan University, 2094 Xietu Road, Shanghai 200032, China; (F.Z.); (H.H.); (J.W.); (J.W.); (J.Z.)
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20
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Wiesli MG, Huber MW, Weisse B, Zboray R, Kiderlen S, González‐Vázquez A, Maniura‐Weber K, Rottmar M, Lackington WA. Immunomodulation Using BMP-7 and IL-10 to Enhance the Mineralization Capacity of Bone Progenitor Cells in a Fracture Hematoma-Like Environment. Adv Healthc Mater 2025; 14:e2400077. [PMID: 38599586 PMCID: PMC11834375 DOI: 10.1002/adhm.202400077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 03/19/2024] [Indexed: 04/12/2024]
Abstract
Following biomaterial implantation, a failure to resolve inflammation during the formation of a fracture hematoma can significantly limit the biomaterial's ability to facilitate bone regeneration. This study aims to combine the immunomodulatory and osteogenic effects of BMP-7 and IL-10 with the regenerative capacity of collagen-hydroxyapatite (CHA) scaffolds to enhance in vitro mineralization in a hematoma-like environment. Incubation of CHA scaffolds with human whole blood leads to rapid adsorption of fibrinogen, significant stiffening of the scaffold, and the formation of a hematoma-like environment characterized by a limited capacity to support the infiltration of human bone progenitor cells, a significant upregulation of inflammatory cytokines and acute phase proteins, and significantly reduced osteoconductivity. CHA scaffolds functionalized with BMP-7 and IL-10 significantly downregulate the production of key inflammatory cytokines, including IL-6, IL-8, and leptin, creating a more permissive environment for mineralization, ultimately enhancing the biomaterial's osteoconductivity. In conclusion, targeting the onset of inflammation in the early phase of bone healing using BMP-7 and IL-10 functionalized CHA scaffolds is a promising approach to effectively downregulate inflammatory processes, while fostering a more permissive environment for bone regeneration.
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Affiliation(s)
- Matthias Guido Wiesli
- Laboratory for BiointerfacesEmpa – Swiss Federal Laboratories for Materials Science and TechnologySt. Gallen9014Switzerland
| | - Matthias Werner Huber
- Laboratory for BiointerfacesEmpa – Swiss Federal Laboratories for Materials Science and TechnologySt. Gallen9014Switzerland
| | - Bernhard Weisse
- Laboratory for Mechanical Systems EngineeringEmpaDübendorf8600Switzerland
| | - Robert Zboray
- Center of X‐ray AnalyticsEmpaDübendorf8600Switzerland
| | | | - Arlyng González‐Vázquez
- Tissue Engineering Research GroupRoyal College of Surgeons in IrelandUniversity of Medicine and Health SciencesDublin 2Ireland
| | - Katharina Maniura‐Weber
- Laboratory for BiointerfacesEmpa – Swiss Federal Laboratories for Materials Science and TechnologySt. Gallen9014Switzerland
| | - Markus Rottmar
- Laboratory for BiointerfacesEmpa – Swiss Federal Laboratories for Materials Science and TechnologySt. Gallen9014Switzerland
| | - William Arthur Lackington
- Laboratory for BiointerfacesEmpa – Swiss Federal Laboratories for Materials Science and TechnologySt. Gallen9014Switzerland
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Wu Y, Liu M, Li J, Gao R, Hu Q, Xie Y, Zhou H, Li H, He X, Li L. Kouqiangjie formula alleviates diabetic periodontitis by regulating alveolar bone homeostasis via miR-29a-3p-mediated Dkk-1/Wnt/β-catenin signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2025; 340:119270. [PMID: 39706357 DOI: 10.1016/j.jep.2024.119270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/18/2024] [Accepted: 12/17/2024] [Indexed: 12/23/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Diabetic periodontitis (DP) is a commonly co-occurring complication in diabetes patients characterized by advanced gum disease and bone resorption. Conventional treatment modalities often fail to adequately address the underlying biological disruptions caused by diabetes. The use of traditional medicinal formulas Kouqiangjie Formula (KQJF) potentially offers novel therapeutic approaches for DP, but its detailed regulatory mechanisms remain unclear. AIM OF THE STUDY This study aims to investigate the impacts of KQJF on osteoblastic activity and inflammatory responses in a rat model and in vitro pre-osteoblast cultures under conditions mimicking DP, focusing on the involvement of the miR-29a-3p-Dkk-1/Wnt/β-catenin signaling pathway. MATERIALS AND METHODS Using network pharmacological analysis, micro-CT, histological staining, and an array of molecular biology methodologies including Western blotting, RT-qPCR, and immunofluorescence, we investigated the systemic and cellular responses to KQJF treatment. Both in vivo (rat model) and in vitro (MC3T3-E1 pre-osteoblasts) models subjected to high glucose and lipopolysaccharide (HG + LPS) stress were used to simulate DP conditions. RESULTS Network pharmacological analyses, incorporating protein-protein interactions and pathway enrichment, disclosed that KQJF interacts with pathways crucial for inflammation and bone metabolism. Experimentally, KQJF significantly preserved alveolar bone architecture, reduced osteoclast activity, and dampened inflammatory cytokine production in DP rats. In pre-osteoblasts, KQJF enhanced cell viability, promoted cell cycle progression, and decreased apoptosis. At the molecular level, KQJF treatment upregulated miR-29a-3p and downregulated Dkk-1, thereby activating the Wnt/β-catenin pathway. The interventional studies with miR-29a-3p antagonists and Dkk-1 knockdown further confirmed the regulatory role of the miR-29a-3p/Dkk-1 axis in mediating the effects of KQJF. CONCLUSION KQJF mitigates the deleterious effects of DP by enhancing osteoblastic activity and reducing inflammatory responses, predominantly through the modulation of the miR-29a-3p-Dkk-1/Wnt/β-catenin signaling pathway. These discoveries underscore the therapeutic promise of KQJF in managing bone and inflammatory complications of DP, offering insights into its mechanism, and supporting its use in clinical settings.
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Affiliation(s)
- Yeke Wu
- Department of Stomatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Min Liu
- Department of Gynaecology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Jiawei Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Ranran Gao
- Department of Gynaecology, Henan Provincial People's Hospital, Zhengzhou, 450000, China.
| | - Qiongying Hu
- Department of Laboratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Yunfei Xie
- Department of Nuclear Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
| | - Hongling Zhou
- Center of Stomatology, West China Xiamen Hospital of Sichuan University, Xiamen, 361021, China.
| | - Huijing Li
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Xiang He
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Li Li
- Department of Radiology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
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Xu Y, Hu T, Jiang P, Wang X, Yao J, Shen H, Zhang Z, Zheng B, Wang T, Ren Y, Wang J, Tan Q. Decreased sirtuin 1 in type 2 diabetes patients with abnormal BMD. Front Endocrinol (Lausanne) 2025; 15:1480847. [PMID: 39944232 PMCID: PMC11813776 DOI: 10.3389/fendo.2024.1480847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 12/10/2024] [Indexed: 05/09/2025] Open
Abstract
Introduction Sirtuin 1, a class III histone deacetylase, plays a critical role in the pathophysiology of both diabetes mellitus and bone metabolism by promoting osteoblast differentiation and inhibiting osteoclast maturation. However, its exact impact on bone mineral density (BMD) and bone metabolism in type 2 diabetes mellitus (T2DM) remains unclear. This study investigates the relationship between Sirtuin 1 levels, BMD, and bone metabolism in newly diagnosed T2DM patients, specifically examining alterations in Sirtuin 1 levels in those with concomitant osteoporosis or osteopenia. Methods A total of 69 newly diagnosed T2DM patients and 82 control subjects with normal glucose tolerance (NGT) were enrolled. Serum Sirtuin 1 levels and bone turnover markers, including osteocalcin (OC), procollagen type 1 N-terminal propeptide (P1NP), and β-C-terminal telopeptide of type I collagen (β-CTX), were measured using enzyme-linked immunosorbent assay (ELISA). BMD was assessed via dual-energy X-ray absorptiometry (DXA). Comparisons of these parameters were made between the T2DM and NGT groups. Results T2DM patients were further categorized into a normal BMD group (DMn) and an osteopenia or osteoporosis group (DMo), and differences in Sirtuin 1 levels between these subgroups were analyzed. Risk factors for osteoporosis/osteopenia in T2DM patients were also evaluated. Serum Sirtuin 1 levels were found to be significantly diminished in the T2DM group relative to the control group (P < 0.05), with no significant differences in lumbar spine BMD, OC, 25(OH)D, and β-CTX between groups (P > 0.05). Osteoporosis incidence was higher in T2DM subjects compared to controls (34.8% vs. 18.3%, P = 0.026). Subgroup analysis revealed that SIRT1 levels in T2DM patients with osteoporosis or osteopenia exhibited a significant reduction compared to those with normal BMD (P < 0.05). Logistic regression indicated that Sirtuin 1, age, HDL-C, P1NP, and β-CTX were independent risk factors for osteoporosis in T2DM patients. Discussion In conclusion, decreased serum Sirtuin 1 levels are associated with bone turnover markers in T2DM patients and may serve as an independent risk factor and potential biomarker for diagnosing bone metabolism disorders in newly diagnosed T2DM patients.
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Affiliation(s)
- Yao Xu
- Department of Endocrinology, No.903 Hospital of PLA Joint Logistic Support Force, Hangzhou, China
| | - Tianxiao Hu
- Department of Endocrinology, No.903 Hospital of PLA Joint Logistic Support Force, Hangzhou, China
| | - Peiwu Jiang
- Department of Vascular Surgery, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiujing Wang
- Department of Endocrinology, No.903 Hospital of PLA Joint Logistic Support Force, Hangzhou, China
| | - Jiaqi Yao
- Department of Endocrinology, No.903 Hospital of PLA Joint Logistic Support Force, Hangzhou, China
| | - Huiling Shen
- Department of Endocrinology, No.903 Hospital of PLA Joint Logistic Support Force, Hangzhou, China
| | - Zhenying Zhang
- Department of Endocrinology, No.903 Hospital of PLA Joint Logistic Support Force, Hangzhou, China
| | - Bojing Zheng
- Department of Endocrinology, No.903 Hospital of PLA Joint Logistic Support Force, Hangzhou, China
| | - Ting Wang
- Department of Endocrinology, No.903 Hospital of PLA Joint Logistic Support Force, Hangzhou, China
| | - Yanxia Ren
- Department of Endocrinology, No.903 Hospital of PLA Joint Logistic Support Force, Hangzhou, China
| | - Jing Wang
- Department of Endocrinology, No.903 Hospital of PLA Joint Logistic Support Force, Hangzhou, China
| | - Qingying Tan
- Department of Endocrinology, No.903 Hospital of PLA Joint Logistic Support Force, Hangzhou, China
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Moraliyska R, Georgiev T. Biochemical markers in hand osteoarthritis: a path to precision medicine. Rheumatol Int 2025; 45:38. [PMID: 39875697 DOI: 10.1007/s00296-025-05792-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 01/06/2025] [Indexed: 01/30/2025]
Abstract
Hand osteoarthritis (HOA) is a heterogeneous joint disease with high radiographic and symptomatic prevalence. The diagnosis of HOA is based on clinical and radiographic features. The identification of potential biomarkers for diagnosis, prognosis, disease severity assessment, and therapeutic efficacy evaluation of НОА remains an active area of research. To summarize the eligible biomarker data, a comprehensive narrative review was performed using the PubMed and Scopus databases covering publications from inception to December 2024. Our search uncovered five distinct groups of biomarkers associated with HOA, categorized based on their origin and involvement in distinct biological processes: (1) cartilage synthesis and catabolism, (2) bone remodeling, (3) inflammation, (4) adipokines, and (5) others classified separately. Each biomarker was evaluated in accordance with the Burden of disease, Investigative, Prognostic, Efficacy of intervention, and Diagnostic (BIPED) criteria. In conclusion, no biomarker has yet demonstrated sufficient sensitivity, specificity, or reproducibility to meet the BIPED criteria for classification. The early diagnosis and treatment of HOA require the development of more sensitive assays, advanced platforms, and rigorous bio-clinical trials to stratify previously studied biomarkers and identify novel ones. Precision medicine in HOA demands reliable biomarkers, cost-effective assays, and standardized, reproducible methodologies for global applicability.
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Affiliation(s)
- Rosina Moraliyska
- Clinic of Rheumatology, University Hospital St. Marina, Varna, 9010, Bulgaria
- Department of Clinical Medical Sciences, Faculty of Dental Medicine, Medical University - Varna, Varna, 9002, Bulgaria
| | - Tsvetoslav Georgiev
- Clinic of Rheumatology, University Hospital St. Marina, Varna, 9010, Bulgaria.
- First Department of Internal Medicine, Faculty of Medicine, Medical University - Varna, Varna, 9002, Bulgaria.
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Zhang H, Wang L, Liu A, Zhou H, Liang X, Kang N. The IL-17 level in gingival crevicular fluid as an indicator of orthodontically induced inflammatory root resorption. J Orofac Orthop 2025:10.1007/s00056-024-00573-8. [PMID: 39838166 DOI: 10.1007/s00056-024-00573-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 07/29/2024] [Indexed: 01/23/2025]
Abstract
PURPOSE Interleukin (IL)-17 expression in the periodontal ligament is associated with orthodontically induced inflammatory root resorption (OIIRR). Seeking a convenient, rapid, and non-invasive IL-17 detection approach could help predict OIIRR. In this study, we assessed the potential of the IL-17 level in gingival crevicular fluid (GCF) to be an indicator of OIIRR. METHODS To enable tooth movement, 8‑ to 10-week-old male Wistar rats were subjected to 20 g/60 g orthodontic force for up to 14 days. GCF and peripheral blood were collected for the IL-17 enzyme-linked immunosorbent assay (ELISA). Histological changes and the expression of IL-17, receptor activator of nuclear factor κB ligand (RANKL), and osteoprotegerin (OPG) in periodontal tissue were evaluated by hematoxylin-eosin and immunohistochemistry staining, respectively. Osteoclasts were visualized by tartrate-resistant acid phosphatase (TARP) staining. RESULTS GCF IL-17 level rapidly rose in the early phase of orthodontic loading, accompanied by bone and tooth root destruction. At the later stage, the GCF IL-17 level gradually decreased, while the inflammatory destruction was reduced and the periodontal tissue began to repair. GCF IL-17 expression generally tended to be coincident with the periodontal tissue reaction: GCF IL-17 was robustly correlated to the RANKL/OPG ratio (rs = 0.72, p = 0.002) or osteoclast number (rs = 0.84, p < 0.001). Additionally, the GCF IL-17 level was correlated to serum IL-17 (rs = 0.61, p = 0.016) or periodontal IL-17 (rs = 0.84, p < 0.001). CONCLUSION The IL-17 level in GCF during orthodontic treatment is associated with OIIRR and, thus, could be an early indicator for developing OIIRR. The advantages of being a convenient, rapid, and non-invasive GCF IL-17 measurement make it a promising method for early detection of OIIRR.
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Affiliation(s)
- Honghong Zhang
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction & Department of Orthodontics, College and Hospital of Stomatology, Guangxi Medical University, 10 Shuangyong Road, 530021, Nanning, Guangxi, China
| | - Lufei Wang
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction & Department of Orthodontics, College and Hospital of Stomatology, Guangxi Medical University, 10 Shuangyong Road, 530021, Nanning, Guangxi, China
| | - Aipeng Liu
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction & Department of Orthodontics, College and Hospital of Stomatology, Guangxi Medical University, 10 Shuangyong Road, 530021, Nanning, Guangxi, China
| | - Hua Zhou
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction & Department of Orthodontics, College and Hospital of Stomatology, Guangxi Medical University, 10 Shuangyong Road, 530021, Nanning, Guangxi, China
| | - Xiao Liang
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction & Department of Orthodontics, College and Hospital of Stomatology, Guangxi Medical University, 10 Shuangyong Road, 530021, Nanning, Guangxi, China
| | - Na Kang
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction & Department of Orthodontics, College and Hospital of Stomatology, Guangxi Medical University, 10 Shuangyong Road, 530021, Nanning, Guangxi, China.
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25
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Nasme F, Behera J, Tyagi P, Debnath N, Falcone JC, Tyagi N. The potential link between the development of Alzheimer's disease and osteoporosis. Biogerontology 2025; 26:43. [PMID: 39832071 DOI: 10.1007/s10522-024-10181-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 12/28/2024] [Indexed: 01/22/2025]
Abstract
Alzheimer's disease (AD) and osteoporosis (OP) pose distinct but interconnected health challenges, both significantly impacting the aging population. AD, a neurodegenerative disorder characterized by memory impairment and cognitive decline, is primarily associated with the accumulation of abnormally folded amyloid beta (Aβ) peptides and neurofibrillary tangles in the brain. OP, a skeletal disorder marked by low bone mineral density, involves dysregulation of bone remodeling and is associated with an increased risk of fractures. Recent studies have revealed an intriguing link between AD and OP, highlighting shared pathological features indicative of common regulatory pathophysiological pathways. In this article, we elucidate the signaling mechanisms that regulate the pathology of AD and OP and offer insights into the intricate network of factors contributing to these conditions. We also examine the role of bone-derived factors in the progression of AD, underscoring the plausibility of bidirectional communication between the brain and the skeletal system. The presence of amyloid plaques in the brain of individuals with AD is akin to the accumulation of brain Aβ in vascular dementia, pointing towards the need for further investigation of shared molecular mechanisms. Moreover, we discuss the role of bone-derived microRNAs that may regulate the pathological progression of AD, providing a novel perspective on the role of skeletal factors in neurodegenerative diseases. The insights presented here should help researchers engaged in exploring innovative therapeutic approaches targeting both neurodegenerative and skeletal disorders in aging populations.
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Affiliation(s)
- Fariha Nasme
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, 40202, USA
| | - Jyotirmaya Behera
- Division of Immunology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Prisha Tyagi
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, 40202, USA
| | - Nabendu Debnath
- Centre for Molecular Biology, Central University of Jammu, Rahya-Suchani (Bagla) Samba, Jammu, Jammu & Kashmir, 181143, India
| | - Jeff C Falcone
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, 40202, USA
| | - Neetu Tyagi
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, 40202, USA.
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26
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Jia Y, Li R, Li Y, Kachler K, Meng X, Gießl A, Qin Y, Zhang F, Liu N, Andreev D, Schett G, Bozec A. Melanoma bone metastasis-induced osteocyte ferroptosis via the HIF1α-HMOX1 axis. Bone Res 2025; 13:9. [PMID: 39814705 PMCID: PMC11735842 DOI: 10.1038/s41413-024-00384-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 09/11/2024] [Accepted: 10/15/2024] [Indexed: 01/30/2025] Open
Abstract
Osteocytes are the main cells in mineralized bone tissue. Elevated osteocyte apoptosis has been observed in lytic bone lesions of patients with multiple myeloma. However, their precise contribution to bone metastasis remains unclear. Here, we investigated the pathogenic mechanisms driving melanoma-induced osteocyte death. Both in vivo models and in vitro assays were combined with untargeted RNA sequencing approaches to explore the pathways governing melanoma-induced osteocyte death. We could show that ferroptosis is the primary mechanism behind osteocyte death in the context of melanoma bone metastasis. HMOX1 was identified as a crucial regulatory factor in this process, directly involved in inducing ferroptosis and affecting osteocyte viability. We uncover a non-canonical pathway that involves excessive autophagy-mediated ferritin degradation, highlighting the complex relationship between autophagy and ferroptosis in melanoma-induced osteocyte death. In addition, HIF1α pathway was shown as an upstream regulator, providing a potential target for modulating HMOX1 expression and influencing autophagy-dependent ferroptosis. In conclusion, our study provides insight into the pathogenic mechanisms of osteocyte death induced by melanoma bone metastasis, with a specific focus on ferroptosis and its regulation. This would enhance our comprehension of melanoma-induced osteocyte death.
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Affiliation(s)
- Yewei Jia
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Rui Li
- Department of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yixuan Li
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Katerina Kachler
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Xianyi Meng
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Andreas Gießl
- Department of Opthalmology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Yi Qin
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Fulin Zhang
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Ning Liu
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Darja Andreev
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Technische Universität Dresden (TUD), Center for Molecular and Cellular Bioengineering (CMCB), Center for Regenerative Therapies Dresden (CRTD), Dresden, Germany
| | - Georg Schett
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Aline Bozec
- Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
- Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
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Burgan J, Rahmati M, Lee M, Saiz AM. Innate immune response to bone fracture healing. Bone 2025; 190:117327. [PMID: 39522707 DOI: 10.1016/j.bone.2024.117327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 11/05/2024] [Accepted: 11/07/2024] [Indexed: 11/16/2024]
Abstract
The field of osteoimmunology has primarily focused on fracture healing in isolated musculoskeletal injuries. The innate immune system is the initial response to fracture, with inflammatory macrophages, cytokines, and neutrophils arriving first at the fracture hematoma, followed by an anti-inflammatory phase to begin the process of new bone formation. This review aims to first discuss the current literature and knowledge gaps on the immune responses governing single fracture healing by encompassing the individual role of macrophages, neutrophils, cytokines, mesenchymal stem cells, bone cells, and other immune cells. This paper discusses the interactive effects of these cellular responses underscoring the field of osteoimmunology. The critical role of the metabolic environment in guiding the immune system properties will be highlighted along with some effective therapeutics for fracture healing in the context of osteoimmunology. However, compared to isolated fractures, which frequently heal well, long bone fractures in over 30 % of polytrauma patients exhibit impaired healing. Clinical evidence suggests there may be distinct physiologic and inflammatory pathways altered in polytrauma resulting in nonunion. Nonunion is associated with worse patient outcomes and increased societal healthcare costs. The dysregulated immunomodulatory/inflammatory response seen in polytrauma may lead to this increased nonunion rate. This paper will investigate the differences in immune response between isolated and polytrauma fractures. Finally, future directions for fracture studies are explored with consideration of the emerging roles of newly discovered immune cell functions in fracture healing, the existing challenges and conflicting results in the field, the translational potential of these studies in clinic, and the more complex nature of polytrauma fractures that can alter cell functions in different tissues.
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Affiliation(s)
- Jane Burgan
- Department of Orthopaedic Surgery, UC Davis Health, 4860 Y Street, Suite 3800, Sacramento, CA 95817, USA; Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | - Maryam Rahmati
- Department of Orthopaedic Surgery, UC Davis Health, 4860 Y Street, Suite 3800, Sacramento, CA 95817, USA; Department of Biomaterials, Institute for Clinical Dentistry, University of Oslo, PO Box 1109, Blindern, NO-0317 Oslo, Norway
| | - Mark Lee
- Department of Orthopaedic Surgery, UC Davis Health, 4860 Y Street, Suite 3800, Sacramento, CA 95817, USA
| | - Augustine Mark Saiz
- Department of Orthopaedic Surgery, UC Davis Health, 4860 Y Street, Suite 3800, Sacramento, CA 95817, USA.
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Ahmad SS, Ahmed F, Ahmad S, Krishnan A, Khan MA. Targeting dipeptidyl peptidase-8/9 to combat inflammation-induced osteoclastogenesis in RAW264.7 macrophages and analysis of anti-osteoclastogenesis potential of chrysin. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2025; 28:516-526. [PMID: 39968082 PMCID: PMC11831742 DOI: 10.22038/ijbms.2025.82219.17784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 11/27/2024] [Indexed: 02/20/2025]
Abstract
Objectives Osteoclasts drive bone resorption under inflammation, with cytokines promoting osteoclastogenesis. The role of proline enzymes like dipeptidyl peptidase-8 and 9 (DPP-8/9) in this process remains unclear. This study aimed to explore the DPP-8/9 involvement in inflammation-driven osteoclastogenesis using the RAW264.7 macrophage model. Materials and Methods Receptor activator of nuclear factor-κB ligand (RANKL) and lipopolysaccharide (LPS) induced osteoclastogenesis, raising interleukin-6 (IL-6), tumor necrosis factor (TNF-α), and IL-23 levels. Using RAW264.7 cells, DPP-8/9 protein and tartrate-resistant acid phosphatase (TRAPc) were assayed. Antibodies for cluster of differentiation (CD86 and CD206) were used to analyze macrophage polarization, while molecular docking was used to assess flavonoid binding to DPP-8/9. Western blot confirmed DPP-8/9 expression in treated macrophages. Results Administering RANKL and LPS increased IL-6 and TNF-α levels, significantly promoting osteoclastogenesis in RAW264.7 macrophages. This treatment also elevated the levels of the inflammatory macrophage marker IL-23. Osteoclast formation was confirmed by measuring TRAPc levels in the culture. Analysis of the cell supernatant revealed elevated DPP-8/9 levels in the RANKL+LPS group. Inhibition of DPP-8/9 with 1G244 decreased inflammatory cytokines and TRAPc levels in the cell culture. Molecular docking analysis of various flavonoids identified chrysin as a potential molecule with sufficient binding energy against DPP-8/9, a finding confirmed by blotting assay. Conclusion This study emphasizes the involvement of DPP-8/9 in inflammatory osteoclastogenesis in RAW264.7 macrophages. Inhibition of DPP-8/9 reduced osteoclastogenesis markers and inflammatory cytokines levels, indicating decreased osteoclast formation. Additionally, chrysin demonstrated potential as an anti-DPP-8/9 agent, highlighting its possible role in future therapeutic strategies targeting inflammation-induced osteoclastogenesis.
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Affiliation(s)
- Syed Sufian Ahmad
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, Hamdard, New Delhi - 110062, India
| | - Faraha Ahmed
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, Hamdard, New Delhi - 110062, India
| | - Sayeed Ahmad
- Bioactive Natural Product Laboratory, School of Pharmaceutical Education and Research, Jamia Hamdard, Hamdard, New Delhi - 110062, India
| | - Anuja Krishnan
- Department of Molecular Medicine, School of Interdisciplinary Science and Technology, Jamia Hamdard, Hamdard, New Delhi - 110062, India
| | - Mohammad Ahmed Khan
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, Hamdard, New Delhi - 110062, India
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29
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Shariati K, Bedar M, Huang KX, Moghadam S, Mirzaie S, LaGuardia JS, Chen W, Kang Y, Ren X, Lee JC. Biomaterial Cues for Regulation of Osteoclast Differentiation and Function in Bone Regeneration. ADVANCED THERAPEUTICS 2025; 8:2400296. [PMID: 39867107 PMCID: PMC11756815 DOI: 10.1002/adtp.202400296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Indexed: 01/28/2025]
Abstract
Tissue regeneration involves dynamic dialogue between and among different cells and their surrounding matrices. Bone regeneration is specifically governed by reciprocity between osteoblasts and osteoclasts within the bone microenvironment. Osteoclast-directed resorption and osteoblast-directed formation of bone are essential to bone remodeling, and the crosstalk between these cells is vital to curating a sequence of events that culminate in the creation of bone tissue. Among bone biomaterial strategies, many have investigated the use of different material cues to direct the development and activity of osteoblasts. However, less attention has been given to exploring features that similarly target osteoclast formation and activity, with even fewer strategies demonstrating or integrating biomaterial-directed modulation of osteoblast-osteoclast coupling. This review aims to describe various biomaterial cues demonstrated to influence osteoclastogenesis and osteoclast function, emphasizing those that enhance a material construct's ability to achieve bone healing and regeneration. Additionally discussed are approaches that influence the communication between osteoclasts and osteoblasts, particularly in a manner that takes advantage of their coupling. Deepening our understanding of how biomaterial cues may dictate osteoclast differentiation, function, and influence on the microenvironment may enable the realization of bone-replacement interventions with enhanced integrative and regenerative capacities.
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Affiliation(s)
- Kaavian Shariati
- Division of Plastic & Reconstructive Surgery, University of California, Los Angeles David Geffen School of Medicine, Los Angeles, CA, 90095, USA
| | - Meiwand Bedar
- Division of Plastic & Reconstructive Surgery, University of California, Los Angeles David Geffen School of Medicine, Los Angeles, CA, 90095, USA
- Research Service, Greater Los Angeles VA Healthcare System, Los Angeles, CA, 91343, USA
| | - Kelly X. Huang
- Division of Plastic & Reconstructive Surgery, University of California, Los Angeles David Geffen School of Medicine, Los Angeles, CA, 90095, USA
| | - Shahrzad Moghadam
- Division of Plastic & Reconstructive Surgery, University of California, Los Angeles David Geffen School of Medicine, Los Angeles, CA, 90095, USA
| | - Sarah Mirzaie
- Division of Plastic & Reconstructive Surgery, University of California, Los Angeles David Geffen School of Medicine, Los Angeles, CA, 90095, USA
| | - Jonnby S. LaGuardia
- Division of Plastic & Reconstructive Surgery, University of California, Los Angeles David Geffen School of Medicine, Los Angeles, CA, 90095, USA
| | - Wei Chen
- Division of Plastic & Reconstructive Surgery, University of California, Los Angeles David Geffen School of Medicine, Los Angeles, CA, 90095, USA
- Research Service, Greater Los Angeles VA Healthcare System, Los Angeles, CA, 91343, USA
| | - Youngnam Kang
- Division of Plastic & Reconstructive Surgery, University of California, Los Angeles David Geffen School of Medicine, Los Angeles, CA, 90095, USA
- Research Service, Greater Los Angeles VA Healthcare System, Los Angeles, CA, 91343, USA
| | - Xiaoyan Ren
- Division of Plastic & Reconstructive Surgery, University of California, Los Angeles David Geffen School of Medicine, Los Angeles, CA, 90095, USA
- Research Service, Greater Los Angeles VA Healthcare System, Los Angeles, CA, 91343, USA
| | - Justine C. Lee
- Division of Plastic & Reconstructive Surgery, University of California, Los Angeles David Geffen School of Medicine, Los Angeles, CA, 90095, USA
- Research Service, Greater Los Angeles VA Healthcare System, Los Angeles, CA, 91343, USA
- Department of Orthopaedic Surgery, Los Angeles, CA, 90095, USA
- UCLA Molecular Biology Institute, Los Angeles, CA, 90095, USA
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Jeon HH, Huang X, Rojas Cortez L, Sripinun P, Lee JM, Hong JJ, Graves DT. Inflammation and mechanical force-induced bone remodeling. Periodontol 2000 2024. [PMID: 39740162 DOI: 10.1111/prd.12619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 09/25/2024] [Accepted: 10/27/2024] [Indexed: 01/02/2025]
Abstract
Periodontitis arises from imbalanced host-microbe interactions, leading to dysbiosis and destructive inflammation. The host's innate and adaptive immune responses produce pro-inflammatory mediators that stimulate destructive events, which cause loss of alveolar bone and connective tissue attachment. There is no consensus on the factors that lead to a conversion from gingivitis to periodontitis, but one possibility is the proximity of the inflammation to the bone, which promotes bone resorption and inhibits subsequent bone formation during coupled bone formation. Conversely, orthodontic tooth movement is triggered by the mechanical force applied to the tooth, resulting in bone resorption on the compression side and new bone formation on the tension side. However, the environment around orthodontic brackets readily retains dental plaque and may contribute to inflammation and bone remodeling. The immune, epithelial, stromal, endothelial and bone cells of the host play an important role in setting the stage for bone remodeling that occurs in both periodontitis and orthodontic tooth movement. Recent advancements in single-cell RNA sequencing have provided new insights into the roles and interactions of different cell types in response to challenges. In this review, we meticulously examine the functions of key cell types such as keratinocytes, leukocytes, stromal cells, osteocytes, osteoblasts, and osteoclasts involved in inflammation- and mechanical force-driven bone remodeling. Moreover, we explore the combined effects of these two conditions: mechanical force-induced bone remodeling combined with periodontal disease (chronic inflammation) and periodontally accelerated osteogenic orthodontics (acute transient inflammation). This comprehensive review enhances our understanding of inflammation- and mechanical force-induced bone remodeling.
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Affiliation(s)
- Hyeran Helen Jeon
- Department of Orthodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Xin Huang
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, China
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Leticia Rojas Cortez
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Puttipong Sripinun
- Department of Orthodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Muang, Chiang Mai, Thailand
| | - Jung-Me Lee
- Division of Nutritional Sciences, College of Human Ecology, Cornell University, Ithaca, New York, USA
| | - Julie J Hong
- Department of Orthodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Dana T Graves
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Huang Y, Tang Y, Zhang R, Wu X, Yan L, Chen X, Wu Q, Chen Y, Lv Y, Su Y. Role of periodontal ligament fibroblasts in periodontitis: pathological mechanisms and therapeutic potential. J Transl Med 2024; 22:1136. [PMID: 39709490 PMCID: PMC11663348 DOI: 10.1186/s12967-024-05944-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 12/05/2024] [Indexed: 12/23/2024] Open
Abstract
Periodontal ligament fibroblasts (PDLFs) play a crucial role in the etiology of periodontitis and periodontal tissue regeneration. In healthy periodontal tissues, PDLFs maintain the homeostasis of periodontal soft and hard tissues as well as the local immune microenvironment. PDLFs also have the potential for multidirectional transdifferentiation and are involved in periodontal tissue regeneration. On the other hand, PDLFs can become dysfunctional and acquire an inflammatory phenotype to secret various inflammatory cytokines when affected by pathological factors. These cytokines further trigger immune and inflammatory events, and lead to destruction of periodontal soft and hard tissues as well as damage to the regenerative potential of PDLFs. This review summarizes the physiological functions of PDLFs. Meanwhile, this review also highlights recent insights into the pathological mechanisms driving the development of periodontitis through dysfunctional PDLFs and the negative impact on periodontal tissue regeneration. Additionally, this paper summarizes strategies for targeting PDLFs to treat periodontitis, involving blocking multiple stages of the inflammatory response induced by PDLFs and promoting the multidirectional transdifferentiation of PDLFs. Future research directions are proposed to address important questions that have not yet been answered in this field. This article provides a reference for understanding the important role of PDLFs in the pathological mechanisms of periodontitis and for developing new strategies for targeting PDLFs in periodontitis treatment.
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Affiliation(s)
- Yijie Huang
- Stomatology Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China
| | - Ying Tang
- Department of Prosthodontics, Huangpu District Dental Disease Prevention and Treatment Institute, Shanghai, 200001, China
| | - Ruiqi Zhang
- Stomatology Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China
| | - Xiao Wu
- Stomatology Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China
| | - Li Yan
- Stomatology Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China
| | - Xiling Chen
- Stomatology Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China
| | - Qianqi Wu
- Stomatology Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China
| | - Yiyan Chen
- Stomatology Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China
| | - Yingtao Lv
- Department of Prosthodontics, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Yuan Su
- Stomatology Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China.
- Department of Periodontology, Stomatological Hospital, Southern Medical University, Guangzhou, China.
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Ke L, He Q, Qu J, Wang X, Li K, Gong X, Li L, Xu J, Yu Q, Yu H, Lin X, Li J, Tan NS, Sun W, Li L, Zhang P, Cheng W. Bone-protective effects of neutralizing angiopoietin-like protein 4 monoclonal antibody in rheumatoid arthritis. Mol Ther 2024; 32:4497-4513. [PMID: 39367607 PMCID: PMC11638830 DOI: 10.1016/j.ymthe.2024.09.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 07/07/2024] [Accepted: 09/30/2024] [Indexed: 10/06/2024] Open
Abstract
Despite recent advances, rheumatoid arthritis (RA) patients remain refractory to therapy. Dysregulated overproduction of angiopoietin-like protein 4 (ANGPTL4) is thought to contribute to the disease development. ANGPTL4 was initially identified as a regulator of lipid metabolism, which is hydrolyzed to N-terminal and C-terminal (cANGPTL4) fragments in vivo. cANGPTL4 is involved in several non-lipid-related processes, including angiogenesis and inflammation. This study revealed that the level of ANGPTL4 was markedly elevated in the sera and synovial tissues from patients with RA versus controls. The administration of a neutralizing antibody against cANGPTL4 (anti-cANGPTL4 Ab) resulted in the inhibition of inflammatory processes and bone loss in animal models of collagen-induced arthritis and adjuvant-induced arthritis (AIA). Transcriptomic and proteomic profiling of synovial tissues from an AIA model indicated that the anti-cANGPTL4 Ab inhibited fibroblast-like synoviocyte (FLS) immigration and inflammatory-induced osteoclastogenesis. Mechanistically, the anti-cANGPTL4 Ab has been shown to inhibit TNF-α-induced inflammatory cascades in RA-FLS through the sirtuin 1/nuclear factor-κB signaling pathway. Moreover, the anti-cANGPTL4 Ab was found to block FLS invasion- and immigration-induced osteoclast activation. Collectively, these findings identify ANGPTL4 as a prospective biomarker for the diagnosis of RA, and targeting cANGPTL4 should represent a potential therapeutic strategy.
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Affiliation(s)
- Liqing Ke
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China
| | - Qifei He
- Department of Bone Joint and Musculoskeletal Tumor, Shenzhen Second People's Hospital (The First Affiliated Hospital of Shenzhen University), Shenzhen, Guangdong 518035, China
| | - Jing Qu
- Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong 518055, China
| | - Xiyue Wang
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China
| | - Kaibo Li
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China
| | - Xun Gong
- Guang'anmen Hospital China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Lan Li
- Department of Pathology, Beijing Jishuitan Hospital, Capital Medical University, Beijing 100035, China
| | - Jiake Xu
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China; Shenzhen University of Advanced Technology, Shenzhen, Guangdong 518060, China; School of Biomedical Sciences, University of Western Australia, Perth, WA 6009, Australia
| | - Qiuliyang Yu
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China; Shenzhen University of Advanced Technology, Shenzhen, Guangdong 518060, China
| | - Hao Yu
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China
| | - Xuefei Lin
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China
| | - Jian Li
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China
| | - Nguan Soon Tan
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore 308232, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore 138673, Singapore
| | - Wei Sun
- Department of Bone Joint and Musculoskeletal Tumor, Shenzhen Second People's Hospital (The First Affiliated Hospital of Shenzhen University), Shenzhen, Guangdong 518035, China
| | - Liang Li
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
| | - Peng Zhang
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China; Shenzhen University of Advanced Technology, Shenzhen, Guangdong 518060, China; The Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China; Shandong Zhongke Advanced Technology Co., Ltd., Jinan, Shandong 250300, China.
| | - Wenxiang Cheng
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China.
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Cosmo LAM, Coutinho RM, de Macedo LGS, Aloise AC, Jayme SJ, Zeferino JPG, Graziano A, Martinez EF, Moy PK, Pelegrine AA. Use of autologous micrografts associated with xenogeneic anorganic bone in vertical bone augmentation procedures with Barbell Technique®. Clin Implant Dent Relat Res 2024; 26:1289-1302. [PMID: 39302718 DOI: 10.1111/cid.13387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 08/22/2024] [Accepted: 08/24/2024] [Indexed: 09/22/2024]
Abstract
INTRODUCTION Bidirectional vertical ridge augmentation in the posterior maxilla is very challenging. PURPOSE To evaluate the regenerative potential of micrografts, derived from periosteum or bone tissue, added to an anorganic xenograft in vertical reconstruction of the posterior maxilla, by a prospective, controlled study. MATERIALS AND METHODS After clinical selection and the analysis of CBCT scans, 24 posterior maxillary sites, in 19 patients, were treated by using Barbell Technique®. Sites requiring both inlay and onlay reconstruction were enrolled in the study. In the Control Group (CG, n = 8), a xenograft was used in the inlay site and for the onlay site, a 1:1 mix of xenograft and an autograft was used. In Test Group 1 (TG1, n = 8), both inlay and onlay sites were grafted with the xenograft associated with the micrografts derived from periosteum. In Test Group 2 (TG2, n = 8), both inlay and onlay sites were grafted with the xenograft associated with the micrografts derived from bone. Six months after the procedures, CBCT scans were obtained, and bone biopsy samples were harvested during implant placement surgery. The bone specimens were analyzed histomorphometrically, by measuring the percentages of vital mineralized tissue (VMT), non vital mineralized tissue (NVMT) and non mineralized tissue (NMT). Immunohistochemically, the levels of VEGF were categorized by a score approach. RESULTS Histomorphometric analysis revealed, for the inlay grafts, no significant difference among the groups for VMT, NVMT and NMT. However, for onlay grafts, CG achieved a higher amount of VMT in comparison with TG2, and the opposite occurred for NMT values. In this regard, no statistical difference was observed between CG and TG1. Concerning immunohistochemistry, the VEGF values for CG and TG1 were slightly higher than those obtained by TG2 for both inlay and onlay grafts, but without statistical significance. CBCT analysis showed a similar level of gain for all groups, for both inlay and onlay bone augmentation sites. Clinically, one implant (in CG) within a total of 50 implants installed, had early failure and was replaced after 3 months. All patients received implant supported prosthesis. CONCLUSION This study indicated that the clinical use of micrograft derived from periosteum may have some potential to increase bone formation in onlay reconstructions, unlike the micrograft derived from bone tissue.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Peter Karyen Moy
- Dental Implant Center, University of California, Los Angeles, California, USA
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Liu T, Wu H, Li J, Zhu C, Wei J. Unraveling the Bone-Brain Axis: A New Frontier in Parkinson's Disease Research. Int J Mol Sci 2024; 25:12842. [PMID: 39684552 DOI: 10.3390/ijms252312842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 11/25/2024] [Accepted: 11/28/2024] [Indexed: 12/18/2024] Open
Abstract
Parkinson's disease (PD), as a widespread neurodegenerative disorder, significantly impacts patients' quality of life. Its primary symptoms include motor disturbances, tremor, muscle stiffness, and balance disorders. In recent years, with the advancement of research, the concept of the bone-brain axis has gradually become a focal point in the field of PD research. The bone-brain axis refers to the interactions and connections between the skeletal system and the central nervous system (CNS), playing a crucial role in the pathogenesis and pathological processes of PD. The purpose of this review is to comprehensively and deeply explore the bone-brain axis in PD, covering various aspects such as the complex relationship between bone metabolism and PD, the key roles of neurotransmitters and hormones in the bone-brain axis, the role of inflammation and immunity, microRNA (miRNA) functional regulation, and potential therapeutic strategies. Through a comprehensive analysis and in-depth discussion of numerous research findings, this review aims to provide a solid theoretical foundation for a deeper understanding of the pathogenesis of PD and to offer strong support for the development of new treatment methods.
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Affiliation(s)
- Tingting Liu
- Institute for Brain Sciences Research, Center for Translational Neurourology, Huaihe Hospital of Henan University, School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Haojie Wu
- Institute for Brain Sciences Research, Center for Translational Neurourology, Huaihe Hospital of Henan University, School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Jingwen Li
- Institute for Brain Sciences Research, Center for Translational Neurourology, Huaihe Hospital of Henan University, School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Chaoyang Zhu
- Institute for Brain Sciences Research, Center for Translational Neurourology, Huaihe Hospital of Henan University, School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Jianshe Wei
- Institute for Brain Sciences Research, Center for Translational Neurourology, Huaihe Hospital of Henan University, School of Life Sciences, Henan University, Kaifeng 475004, China
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Miller RC, Temenoff JS. Biomaterials for Cell Manufacturing. ACS Macro Lett 2024; 13:1521-1530. [PMID: 39466845 PMCID: PMC11580378 DOI: 10.1021/acsmacrolett.4c00634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 10/18/2024] [Accepted: 10/22/2024] [Indexed: 10/30/2024]
Abstract
Cell therapies, potent populations of cells used to treat disease and injury, can be strategically manufactured with biomaterial intervention to improve clinical translation. In this viewpoint, we discuss biomaterial design and integration into cell manufacturing steps to achieve three main goals: scale-up, phenotype control, and selection of potent cells. Material properties can be engineered to influence the cell-biomaterial interface and, therefore, impart desirable cell behavior such as growth, secretory activity, and differentiation. Future directions for the field should capitalize on the combinatorial design of biomaterial properties to yield highly specific and potent cell populations. Furthermore, future biomaterials could contribute to novel high-throughput cell separation technologies that can individually select the most therapeutically relevant cells within a produced batch.
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Affiliation(s)
- Ryan C. Miller
- Wallace
H. Coulter Department of Biomedical Engineering, Georgia Tech/Emory University, Atlanta, Georgia 30332, United States
| | - Johnna S. Temenoff
- Wallace
H. Coulter Department of Biomedical Engineering, Georgia Tech/Emory University, Atlanta, Georgia 30332, United States
- Parker
H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
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Song I, Kim PJ, Choi YJ, Chung YS, Lee S, Baek JH, Woo KM. Exploring the Interplay Between Senescent Osteocytes and Bone Remodeling in Young Rodents. J Aging Res 2024; 2024:4213141. [PMID: 39583064 PMCID: PMC11585373 DOI: 10.1155/2024/4213141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 07/25/2024] [Accepted: 09/14/2024] [Indexed: 11/26/2024] Open
Abstract
This study identifies senescent osteocytes in the femur and tibia of young rodents and explores their role in bone remodeling. The proximity of osteoclasts to senescent osteocytes was observed, which is a new finding. Cultured osteocytes, sorted using a podoplanin antibody in FACS, exhibited osteocytic characteristics and increased senescence-related genes. Senescent osteocytes secreted cytokines associated with senescence, remodeling, and inflammation. Notably, IGF1 and MMP2 were elevated in podoplanin-positive (pdpn+) osteocytes. Migration assays demonstrated significant osteoclast precursor migration towards senescent osteocytes, further confirmed by co-culture experiments leading to osteoclast differentiation. These findings suggest that senescent osteocytes have a pivotal role in initiating bone resorption, with recruitment of osteoclast precursors during early bone remodeling stages. In conclusion, our research enhances our understanding of complicated bone remodeling mechanisms and bone homeostasis.
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Affiliation(s)
- Insun Song
- Dental Research Institute, Seoul National University, Seoul 08826, Republic of Korea
| | - Pil-Jong Kim
- School of Dentistry and Dental Research Institute, Seoul National University, Seoul 08826, Republic of Korea
| | - Yong Jun Choi
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Yoon-Sok Chung
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Soonchul Lee
- Department of Orthopaedic Surgery, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam-si 13496, Republic of Korea
| | - Jeong-Hwa Baek
- Dental Research Institute, Seoul National University, Seoul 08826, Republic of Korea
- Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 08826, Republic of Korea
| | - Kyung Mi Woo
- Dental Research Institute, Seoul National University, Seoul 08826, Republic of Korea
- Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 08826, Republic of Korea
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Goel B, Virmani T, Jain V, Kumar G, Sharma A, Al Noman A. Unveiling the Link Between Breast Cancer Treatment and Osteoporosis: Implications for Anticancer Therapy and Bone Health. BIOMED RESEARCH INTERNATIONAL 2024; 2024:5594542. [PMID: 39574432 PMCID: PMC11581800 DOI: 10.1155/2024/5594542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 09/19/2024] [Accepted: 10/07/2024] [Indexed: 11/24/2024]
Abstract
Background: The interplay between breast cancer treatment and osteoporosis has important consequences for anticancer therapy and patient bone health. Many breast cancer therapies involve hormonal treatments that lower estrogen levels, which can lead to an increased risk of osteoporosis due to reduced bone mineral density. Aromatase inhibitors, chemotherapy, and surgeries such as oophorectomy can further aggravate bone loss, highlighting the necessity of prioritizing bone health during cancer treatment. Objective: This review is aimed at investigating the complex relationship between breast cancer therapies and bone health by examining the molecular and cellular mechanisms through which anticancer treatments lead to bone loss. It also seeks to assess the effects of various treatment options, such as selective estrogen receptor modulators (SERMs) and bisphosphonates, on reducing bone loss and maintaining bone health during cancer therapy. Method: The review explores the mechanisms underlying bone loss in breast cancer patients undergoing treatment, focusing on factors such as estrogen depletion, inflammatory cytokines, and changes in bone remodelling processes. Additionally, it evaluates the efficacy of different therapeutic interventions, including pharmacological treatments like bisphosphonates and third-generation SERMs, in mitigating bone-related side effects. Results: The findings indicate a critical need to balance the effectiveness of breast cancer treatments with the preservation of bone health. Pharmacological treatments like bisphosphonates and denosumab have been identified as essential for managing bone health in breast cancer patients. Furthermore, third-generation SERMs show potential in reducing bone loss associated with cancer therapy.
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Affiliation(s)
- Bhawna Goel
- School of Pharmaceutical Sciences, MVN University 121102, Palwal, Haryana, India
| | - Tarun Virmani
- Amity Institute of Pharmacy, Amity University, Greater Noida 2011308, Uttar Pradesh, India
| | - Vikas Jain
- Department of Pharmacy, JSS College of Pharmacy, Sri Shivarathreeshwara Nagara 570015, Mysuru, Karnataka, India
| | - Girish Kumar
- Amity Institute of Pharmacy, Amity University, Greater Noida 2011308, Uttar Pradesh, India
| | - Ashwani Sharma
- Department of Pharmaceutics, Delhi Pharmaceutical Sciences Research University, Delhi, India
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Hsu CN, Kao CH, Yang CH, Cheng MT, Hsu YP, Hong SG, Yao CL, Chen YH. Leptin Promotes the Expression of Pro-inflammatory Mediator Genes but Does Not Alter Osteoclastogenesis and Early Stage Differentiation of Osteoblasts. JOURNAL OF PHYSIOLOGICAL INVESTIGATION 2024; 67:355-363. [PMID: 39569657 DOI: 10.4103/ejpi.ejpi-d-24-00038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 09/12/2024] [Indexed: 11/22/2024]
Abstract
ABSTRACT Leptin, a hormone secreted by adipose tissue, plays a pivotal role in maintaining energy metabolism and bone quality. Dysregulation of leptin can lead to the development of various pathological conditions. For example, the concentration of leptin is increased in individuals with obesity, and this increased concentration is positively correlated with higher bone mass. In addition, mice lacking leptin or the leptin receptor exhibit substantial bone loss, further highlighting the pivotal role of leptin in regulating bone metabolism. However, the precise mechanism through which leptin affects bone remodeling remains unclear. The present study investigated the effect of leptin on osteoclastogenesis and osteoblastogenesis. Osteoblasts derived from MC3T3-E1 cells and osteoclasts derived from RAW 264.7 cells were used. The findings revealed that leptin did not substantially affect osteoclastogenesis or osteoblastogenesis. Furthermore, leptin did not affect cell viability during osteoclast differentiation. The expression of inflammatory mediators was increased in differentiating RAW 264.7 cells. However, the expression of critical bone resorptive genes, including Ctsk and tartrate-resistant acid phosphatase, was not elevated following leptin stimulation. By contrast, leptin did not alter the expression of key osteogenic genes in preosteoblasts in the early stage of differentiation. These data demonstrate that leptin can stimulate the expression of pro-inflammatory mediators in differentiating osteoclasts. These changes do not affect osteoblastogenesis or osteoclastogenesis. Leptin may downregulate bone resorption and enhance mineralization to increase bone mass.
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Affiliation(s)
- Chien-Ning Hsu
- Department of Chemical Engineering and Materials Science, Yuan Ze University, Taoyuan, Taiwan
- Department of Orthopedic Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
| | - Chih-Hong Kao
- Department of Cardiovascular Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
| | - Chin-Hua Yang
- Department of Radiology, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
- Department of Biomedical Engineering and Environmental Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Ming-Te Cheng
- Department of Orthopedic Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
- Sinwu Branch, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Biomedical Engineering, Chung Yung Christian University, Taoyuan, Taiwan
| | - Yu-Pao Hsu
- Department of Orthopedic Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
| | - Shinn-Gwo Hong
- Department of Chemical Engineering and Materials Science, Yuan Ze University, Taoyuan, Taiwan
| | - Chao-Ling Yao
- Department of Chemical Engineering and Materials Science, Yuan Ze University, Taoyuan, Taiwan
- Department of Chemical Engineering, National Cheng Kung University, Tainan City, Taiwan
| | - Yu-Hsu Chen
- Department of Orthopedic Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
- Department of Orthopedics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan
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Uçan Yarkaç F, Babayiğit O, Gokturk O. Associations between immune-inflammatory markers, age, and periodontal status: a cross-sectional study. Odontology 2024; 112:1296-1306. [PMID: 38443702 DOI: 10.1007/s10266-024-00907-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 01/29/2024] [Indexed: 03/07/2024]
Abstract
Since periodontal disease is associated with many systemic diseases, it is important to evaluate its effects on host responses in elderly individuals. To this end, this study investigated salivary interleukin (IL)-17, IL-18, toll-like receptor (TLR) 2, TLR4, and tumor necrosis factor-alpha (TNF-α) levels in patient groups with different periodontal health statuses and immunologically evaluated the relationship between age and periodontal health status. A total of 60 individuals aged 18-40 years (young individuals) and 60 individuals aged 65 years or older (elderly individuals) were included in this study. According to periodontal disease status, the patients were divided into periodontally healthy, gingivitis, and periodontitis subgroups. Clinical periodontal parameters, including probing depth (PD), clinical attachment level (CAL), plaque index (PI), and gingival index (GI), were recorded. Saliva samples were collected and analyzed using ELISA to determine the levels of IL-17, IL-18, TLR2, TLR4, and TNF-α. Higher clinical periodontal parameter (PD, CAL, PI, and GI) and inflammatory marker (IL-17, IL-18, TNF-α, TLR2, and TLR4) levels were found in patients with periodontitis than those in periodontally healthy individuals and patients with gingivitis (P < 0.05). Salivary inflammatory marker levels were significantly higher in elderly individuals than those in young individuals in all subgroups (P < 0.05). A positive correlation was found between inflammatory marker levels and clinical periodontal parameters, but there was no correlation between TLR2 and PI or GI. This study suggests a significant increase in host response to periodontal disease as the disease progresses, with the levels of cytokines and TLR expression exhibiting an increasing trend with age. Increased IL-17, IL-18, TLR2, TLR4, and TNF-α levels in elderly individuals in all periodontal health subgroups might suggest the role of these cytokines and TLR pathway in the pathogenesis of periodontal diseases.
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Affiliation(s)
- Fatma Uçan Yarkaç
- Department of Periodontology, Necmettin Erbakan University Faculty of Dentistry, Konya, Turkey
| | - Osman Babayiğit
- Department of Periodontology, Necmettin Erbakan University Faculty of Dentistry, Konya, Turkey.
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40
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Zhang Z, Wang Y, Di W, Ma C, Wang Y. Influence of Preoperative Inflammatory Status on Outcomes of Alveolar Bone Grafting in Patients With Cleft Lip. J Craniofac Surg 2024; 35:2105-2109. [PMID: 39418509 DOI: 10.1097/scs.0000000000010534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Accepted: 07/11/2024] [Indexed: 10/19/2024] Open
Abstract
After secondary alveolar bone grafting, the outcome of bone formation is always a problem that leads to repeat surgery. Bone formation is closely related to the inflammatory and immune status of patients. To achieve better bone formation results, this study aimed to investigate the influence of preoperative inflammatory indicators on the bone survival ratio (BSR) of secondary alveolar bone grafting. A retrospective study was conducted on 62 patients who underwent surgery by the same surgeon between January 2016 to December 2022. Demographic and laboratory data were included as independent variables. The BSR calculated from computed tomography data was included as the dependent variable. Pearson correlation analysis, Spearman correlation analysis, and multiple linear regression analysis were performed. The analysis results revealed significant correlations between BSR and preoperative inflammatory markers, including neutrophil percentage, neutrophil-to-lymphocyte ratio, lymphocyte percentage (L%), lymphocyte count, and monocyte-to-lymphocyte ratio. Multiple linear regression identified L% as an independent factor of BSR, with lower L% associated with higher BSR. Preoperative inflammatory markers may influence BSR after alveolar bone grating. A lower value of L% indicates a better postoperative bone formation outcome. Understanding these associations can aid clinicians in treatment planning and patient stratification.
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Affiliation(s)
- Zhilu Zhang
- Center for Cleft Lip and Palate Treatment, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yu Wang
- Center for Cleft Lip and Palate Treatment, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wenjun Di
- Center for Cleft Lip and Palate Treatment, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chenhao Ma
- Research Ward, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongqian Wang
- Center for Cleft Lip and Palate Treatment, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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41
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Wang J, Huang Y, Chen F, Li W. The age-related effects on orthodontic tooth movement and the surrounding periodontal environment. Front Physiol 2024; 15:1460168. [PMID: 39308977 PMCID: PMC11412856 DOI: 10.3389/fphys.2024.1460168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 08/28/2024] [Indexed: 09/25/2024] Open
Abstract
Orthodontic treatment in adults is often related to longer treatment time as well as higher periodontal risks compared to adolescents. The aim of this review is to explore the influence of age-related chages on orthodontic tooth movement (OTM) from macro and micro perspectives. Adults tend to show slower tooth movement speed compared to adolescence, especially during the early phase. Under orthodontic forces, the biological responses of the periodontal ligament (PDL) and alveolar bone is different between adult and adolescents. The adult PDL shows extended disorganization time, increased cell senescence, less cell signaling and a more inflammatory microenvironment than the adolescent PDL. In addition, the blood vessel surface area is reduced during the late movement phase, and fiber elasticity decreases. At the same time, adult alveolar bone shows a higher density, as well as a reduced osteoblast and osteoclast activation, under orthodontic forces. The local cytokine expression also differs between adults and adolescents. Side-effects, such as excessive root resorption, greater orthodontic pain, and reduced pulpal blood flow, also occur more frequently in adults than in adolescents.
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Affiliation(s)
- Jiayi Wang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, NHC Key Laboratory of Digital Stomatology, NMPA Key Laboratory for Dental Materials, Beijing, China
| | - Yiping Huang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, NHC Key Laboratory of Digital Stomatology, NMPA Key Laboratory for Dental Materials, Beijing, China
| | - Feng Chen
- National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory for Digital Stomatology, Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, NMPA Key Laboratory for Dental Materials, Beijing, China
- Central laboratory, Peking University School and Hospital of Stomatology, Beijing, China
| | - Weiran Li
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, NHC Key Laboratory of Digital Stomatology, NMPA Key Laboratory for Dental Materials, Beijing, China
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42
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Kolipaka R, Magesh I, Bharathy MA, Karthik S, Saranya I, Selvamurugan N. A potential function for MicroRNA-124 in normal and pathological bone conditions. Noncoding RNA Res 2024; 9:687-694. [PMID: 38577015 PMCID: PMC10990750 DOI: 10.1016/j.ncrna.2024.02.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 02/22/2024] [Accepted: 02/25/2024] [Indexed: 04/06/2024] Open
Abstract
Cells produce short single-stranded non-coding RNAs (ncRNAs) called microRNAs (miRNAs), which actively regulate gene expression at the posttranscriptional level. Several miRNAs have been observed to exert significant impacts on bone health and bone-related disorders. One of these, miR-124, is observed in bone microenvironments and is conserved across species. It affects bone cell growth and differentiation by activating different transcription factors and signaling pathways. In-depth functional analyses of miR-124 have revealed several physiological and pathological roles exerted through interactions with other ncRNAs. Deciphering these RNA-mediated signaling networks and pathways is essential for understanding the potential impacts of dysregulated miRNA functions on bone biology. In this review, we aim to provide a comprehensive analysis of miR-124's involvement in bone physiology and pathology. We highlight the importance of miR-124 in controlling transcription factors and signaling pathways that promote bone growth. This review reveals therapeutic implications for the treatment of bone-related diseases.
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Affiliation(s)
- Rushil Kolipaka
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603203, Tamil Nadu, India
| | - Induja Magesh
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603203, Tamil Nadu, India
| | - M.R. Ashok Bharathy
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603203, Tamil Nadu, India
| | - S. Karthik
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603203, Tamil Nadu, India
| | - I. Saranya
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603203, Tamil Nadu, India
| | - N. Selvamurugan
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603203, Tamil Nadu, India
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Hu YQ, Jin XJ, Lei SF, Yu XH, Bo L. Inflammatory bowel disease and osteoporosis: Common genetic effects, pleiotropy, and causality. Hum Immunol 2024; 85:110856. [PMID: 39018711 DOI: 10.1016/j.humimm.2024.110856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 06/28/2024] [Accepted: 07/09/2024] [Indexed: 07/19/2024]
Abstract
INTRODUCTION Previous studies have shown that inflammatory bowel disease (IBD) is associated with osteoporosis (OP) and bone mineral density (BMD), but the underlying genetic mechanisms are unclear. Our study wanted to explore the genetic and causal relationship between IBD and OP. MATERIALS AND METHODS Based on large-scale genome-wide association summary statistics and individual-level datasets (i.e., the UK Biobank), this study performed linkage disequilibrium score regression (LDSC), pleiotropic analysis under the composite null hypothesis (PLACO), and Mendelian randomization (MR) analyses to explore the genetic association, the pleiotropic genes and the causal relationship between IBD and BMD. RESULTS LDSC revealed significant genetic correlations between IBD and BMD (e.g., forearm BMD (rg = -0.3479, P = 0.019) and femoral neck BMD (rg = -0.1335, P = 0.0307). PLACO identified 14 overlapping pleiotropic loci, 1 shared risk gene (CDYL), and multiple shared pathways, revealing possible mechanisms for IBD and OP. MR analysis demonstrated a causal association between IBD and BMD. CONCLUSIONS Our study indicates that IBD may increase the risk of OP and reveals a complex genetic mechanism linking IBD and the risk of osteoporosis, which has important implications for diagnosing and treating IBD and OP.
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Affiliation(s)
- Ya-Qi Hu
- Department of Rheumatology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; Department of Hematology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Xiao-Jia Jin
- Department of Rheumatology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Shu-Feng Lei
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, 199 Renai Road, Suzhou, Jiangsu, China
| | - Xing-Hao Yu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| | - Lin Bo
- Department of Rheumatology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
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Xu S, Zhang Y, Zheng Z, Sun J, Wei Y, Ding G. Mesenchymal stem cells and their extracellular vesicles in bone and joint diseases: targeting the NLRP3 inflammasome. Hum Cell 2024; 37:1276-1289. [PMID: 38985391 DOI: 10.1007/s13577-024-01101-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 07/04/2024] [Indexed: 07/11/2024]
Abstract
The nucleotide-binding oligomerization domain-like-receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a cytosolic multi-subunit protein complex, and recent studies have demonstrated the vital role of the NLRP3 inflammasome in the pathological and physiological conditions, which cleaves gasdermin D to induce inflammatory cell death called pyroptosis and mediates the release of interleukin-1 beta and interleukin-18 in response to microbial infection or cellular injury. Over-activation of the NLRP3 inflammasome is associated with the pathogenesis of many disorders affecting bone and joints, including gouty arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, and periodontitis. Moreover, mesenchymal stem cells (MSCs) have been discovered to facilitate the inhibition of NLRP3 and maybe ideal for treating bone and joint diseases. In this review, we implicate the structure and activation of the NLRP3 inflammasome along with the detail on the involvement of NLRP3 inflammasome in bone and joint diseases pathology. In addition, we focused on MSCs and MSC-extracellular vesicles targeting NLRP3 inflammasomes in bone and joint diseases. Finally, the existing problems and future direction are also discussed.
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Affiliation(s)
- Shuangshuang Xu
- School of Stomatology, Shandong Second Medical University, Baotong West Street No. 7166, Weifang, Shandong Province, China
| | - Ying Zhang
- School of Stomatology, Shandong Second Medical University, Baotong West Street No. 7166, Weifang, Shandong Province, China
| | - Zejun Zheng
- School of Stomatology, Shandong Second Medical University, Baotong West Street No. 7166, Weifang, Shandong Province, China
| | - Jinmeng Sun
- School of Stomatology, Shandong Second Medical University, Baotong West Street No. 7166, Weifang, Shandong Province, China
| | - Yanan Wei
- School of Stomatology, Shandong Second Medical University, Baotong West Street No. 7166, Weifang, Shandong Province, China
| | - Gang Ding
- School of Stomatology, Shandong Second Medical University, Baotong West Street No. 7166, Weifang, Shandong Province, China.
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Long L, Luo H, Wang Y, Gu J, Xiong J, Tang X, Lv H, Zhou F, Cao K, Lin S. Kurarinone, a flavonoid from Radix Sophorae Flavescentis, inhibits RANKL-induced osteoclastogenesis in mouse bone marrow-derived monocyte/macrophages. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:7071-7087. [PMID: 38643449 DOI: 10.1007/s00210-024-03100-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 04/11/2024] [Indexed: 04/22/2024]
Abstract
Inflammation-induced osteoclast proliferation is a crucial contributor to impaired bone metabolism. Kurarinone (KR), a flavonoid extracted from the Radix Sophorae Flavescentis, exhibits notable anti-inflammatory properties. Nevertheless, the precise influence of KR on osteoclast formation remains unclear. This study's objective was to assess the impact of KR on osteoclast activity in vitro and unravel its underlying mechanism. Initially, a target network for KR-osteoclastogenesis-osteoporosis was constructed using network pharmacology. Subsequently, the intersecting targets were identified through the Venny platform and a PPI network was created using Cytoscape 3.9.1. Key targets within the network were identified employing topological algorithms. GO enrichment and KEGG pathway analysis were then performed on these targets to explore their specific functions and pathways. Additionally, molecular docking of potential core targets of KR was conducted, and the results were validated through cell experiments. A total of 83 target genes overlapped between KR and osteoclastogenesis-osteoporosis targets. Enrichment analysis revealed their role in inflammatory response, protein tyrosine kinase activity, osteoclast differentiation, and MAPK and NF-κB signaling pathways. PPI analysis and molecular docking demonstrate that key targets MAPK14 and MAPK8 exhibit more stable binding with KR compared to other proteins. In vitro experiments demonstrate that KR effectively inhibits osteoclast differentiation and bone resorption without cellular toxicity. It suppresses key osteoclast genes (NFATc1, c-Fos, TRAP, MMP9, Ctsk, Atp6v2), hinders IκB-α degradation, and inhibits ERK and JNK phosphorylation, while not affecting p38 phosphorylation. The results indicate that KR may inhibit osteoclast maturation and bone resorption by blocking NF-κB and MAPK signaling pathways, suggesting its potential as a natural therapeutic agent for osteoporosis.
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Affiliation(s)
- Ling Long
- Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, 332000, Jiangxi, China
| | - Hao Luo
- Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, 332000, Jiangxi, China
| | - Yi Wang
- Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, 332000, Jiangxi, China
| | - Jiaxiang Gu
- Orthopedic Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330209, Jiangxi, China
| | - Jiachao Xiong
- Orthopedic Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330209, Jiangxi, China
| | - Xiaokai Tang
- Orthopedic Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330209, Jiangxi, China
| | - Hao Lv
- Orthopedic Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330209, Jiangxi, China
| | - Faxin Zhou
- Orthopedic Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330209, Jiangxi, China
| | - Kai Cao
- Orthopedic Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330209, Jiangxi, China.
| | - Sijian Lin
- Rehabilitation Medicine Department, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China.
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Karnam S, Donthi MR, Jindal AB, Paul AT. Recent innovations in topical delivery for management of rheumatoid arthritis: A focus on combination drug delivery. Drug Discov Today 2024; 29:104071. [PMID: 38942070 DOI: 10.1016/j.drudis.2024.104071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 06/14/2024] [Accepted: 06/24/2024] [Indexed: 06/30/2024]
Abstract
Rheumatoid arthritis (RA) is an immune-mediated disease that necessitates a thorough understanding of its intricate pathophysiological mechanism for precise and effective therapeutic targeting. The European League Against Rheumatism (EULAR) has established guidelines for RA treatment, endorsing monotherapy or combination therapy with corticosteroids and synthetic disease-modifying antirheumatic drugs (sDMARDs). This review delves into clinical trials and research outcomes related to combination drug delivery, with an emphasis on the role of natural products in combination with synthetic drugs. Given the significant adverse effects associated with systemic administration, topical delivery has emerged as an alternative avenue for effective management of RA.
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Affiliation(s)
- Sriravali Karnam
- Laboratory of Natural Product Chemistry, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031, India
| | - Mahipal Reddy Donthi
- Laboratory of Natural Product Chemistry, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031, India
| | - Anil B Jindal
- Laboratory of Natural Product Chemistry, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031, India
| | - Atish T Paul
- Laboratory of Natural Product Chemistry, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031, India.
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Grass DM, Malek G, Taïeb HM, Ittah E, Richard H, Reznikov N, Laverty S. Characterization and quantification of in-vitro equine bone resorption in 3D using μCT and deep learning-aided feature segmentation. Bone 2024; 185:117131. [PMID: 38777311 DOI: 10.1016/j.bone.2024.117131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 05/18/2024] [Accepted: 05/19/2024] [Indexed: 05/25/2024]
Abstract
High cyclic strains induce formation of microcracks in bone, triggering targeted bone remodeling, which entails osteoclastic resorption. Racehorse bone is an ideal model for studying the effects of high-intensity loading, as it is subject to focal formation of microcracks and subsequent bone resorption. The volume of resorption in vitro is considered a direct indicator of osteoclast activity but indirect 2D measurements are used more often. Our objective was to develop an accurate, high-throughput method to quantify equine osteoclast resorption volume in μCT 3D images. Here, equine osteoclasts were cultured on equine bone slices and imaged with μCT pre- and postculture. Individual resorption events were then isolated and analyzed in 3D. Modal volume, maximum depth, and aspect ratio of resorption events were calculated. A convolutional neural network (CNN U-Net-like) was subsequently trained to identify resorption events on post-culture μCT images alone, without the need for pre-culture imaging, using archival bone slices with known resorption areas and paired CTX-I biomarker levels in culture media. 3D resorption volume measurements strongly correlated with both the CTX-I levels (p < 0.001) and area measurements (p < 0.001). Our 3D analysis shows that the shapes of resorption events form a continuous spectrum, rather than previously reported pit and trench categories. With more extensive resorption, shapes of increasing complexity appear, although simpler resorption cavity morphologies (small, rounded) remain most common, in acord with the left-hand limit paradigm. Finally, we show that 2D measurements of in vitro osteoclastic resorption are a robust and reliable proxy.
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Affiliation(s)
- Debora M Grass
- Comparative Orthopaedic Research Laboratory, Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Montreal, 3200 Sicotte, St-Hyacinthe, QC J2S 2M2, Canada
| | - Gwladys Malek
- Comparative Orthopaedic Research Laboratory, Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Montreal, 3200 Sicotte, St-Hyacinthe, QC J2S 2M2, Canada
| | - Hubert M Taïeb
- Department of Bioengineering, Faculty of Engineering, McGill University, 3480 University Street, Montreal, Quebec H3A 0E9, Canada
| | - Eran Ittah
- Department of Bioengineering, Faculty of Engineering, McGill University, 3480 University Street, Montreal, Quebec H3A 0E9, Canada
| | - Hélène Richard
- Comparative Orthopaedic Research Laboratory, Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Montreal, 3200 Sicotte, St-Hyacinthe, QC J2S 2M2, Canada
| | - Natalie Reznikov
- Department of Bioengineering, Faculty of Engineering, McGill University, 3480 University Street, Montreal, Quebec H3A 0E9, Canada
| | - Sheila Laverty
- Comparative Orthopaedic Research Laboratory, Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Montreal, 3200 Sicotte, St-Hyacinthe, QC J2S 2M2, Canada.
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Wu Z, Li W, Jiang K, Lin Z, Qian C, Wu M, Xia Y, Li N, Zhang H, Xiao H, Bai J, Geng D. Regulation of bone homeostasis: signaling pathways and therapeutic targets. MedComm (Beijing) 2024; 5:e657. [PMID: 39049966 PMCID: PMC11266958 DOI: 10.1002/mco2.657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 06/22/2024] [Accepted: 06/25/2024] [Indexed: 07/27/2024] Open
Abstract
As a highly dynamic tissue, bone is continuously rebuilt throughout life. Both bone formation by osteoblasts and bone resorption by osteoclasts constitute bone reconstruction homeostasis. The equilibrium of bone homeostasis is governed by many complicated signaling pathways that weave together to form an intricate network. These pathways coordinate the meticulous processes of bone formation and resorption, ensuring the structural integrity and dynamic vitality of the skeletal system. Dysregulation of the bone homeostatic regulatory signaling network contributes to the development and progression of many skeletal diseases. Significantly, imbalanced bone homeostasis further disrupts the signaling network and triggers a cascade reaction that exacerbates disease progression and engenders a deleterious cycle. Here, we summarize the influence of signaling pathways on bone homeostasis, elucidating the interplay and crosstalk among them. Additionally, we review the mechanisms underpinning bone homeostatic imbalances across diverse disease landscapes, highlighting current and prospective therapeutic targets and clinical drugs. We hope that this review will contribute to a holistic understanding of the signaling pathways and molecular mechanisms sustaining bone homeostasis, which are promising to contribute to further research on bone homeostasis and shed light on the development of targeted drugs.
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Affiliation(s)
- Zebin Wu
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Wenming Li
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Kunlong Jiang
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Zhixiang Lin
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Chen Qian
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Mingzhou Wu
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Yu Xia
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Ning Li
- Department of OrthopedicsCentre for Leading Medicine and Advanced Technologies of IHMDivision of Life Sciences and MedicineThe First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHefeiChina
| | - Hongtao Zhang
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Haixiang Xiao
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
- Department of OrthopedicsJingjiang People's HospitalSeventh Clinical Medical School of Yangzhou UniversityJingjiangJiangsu ProvinceChina
| | - Jiaxiang Bai
- Department of OrthopedicsCentre for Leading Medicine and Advanced Technologies of IHMDivision of Life Sciences and MedicineThe First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHefeiChina
| | - Dechun Geng
- Department of OrthopedicsThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
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Dawalibi A, Alosaimi AA, Mohammad KS. Balancing the Scales: The Dual Role of Interleukins in Bone Metastatic Microenvironments. Int J Mol Sci 2024; 25:8163. [PMID: 39125732 PMCID: PMC11311339 DOI: 10.3390/ijms25158163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 07/15/2024] [Accepted: 07/19/2024] [Indexed: 08/12/2024] Open
Abstract
Bone metastases, a common and debilitating consequence of advanced cancers, involve a complex interplay between malignant cells and the bone microenvironment. Central to this interaction are interleukins (ILs), a group of cytokines with critical roles in immune modulation and inflammation. This review explores the dualistic nature of pro-inflammatory and anti-inflammatory interleukins in bone metastases, emphasizing their molecular mechanisms, pathological impacts, and therapeutic potential. Pro-inflammatory interleukins, such as IL-1, IL-6, and IL-8, have been identified as key drivers in promoting osteoclastogenesis, tumor proliferation, and angiogenesis. These cytokines create a favorable environment for cancer cell survival and bone degradation, contributing to the progression of metastatic lesions. Conversely, anti-inflammatory interleukins, including IL-4, IL-10, and IL-13, exhibit protective roles by modulating immune responses and inhibiting osteoclast activity. Understanding these opposing effects is crucial for developing targeted therapies aimed at disrupting the pathological processes in bone metastases. Key signaling pathways, including NF-κB, JAK/STAT, and MAPK, mediate the actions of these interleukins, influencing tumor cell survival, immune cell recruitment, and bone remodeling. Targeting these pathways presents promising therapeutic avenues. Current treatment strategies, such as the use of denosumab, tocilizumab, and emerging agents like bimekizumab and ANV419, highlight the potential of interleukin-targeted therapies in mitigating bone metastases. However, challenges such as therapeutic resistance, side effects, and long-term efficacy remain significant hurdles. This review also addresses the potential of interleukins as diagnostic and prognostic biomarkers, offering insights into patient stratification and personalized treatment approaches. Interleukins have multifaceted roles that depend on the context, including the environment, cell types, and cellular interactions. Despite substantial progress, gaps in research persist, particularly regarding the precise mechanisms by which interleukins influence the bone metastatic niche and their broader clinical implications. While not exhaustive, this overview underscores the critical roles of interleukins in bone metastases and highlights the need for continued research to fully elucidate their complex interactions and therapeutic potential. Addressing these gaps will be essential for advancing our understanding and treatment of bone metastases in cancer patients.
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Affiliation(s)
- Ahmad Dawalibi
- Department of Anatomy, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia;
| | - Amal Ahmed Alosaimi
- College of Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh 11432, Saudi Arabia;
| | - Khalid S. Mohammad
- Department of Anatomy, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia;
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Hao M, Xue L, Wen X, Sun L, Zhang L, Xing K, Hu X, Xu J, Xing D. Advancing bone regeneration: Unveiling the potential of 3D cell models in the evaluation of bone regenerative materials. Acta Biomater 2024; 183:1-29. [PMID: 38815683 DOI: 10.1016/j.actbio.2024.05.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 05/23/2024] [Accepted: 05/24/2024] [Indexed: 06/01/2024]
Abstract
Bone, a rigid yet regenerative tissue, has garnered extensive attention for its impressive healing abilities. Despite advancements in understanding bone repair and creating treatments for bone injuries, handling nonunions and large defects remains a major challenge in orthopedics. The rise of bone regenerative materials is transforming the approach to bone repair, offering innovative solutions for nonunions and significant defects, and thus reshaping orthopedic care. Evaluating these materials effectively is key to advancing bone tissue regeneration, especially in difficult healing scenarios, making it a critical research area. Traditional evaluation methods, including two-dimensional cell models and animal models, have limitations in predicting accurately. This has led to exploring alternative methods, like 3D cell models, which provide fresh perspectives for assessing bone materials' regenerative potential. This paper discusses various techniques for constructing 3D cell models, their pros and cons, and crucial factors to consider when using these models to evaluate bone regenerative materials. We also highlight the significance of 3D cell models in the in vitro assessments of these materials, discuss their current drawbacks and limitations, and suggest future research directions. STATEMENT OF SIGNIFICANCE: This work addresses the challenge of evaluating bone regenerative materials (BRMs) crucial for bone tissue engineering. It explores the emerging role of 3D cell models as superior alternatives to traditional methods for assessing these materials. By dissecting the construction, key factors of evaluating, advantages, limitations, and practical considerations of 3D cell models, the paper elucidates their significance in overcoming current evaluation method shortcomings. It highlights how these models offer a more physiologically relevant and ethically preferable platform for the precise assessment of BRMs. This contribution is particularly significant for "Acta Biomaterialia" readership, as it not only synthesizes current knowledge but also propels the discourse forward in the search for advanced solutions in bone tissue engineering and regeneration.
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Affiliation(s)
- Minglu Hao
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China; Cancer institute, Qingdao University, Qingdao 266071, China.
| | - Linyuan Xue
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China; Cancer institute, Qingdao University, Qingdao 266071, China
| | - Xiaobo Wen
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China; Cancer institute, Qingdao University, Qingdao 266071, China
| | - Li Sun
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China; Cancer institute, Qingdao University, Qingdao 266071, China
| | - Lei Zhang
- Department of Chemical Engineering and Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, Ontario N2L3G1, Canada
| | - Kunyue Xing
- Alliance Manchester Business School, The University of Manchester, Manchester M139PL, UK
| | - Xiaokun Hu
- Department of Interventional Medical Center, Affiliated Hospital of Qingdao University, Qingdao 26600, China
| | - Jiazhen Xu
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China; Cancer institute, Qingdao University, Qingdao 266071, China.
| | - Dongming Xing
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China; Cancer institute, Qingdao University, Qingdao 266071, China; School of Life Sciences, Tsinghua University, Beijing 100084, China.
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