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Tang K, Deng W, Huang Z, Chen S, Zhu Z, Lin S, Zhong L, Zheng Q, Zhao W, Zhang Z, Mo L. Neoandrographolide inhibits mature osteoclast differentiation to alleviate bone loss and treat osteoporosis. Front Pharmacol 2025; 16:1466057. [PMID: 40008134 PMCID: PMC11851123 DOI: 10.3389/fphar.2025.1466057] [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: 07/17/2024] [Accepted: 01/02/2025] [Indexed: 02/27/2025] Open
Abstract
Background Osteoporosis (OP), as the prevalent systemic metabolic bone disease worldwide, progresses insidiously and slowly. The clinical discomfort and complications associated with OP impose a significant burden on patients. Therefore, finding more effective treatments for OP remains an urgent challenge. Method We first conducted in vitro experiments to determine whether Neoandrographolide (NEO) exhibits cytotoxic or proliferative effects on bone marrow macrophages (BMMs) and to explore the specific timeframe during which NEO exerts its inhibitory action on osteoclast (OC) differentiation. Through Reverse Transcription Polymerase Chain Reaction (RT-PCR) and Western blot analysis, we examined the relative expression levels of genes and proteins associated with OC differentiation like CTSK,c-Fos,MMP9,NFATc1, and verified the underlying mechanisms. Finally, we performed in vivo experiments to further investigate the inflammation. Results NEO exhibits no significant cytotoxic effects on BMMs at concentrations less than or equal to 30 μM while exerting inhibitory effects on OC differentiation during its early and middle stages. RT-PCR and Western blot results reveal that NEO suppresses the expression of genes and proteins including CTSK,c-Fos,MMP9,NFATc1. Western blot findings also indicate that NEO inhibits the phosphorylation of ERK, P38, JNK, and P65 but does not reverse the degradation of IκB-α. Additionally, NEO affects the phosphorylation of proteins in the PI3K/AKT, GSK3β, and PPARγ signaling pathways, demonstrating that NEO can inhibit OC formation through multiple pathways and targets. In vivo experiments further validated the in vitro findings by constructing an OP model, showing that NEO can mitigate bone loss induced by OC differentiation. Conclusion NEO has the potential to serve as a therapeutic agent for OP by targeting multiple sites and inhibiting the formation of mature OC through various signaling pathways.
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Affiliation(s)
- Kai Tang
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
- The Laboratory of Orthopaedics and Traumatology of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Wei Deng
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
- The Laboratory of Orthopaedics and Traumatology of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Zhiying Huang
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- The Laboratory of Orthopaedics and Traumatology of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- The Eighth School of Clinical Medicine of Guangzhou University of Chinese Medicine, Foshan, Guangdong, China
| | - Simin Chen
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
- The Laboratory of Orthopaedics and Traumatology of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Zilin Zhu
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- The Laboratory of Orthopaedics and Traumatology of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Shukun Lin
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- The Laboratory of Orthopaedics and Traumatology of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Lubin Zhong
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- The Laboratory of Orthopaedics and Traumatology of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Quanxin Zheng
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- The Laboratory of Orthopaedics and Traumatology of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Wenhua Zhao
- Department of Spine Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Zhida Zhang
- Department of Spine Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Ling Mo
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- The Laboratory of Orthopaedics and Traumatology of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Research Institute for Orthopedics and Traumatology of Chinese Medicine, Guangzhou, Guangdong, China
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Pérez-Chacón G, Santamaría PG, Redondo-Pedraza J, González-Suárez E. RANK/RANKL Signaling Pathway in Breast Development and Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1464:309-345. [PMID: 39821032 DOI: 10.1007/978-3-031-70875-6_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2025]
Abstract
RANK pathway has attracted increasing interest as a promising target in breast cancer, given the availability of denosumab, an anti-RANKL drug. RANK signaling mediates progesterone-driven regulation of mammary gland development and favors breast cancer initiation by controlling mammary cell proliferation and stem cell fate. RANK activation promotes luminal mammary epithelial cell senescence, acting as an initial barrier to tumorigenesis but ultimately facilitating tumor progression and metastasis. Comprehensive analyses have demonstrated that RANK protein expression is an independent biomarker of poor prognosis in postmenopausal and estrogen receptor-negative breast cancer patients. RANK pathway also has multiple roles in immunity and inflammation, regulating innate and adaptive responses. In the tumor microenvironment, RANK and RANKL are expressed by different immune cell populations and contribute to the regulation of tumor immune surveillance, mainly driving immunosuppressive effects.Herein, we discuss the preventive and therapeutic potential of targeting RANK signaling in breast cancer given its tumor cell intrinsic and extrinsic effects. RANKL inhibition has been shown to induce mammary tumor cell differentiation and an antitumor immune response. Moreover, loss of RANK signaling increases sensitivity of breast cancer cells to chemotherapy, targeted therapies such as HER2 and CDK4/6 inhibitors, and immunotherapy. Finally, we describe clinical trials of denosumab for breast cancer prevention, such as those ongoing in women with high risk of developing breast cancer, large phase III clinical trials where the impact of adjuvant denosumab on disease-free survival has been assessed, and window trials to evaluate the immunomodulatory effects of denosumab in breast cancer and other solid tumors.
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Affiliation(s)
- Gema Pérez-Chacón
- Molecular Oncology, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | | | | | - Eva González-Suárez
- Molecular Oncology, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
- Oncobell, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
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Bai L, Zhou D, Li G, Liu J, Chen X, Su J. Engineering bone/cartilage organoids: strategy, progress, and application. Bone Res 2024; 12:66. [PMID: 39567500 PMCID: PMC11579019 DOI: 10.1038/s41413-024-00376-y] [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: 04/01/2024] [Revised: 09/19/2024] [Accepted: 10/10/2024] [Indexed: 11/22/2024] Open
Abstract
The concept and development of bone/cartilage organoids are rapidly gaining momentum, providing opportunities for both fundamental and translational research in bone biology. Bone/cartilage organoids, essentially miniature bone/cartilage tissues grown in vitro, enable the study of complex cellular interactions, biological processes, and disease pathology in a representative and controlled environment. This review provides a comprehensive and up-to-date overview of the field, focusing on the strategies for bone/cartilage organoid construction strategies, progresses in the research, and potential applications. We delve into the significance of selecting appropriate cells, matrix gels, cytokines/inducers, and construction techniques. Moreover, we explore the role of bone/cartilage organoids in advancing our understanding of bone/cartilage reconstruction, disease modeling, drug screening, disease prevention, and treatment strategies. While acknowledging the potential of these organoids, we discuss the inherent challenges and limitations in the field and propose potential solutions, including the use of bioprinting for organoid induction, AI for improved screening processes, and the exploration of assembloids for more complex, multicellular bone/cartilage organoids models. We believe that with continuous refinement and standardization, bone/cartilage organoids can profoundly impact patient-specific therapeutic interventions and lead the way in regenerative medicine.
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Affiliation(s)
- Long Bai
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Organoid Research Center, Institute of Translational Medicine, Shanghai University, Shanghai, China
- National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai, China
- Wenzhou Institute of Shanghai University, Wenzhou, Zhejiang, China
| | - Dongyang Zhou
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Organoid Research Center, Institute of Translational Medicine, Shanghai University, Shanghai, China
- National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai, China
| | - Guangfeng Li
- Department of Orthopedics, Shanghai Zhongye Hospital, Shanghai, China
| | - Jinlong Liu
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Organoid Research Center, Institute of Translational Medicine, Shanghai University, Shanghai, China.
- National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai, China.
| | - Xiao Chen
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Organoid Research Center, Institute of Translational Medicine, Shanghai University, Shanghai, China.
- National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai, China.
| | - Jiacan Su
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Organoid Research Center, Institute of Translational Medicine, Shanghai University, Shanghai, China.
- National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai, China.
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Peng Z, Huang W, Xiao Z, Wang J, Zhu Y, Zhang F, Lan D, He F. Immunotherapy in the Fight Against Bone Metastases: A Review of Recent Developments and Challenges. Curr Treat Options Oncol 2024; 25:1374-1389. [PMID: 39436492 PMCID: PMC11541271 DOI: 10.1007/s11864-024-01256-7] [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] [Accepted: 08/14/2024] [Indexed: 10/23/2024]
Abstract
OPINION STATEMENT Bone metastasis, a frequent and detrimental complication of advanced cancers, often triggers bone deterioration events that severely compromise patient quality of life and prognosis. The past few years have witnessed the emergence and continuous advancements in immunotherapy, ushering in innovative therapeutic prospects for bone metastasis. These advancements include not only the use of immune checkpoint inhibitors (ICIs), both as standalone and combined treatments, but also the investigation of novel targets within immune cells residing in bone metastases. These breakthroughs have instilled fresh optimism for effectively managing patients with bone metastasis. This article endeavors to present an exhaustive review of the recent progress made across a spectrum of immunotherapeutic strategies and targeted therapies specifically designed for individuals battling bone metastasis from malignant tumors. By doing so, it seeks to offer insights that can inform clinical practices and guide further medical research in this domain.
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Affiliation(s)
- Zhonghui Peng
- Medical School, Hunan University of Chinese Medicine, Changsha, China
| | - Wei Huang
- Medical School, Hunan University of Chinese Medicine, Changsha, China
| | - Ziyu Xiao
- Medical School, Hunan University of Chinese Medicine, Changsha, China
| | - Jinge Wang
- Medical School, Hunan University of Chinese Medicine, Changsha, China
| | - Yongzhe Zhu
- Medical School, Hunan University of Chinese Medicine, Changsha, China
| | - Fudou Zhang
- Medical School, Hunan University of Chinese Medicine, Changsha, China
| | - Dongqiang Lan
- Department of Oncology, Hunan Academy of Traditional Chinese Medicine Affiliated Hospital, Changsha, China
| | - Fengjiao He
- Department of Oncology, Hunan Academy of Traditional Chinese Medicine Affiliated Hospital, Changsha, China.
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Wen S, Zheng X, Yin W, Liu Y, Wang R, Zhao Y, Liu Z, Li C, Zeng J, Rong M. Dental stem cell dynamics in periodontal ligament regeneration: from mechanism to application. Stem Cell Res Ther 2024; 15:389. [PMID: 39482701 PMCID: PMC11526537 DOI: 10.1186/s13287-024-04003-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 10/17/2024] [Indexed: 11/03/2024] Open
Abstract
Periodontitis, a globally prevalent chronic inflammatory disease is characterized by the progressive degradation of tooth-supporting structures, particularly the periodontal ligament (PDL), which can eventually result in tooth loss. Despite the various clinical interventions available, most focus on symptomatic relief and lack substantial evidence of supporting the functional regeneration of the PDL. Dental stem cells (DSCs), with their homology and mesenchymal stem cell (MSC) properties, have gained significant attention as a potential avenue for PDL regeneration. Consequently, multiple therapeutic strategies have been developed to enhance the efficacy of DSC-based treatments and improve clinical outcomes. This review examines the mechanisms by which DSCs and their derivatives promote PDL regeneration, and explores the diverse applications of exogenous implantation and endogenous regenerative technology (ERT) aimed at amplifying the regenerative capacity of endogenous DSCs. Additionally, the persistent challenges and controversies surrounding DSC therapies are discussed, alongside an evaluation of the limitations in current research on the underlying mechanisms and innovative applications of DSCs in PDL regeneration with the aim of providing new insights for future development. Periodontitis, a chronic inflammatory disease, represents a major global public health concern, affecting a significant proportion of the population and standing as the leading cause tooth loss in adults. The functional periodontal ligament (PDL) plays an indispensable role in maintaining periodontal health, as its structural and biological integrity is crucial for the long-term prognosis of periodontal tissues. It is widely recognized as the cornerstone of periodontal regeneration Despite the availability of various treatments, ranging from nonsurgical interventions to guided tissue regeneration (GTR) techniques, these methods have shown limited success in achieving meaningful PDL regeneration. As a result, the inability to fully restore PDL function underscores the urgent need for innovative therapeutic strategies at reconstructing this essential structure. Stem cell therapy, known for its regenerative and immunomodulatory potential, offers a promising approach for periodontal tissue repair. Their application marks a significant paradigm shift in the treatment of periodontal diseases, opening new avenues for functional PDL regeneration. However, much of the current research has primarily focused on the regeneration of alveolar bone and gingiva, as these hard and soft tissues can be more easily evaluated through visual assessment. The complexity of PDL structure, coupled with the intricate interactions among cellular and molecular components, presents significant scientific and clinical hurdles in translating DSC research into practical therapeutic applications. This review provides a thorough exploration of DSC dynamics in periodontal regeneration, detailing their origins, properties, and derived products, while also examining their potential mechanisms and applications in PDL regeneration. It offers an in-depth analysis of the current research, landscape, acknowledging both the progress made and the challenges that remain in bridging the gap between laboratory findings and clinical implementation. Finally, the need for continued investigation into the intricate mechanisms governing DSC behavior and the optimization of their use in regenerative therapies for periodontal diseases is also emphasized.
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Affiliation(s)
- Shuyi Wen
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, 510280, China
| | - Xiao Zheng
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, 510280, China
| | - Wuwei Yin
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, 510280, China
| | - Yushan Liu
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, 510280, China
| | - Ruijie Wang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, 510280, China
| | - Yaqi Zhao
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, 510280, China
| | - Ziyi Liu
- Department of Stomatology, Shunde Hospital, Southern Medical University, The First People's Hospital of Shunde, Foshan, Guangdong, 528308, China
| | - Cong Li
- Dongguan Key Laboratory of Metabolic Immunology and Oral Diseases, Dongguan Maternal and Child Health Care Hospital, Dongguan, Guangdong, 523000, China
| | - Jincheng Zeng
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong, 523808, China.
| | - Mingdeng Rong
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, 510280, China.
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Yang Y, Li R, Wang P, Zhao Y, Li J, Jiao J, Zheng H. Osteoking prevents bone loss and enhances osteoblastic bone formation by modulating the AGEs/IGF-1/β-catenin/OPG pathway in type 2 diabetic db/db mice. Cell Biol Int 2024; 48:1507-1519. [PMID: 38937979 DOI: 10.1002/cbin.12215] [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: 09/14/2023] [Revised: 05/24/2024] [Accepted: 06/07/2024] [Indexed: 06/29/2024]
Abstract
Type 2 diabetic osteoporosis (T2DOP) is a skeletal metabolic syndrome characterized by impaired bone remodeling due to type 2 diabetes mellitus, and there are drawbacks in the present treatment. Osteoking (OK) is widely used for treating fractures and femoral head necrosis. However, OK is seldom reported in the field of T2DOP, and its role and mechanism of action need to be elucidated. Consequently, this study investigated whether OK improves bone remodeling and the mechanisms of diabetes-induced injury. We used db/db mice as a T2DOP model and stimulated MC3T3-E1 cells (osteoblast cell line) with high glucose (HG, 50 mM) and advanced glycation end products (AGEs, 100 µg/mL), respectively. The effect of OK on T2DOP was assessed using a combined 3-point mechanical bending test, hematoxylin and eosin staining, and enzyme-linked immunosorbent assay. The effect of OK on enhancing MC3T3-E1 cell differentiation and mineralization under HG and AGEs conditions was assessed by an alkaline phosphatase activity assay and alizarin red S staining. The AGEs/insulin-like growth factor-1(IGF-1)/β-catenin/osteoprotegerin (OPG) pathway-associated protein levels were assayed by western blot analysis and immunohistochemical staining. We found that OK reduced hyperglycemia, attenuated bone damage, repaired bone remodeling, increased tibial and femoral IGF-1, β-catenin, and OPG expression, and decreased receptor activator of nuclear kappa B ligand and receptor activator of nuclear kappa B expression in db/db mice. Moreover, OK promoted the differentiation and mineralization of MC3T3-E1 cells under HG and AGEs conditions, respectively, and regulated the levels of AGEs/IGF-1/β-catenin/OPG pathway-associated proteins. In conclusion, our results suggest that OK may lower blood glucose, alleviate bone damage, and attenuate T2DOP, in part through activation of the AGEs/IGF-1/β-catenin/OPG pathway.
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Affiliation(s)
- Yi Yang
- Department of Laboratory Animal Science, Kunming Medical University, Kunming, China
| | - Rong Li
- Department of Laboratory Animal Science, Kunming Medical University, Kunming, China
| | - Peijin Wang
- Department of Laboratory Animal Science, Kunming Medical University, Kunming, China
| | - Yulan Zhao
- Department of Laboratory Animal Science, Kunming Medical University, Kunming, China
| | - Jintao Li
- Department of Laboratory Animal Science, Kunming Medical University, Kunming, China
| | - Jianlin Jiao
- Science and Technology Achievement Incubation Center, Kunming Medical University, Kunming, China
| | - Hong Zheng
- Department of Laboratory Animal Science, Kunming Medical University, Kunming, China
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Jiang C, Ruan Y, Li J, Huang J, Xiao M, Xu H. Tissue expression and promoter activity analysis of the porcine TNFSF11 gene. Theriogenology 2024; 226:277-285. [PMID: 38954996 DOI: 10.1016/j.theriogenology.2024.06.018] [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: 04/17/2024] [Revised: 06/20/2024] [Accepted: 06/20/2024] [Indexed: 07/04/2024]
Abstract
Tumour necrosis factor (TNF) superfamily member 11 (TNFSF11), also known as RANKL, plays a crucial role in regulating several physiological and pathological activities. Additionally, it is a vital factor in bone physiology, and the sex hormone progesterone regulates the expansion of stem cells and the proliferation of mammary epithelial cells. It is essential for animal growth and reproductive physiological processes. This study aimed to evaluate the tissue-specific expression characteristics and promoter activity of the TNFSF11 gene in pigs. As a result, the study examined the presence of TNFSF11 expression in the tissues of Xiangsu pigs at 0.6 and 12 months of age. Moreover, the core promoter region of TNFSF11 was also identified by utilizing a combination of bioinformatic prediction and dual-luciferase activity tests. Finally, the effect of transcription factors on the transcriptional activity of the core promoter region was determined using site-directed mutagenesis. TNFSF11 was uniformly expressed in all tissues; however, its expression in muscles was comparatively low. The core promoter region of TNFSF11 was located in the -555 to -1 region. The prediction of the transcription start site of TNFSF11 gene-2000 ∼ + 500bp showed that there was a CpG site in 17 ∼ + 487bp. Analysis of mutations in the transcription factor binding sites revealed that mutations in the Stat5b, Myog, Trl, and EN1 binding sites had significant effects on the transcriptional activity of the TNFSF11 gene, particularly following the EN1 binding site mutation (P < 0.001). This study provides insights into both the tissue-specific expression patterns of TNFSF11 in the tissues of Xiangsu pigs and the potential regulatory effects of transcription factors on its promoter activity. These results may be helpful for future research aimed at clarifying the expression and role of the porcine TNFSF11 gene.
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Affiliation(s)
- Chuanmei Jiang
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang, China; Guizhou Provincial Key Laboratory of Animal Genetics, Breeding and Reproduction, Guizhou University, Guiyang, China; College of Animal Science, Guizhou University, Guiyang, China
| | - Yong Ruan
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang, China; Guizhou Provincial Key Laboratory of Animal Genetics, Breeding and Reproduction, Guizhou University, Guiyang, China; College of Animal Science, Guizhou University, Guiyang, China
| | - Jifeng Li
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang, China; Guizhou Provincial Key Laboratory of Animal Genetics, Breeding and Reproduction, Guizhou University, Guiyang, China; College of Animal Science, Guizhou University, Guiyang, China
| | - Jiajin Huang
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang, China; Guizhou Provincial Key Laboratory of Animal Genetics, Breeding and Reproduction, Guizhou University, Guiyang, China; College of Animal Science, Guizhou University, Guiyang, China
| | - Meimei Xiao
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang, China; Guizhou Provincial Key Laboratory of Animal Genetics, Breeding and Reproduction, Guizhou University, Guiyang, China; College of Animal Science, Guizhou University, Guiyang, China
| | - Houqiang Xu
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang, China; Guizhou Provincial Key Laboratory of Animal Genetics, Breeding and Reproduction, Guizhou University, Guiyang, China; College of Animal Science, Guizhou University, Guiyang, China.
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Arturo NVC, Ivan GNJ, Betsabe CH, Emilio PGE, Yussef EG, Alejandra RJN, Tonatiuh GH, Alejandra VV, Ismael NA, Elena TSS, Manuel PGJ, Heriberto JC, Gerardo AAE, Laura GL, Miriam SCA. Genetic Variants of the Receptor Activator Nuclear of κB Ligand Gene Increase the Risk of Rheumatoid Arthritis in a Mexican Mestizo Population: A Case-Control Study. Genes (Basel) 2024; 15:907. [PMID: 39062686 PMCID: PMC11275863 DOI: 10.3390/genes15070907] [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: 06/20/2024] [Revised: 07/06/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
The Receptor Activator Nuclear of κB Ligand (RANKL) plays an important function in immune responses, activating osteoclast cells and unchanged bone resorption, which in turn leads to bone erosion and inflammation. Genetic variants in the promoter region of the RANKL gene could lead to a higher risk of rheumatoid arthritis (RA). OBJECTIVE To assess the association of rs9533155 (-693C>G) and rs9533156 (-643T>C) genetic variants with RA risk. METHODS A case-control study was carried out. A total of 94 patients with RA (RA group) and 134 subjects without any rheumatologic disease (control group) were included. Genetic DNA was extracted from peripheral white blood cells (leukocytes). Genetic variant rs9533155 (-693C>G) was screened by an approach based on Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP), while rs9533156 (-643T>C) was screened using quantitative polymerase chain reaction (qPCR) with TaqMan probes. RANKL serum levels were measured by ELISA. RESULTS For rs9533155 (-693C>G), the polymorphic homozygous genotype frequencies (CC) were higher in the RA group (p = 0.006). Individuals carrying the risk genotype presented higher levels of serum RANKL. Carriers of the polymorphic homozygous genotype in the dominant model (CC vs. CG + GG) had an increased risk of developing RA (OR: 1.8, 95% CI 1.04 to 3.1). No association between rs9533156 (-643T>C) and the haplotypes with RA risk was observed. CONCLUSION The rs9533155 (-693C>G) genetic variant exhibits a potential role in RA risk. The studied population had no association with the rs9533156 (-643T>C) genetic variant.
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Affiliation(s)
- Nava-Valdivia Cesar Arturo
- Departamento de Microbiología y Patología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Gamez-Nava Jorge Ivan
- Programa de Doctorado en Farmacología, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
- Instituto de Terapéutica Experimental y Clínica, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Contreras-Haro Betsabe
- Unidad de Investigación Biomédica 02, UMAE, Hospital de Especialidades, Centro Médico Nacional de Occidente, IMSS, Guadalajara 44349, Mexico
- Departamento de Ciencias Biomédicas, Centro Universitario de Tonalá, Universidad de Guadalajara, Guadalajara 45400, Mexico
| | - Perez-Guerrero Edsaul Emilio
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Esparza-Guerrero Yussef
- Programa de Doctorado en Farmacología, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Rodriguez-Jimenez Norma Alejandra
- Instituto de Terapéutica Experimental y Clínica, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Gonzalez-Heredia Tonatiuh
- Unidad de Investigación Biomédica 02, UMAE, Hospital de Especialidades, Centro Médico Nacional de Occidente, IMSS, Guadalajara 44349, Mexico
| | - Villagomez-Vega Alejandra
- Departamento de Ciencias Biomédicas, Centro Universitario de Tonalá, Universidad de Guadalajara, Guadalajara 45400, Mexico
| | - Nuño-Arana Ismael
- Departamento de Ciencias Biomédicas, Centro Universitario de Tonalá, Universidad de Guadalajara, Guadalajara 45400, Mexico
| | - Totsuka-Sutto Sylvia Elena
- Instituto de Terapéutica Experimental y Clínica, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Ponce-Guarneros Juan Manuel
- Instituto de Terapéutica Experimental y Clínica, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Jacobo-Cuevas Heriberto
- Instituto de Terapéutica Experimental y Clínica, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Alvarez-Ayala Efren Gerardo
- Programa de Doctorado en Farmacología, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Gonzalez-Lopez Laura
- Programa de Doctorado en Farmacología, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
- Instituto de Terapéutica Experimental y Clínica, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Saldaña-Cruz Ana Miriam
- Instituto de Terapéutica Experimental y Clínica, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
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9
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Sugiharto S, Salmah S, Fauziah E, Ramadany S, Wajdiyah U, Achmad H. The potential calcium content of anchovy (Stolephorus sp.) on mandibular bone growth through osteoprotegerin expression analysis. J Oral Maxillofac Pathol 2024; 28:374-380. [PMID: 39670138 PMCID: PMC11633926 DOI: 10.4103/jomfp.jomfp_484_23] [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: 11/12/2023] [Revised: 08/08/2024] [Accepted: 08/12/2024] [Indexed: 12/14/2024] Open
Abstract
Background Anchovy (Stolephorus sp.) is a commonly used food ingredient due to its high calcium content, which supports craniofacial growth. Calcium stimulates the formation of osteoblasts, which produce osteoprotegerin (OPG). OPG binds to RANKL, blocking RANKL-RANK bonding and limiting osteoclast development. Objective The objective of this study was to analyze OPG expression in mandibular bones to assess the potential calcium content of anchovies. Methods Three groups of 27 male Wistar rats were created: control, anchovy, and milk. After 40 days, the rats were decapitated, and their mandibular bones were surgically extracted, decalcified, and prepared for microscopic examination. The results showed a significant difference in OPG expression of rat mandibles between control, anchovy, and milk groups (P < 0.05), as determined by one-way analysis of variance (ANOVA). Tukey's HSD test revealed a significant difference in the average quantity of rat mandibular OPG expression between the control group and each of the anchovy and milk groups, with probability values of 0.00 and 0.003 (P < 0.05), respectively. However, the average level of OPG expression in anchovy and milk groups did not differ significantly, as indicated by the probability value of 0.064 (P > 0.05). Conclusion The mandibular development increases after feeding anchovies compared to the control group. Anchovy is not statistically superior to milk in terms of increasing mandibular development. However, as a high-calcium food, anchovy is well-suited to support children's craniofacial development and growth.
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Affiliation(s)
- Sumintarti Sugiharto
- Department of Oral Medicine, Faculty of Dentistry, Hasanuddin University, Makassar, Indonesia
| | - Shelly Salmah
- Department of Histology, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| | - Eva Fauziah
- Department of Pediatric Dentistry, Faculty of Dentistry, University of Indonesia, Jakarta, Indonesia
| | - Sri Ramadany
- Department of Public Health, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| | - Ummi Wajdiyah
- Department of Pediatric Dentistry, Faculty of Dentistry, Hasanuddin University, Makassar, Indonesia
| | - Harun Achmad
- Department of Pediatric Dentistry, Faculty of Dentistry, Hasanuddin University, Makassar, Indonesia
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10
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Duarte PM, Gurgel BCDV, Miranda TS, Sardenberg J, Gu T, Aukhil I. Distinctive genes and signaling pathways associated with type 2 diabetes-related periodontitis: Preliminary study. PLoS One 2024; 19:e0296925. [PMID: 38241313 PMCID: PMC10798476 DOI: 10.1371/journal.pone.0296925] [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: 06/27/2023] [Accepted: 12/22/2023] [Indexed: 01/21/2024] Open
Abstract
The biological mechanisms underlying the pathogenesis of type 2 diabetes (T2DM)-related periodontitis remain unclear. This cross-sectional study evaluated the distinctive transcriptomic changes between tissues with periodontal health and with periodontitis in patients with T2DM. In this cross-sectional study, whole transcriptome sequencing was performed on gingival biopsies from non-periodontitis and periodontitis tissues from non-diabetic and diabetic patients. A differentially expressed gene (DEG) analysis and Ingenuity Pathway Analysis (IPA) assessed the genes and signaling pathways associated with T2DM-related periodontitis. Immunohistochemistry was performed to validate selected DEGs possibly involved in T2DM-related periodontitis. Four hundred and twenty and one thousand five hundred and sixty-three DEGs (fold change ≥ 2) were uniquely identified in the diseased tissues of non-diabetic and diabetic patients, respectively. The IPA predicted the activation of Phagosome Formation, Cardiac β-adrenergic, tRNA Splicing, and PI3K/AKT pathways. The IPA also predicted the inhibition of Cholesterol Biosynthesis, Adrenomedullin, and Inositol Phosphate Compounds pathways in T2DM-related periodontitis. Validation of DEGs confirmed changes in protein expression of PTPN2, PTPN13, DHCR24, PIK3R2, CALCRL, IL1RN, IL-6R and ITGA4 in diseased tissues in diabetic subjects. Thus, these preliminary findings indicate that there are specific genes and functional pathways that may be involved in the pathogenesis of T2DM-related periodontitis.
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Affiliation(s)
- Poliana Mendes Duarte
- Department of Periodontology, University of Florida College of Dentistry, Gainesville, FL, United States of America
| | | | | | - Juliana Sardenberg
- Department of Periodontology, University of Florida College of Dentistry, Gainesville, FL, United States of America
| | - Tongjun Gu
- ICBR Bioinformatics, University of Florida, Gainesville, FL, United States of America
| | - Ikramuddin Aukhil
- ECU School of Dental Medicine, East Carolina University, Greenville, NC, United States of America
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11
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Harriott NC, Ryan AL. Proteomic profiling identifies biomarkers of COVID-19 severity. Heliyon 2024; 10:e23320. [PMID: 38163173 PMCID: PMC10755324 DOI: 10.1016/j.heliyon.2023.e23320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 11/27/2023] [Accepted: 11/30/2023] [Indexed: 01/03/2024] Open
Abstract
SARS-CoV-2 infection remains a major public health concern, particularly for the aged and those individuals with co-morbidities at risk for developing severe COVID-19. Understanding the pathogenesis and biomarkers associated with responses to SARS-CoV-2 infection remain critical components in developing effective therapeutic approaches, especially in cases of severe and long-COVID-19. In this study blood plasma protein expression was compared in subjects with mild, moderate, and severe COVID-19 disease. Evaluation of an inflammatory protein panel confirms upregulation of proteins including TNFβ, IL-6, IL-8, IL-12, already associated with severe cytokine storm and progression to severe COVID-19. Importantly, we identify several proteins not yet associated with COVID-19 disease, including mesothelin (MSLN), that are expressed at significantly higher levels in severe COVID-19 subjects. In addition, we find a subset of markers associated with T-cell and dendritic cell responses to viral infection that are significantly higher in mild cases and decrease in expression as severity of COVID-19 increases, suggesting that an immediate and effective activation of T-cells is critical in modulating disease progression. Together, our findings identify new targets for further investigation as therapeutic approaches for the treatment of SARS-CoV-2 infection and prevention of complications of severe COVID-19.
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Affiliation(s)
- Noa C. Harriott
- Hastings Center for Pulmonary Research, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Southern California, Los Angeles CA 90033, USA
- Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles CA 90033, USA
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City IA 52240, USA
| | - Amy L. Ryan
- Hastings Center for Pulmonary Research, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Southern California, Los Angeles CA 90033, USA
- Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles CA 90033, USA
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City IA 52240, USA
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12
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Chen HW, Chen CF, Lee PR, Yiin SJ, Liang JY, Hsu JL, Chang CI, Chern CL. 2,5-Dihydroxyacetophenone attenuates RANKL-mediated osteoclastogenesis by affecting the NFATc1 signaling pathway in vitro. Bioorg Med Chem Lett 2023; 96:129500. [PMID: 39491119 DOI: 10.1016/j.bmcl.2023.129500] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/03/2023] [Accepted: 10/04/2023] [Indexed: 11/05/2024]
Abstract
Excessive bone resorption activity of osteoclasts is a common characteristic of osteolytic conditions such as osteoporosis and inflammatory bone diseases. Natural compounds with antiosteoclastogenic function seem to be beneficial for the treatment of osteolytic diseases. In this study, we evaluated the effects of 2,5-dihydroxyacetophenone (DHAP), a phenolic compound in Ganoderma bambusicola, on osteoclastogenesis induced in vitro by the receptor activator of nuclear factor-κB ligand (RANKL). DHAP inhibited the differentiation, actin ring formation, and bone resorption activity of osteoclasts. In particular, DHAP inhibited the transcriptional activity of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) during osteoclastogenesis. This inhibition resulted in reduced expression levels of cathepsin k (Ctsk), tartrate-resistant acid phosphatase (Trap), and NFATc1 (Nfatc1), thereby reducing the differentiation of osteoclasts. However, DHAP did not affect reactive oxygen species production or activator protein 1 (AP-1) and nuclear factor kappa B (NF-κB) signaling. Our findings suggest that DHAP inhibits RANKL-induced osteoclastogenesis by inhibiting the NFATc1 signaling pathway.
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Affiliation(s)
- Hai-Wei Chen
- Department of Orthopedic Surgery, Fooyin University Hospital, Pingtung 92849, Taiwan; Department of Medical Laboratory Sciences and Biotechnology, Fooyin University, Kaohsiung 83102, Taiwan
| | - Chi-Fen Chen
- Department of Laboratory Medicine, Yuan's General Hospital, Kaohsiung 80249, Taiwan
| | - Pei-Rong Lee
- Department of Medical Laboratory Sciences and Biotechnology, Fooyin University, Kaohsiung 83102, Taiwan; Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan
| | - Shuenn-Jium Yiin
- Department of Nursing, National Tainan Junior College of Nursing, Tainan 70043, Taiwan
| | - Jia-Yun Liang
- Department of Medical Laboratory Sciences and Biotechnology, Fooyin University, Kaohsiung 83102, Taiwan
| | - Jue-Liang Hsu
- Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
| | - Chi-I Chang
- Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan.
| | - Chi-Liang Chern
- Department of Medical Laboratory Sciences and Biotechnology, Fooyin University, Kaohsiung 83102, Taiwan.
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13
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Jayash SN, Hamoudi D, Stephen LA, Argaw A, Huesa C, Joseph S, Wong SC, Frenette J, Farquharson C. Anti-RANKL Therapy Prevents Glucocorticoid-Induced Bone Loss and Promotes Muscle Function in a Mouse Model of Duchenne Muscular Dystrophy. Calcif Tissue Int 2023; 113:449-468. [PMID: 37470794 PMCID: PMC10516841 DOI: 10.1007/s00223-023-01116-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 07/12/2023] [Indexed: 07/21/2023]
Abstract
Bisphosphonates prevent bone loss in glucocorticoid (GC)-treated boys with Duchenne muscular dystrophy (DMD) and are recommended as standard of care. Targeting receptor activator of nuclear factor kappa-B ligand (RANKL) may have advantages in DMD by ameliorating dystrophic skeletal muscle function in addition to their bone anti-resorptive properties. However, the potential effects of anti-RANKL treatment upon discontinuation in GC-induced animal models of DMD are unknown and need further investigation prior to exploration in the clinical research setting. In the first study, the effects of anti-RANKL and deflazacort (DFZ) on dystrophic skeletal muscle function and bone microstructure were assessed in mdx mice treated with DFZ or anti-RANKL, or both for 8 weeks. Anti-RANKL and DFZ improved grip force performance of mdx mice but an additive effect was not noted. However, anti-RANKL but not DFZ improved ex vivo contractile properties of dystrophic muscles. This functional improvement was associated with a reduction in muscle damage and fibrosis, and inflammatory cell number. Anti-RANKL treatment, with or without DFZ, also improved trabecular bone structure of mdx mice. In a second study, intravenous zoledronate (Zol) administration (1 or 2 doses) following 2 months of discontinuation of anti-RANKL treatment was mostly required to record an improvement in bone microarchitecture and biomechanical properties in DFZ-treated mdx mice. In conclusion, the ability of anti-RANKL therapy to restore muscle function has profound implications for DMD patients as it offers the possibility of improving skeletal muscle function without the steroid-related skeletal side effects.
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Affiliation(s)
- Soher Nagi Jayash
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG UK
| | - Dounia Hamoudi
- Centre de Recherche du Centre Hospitalier, Universitaire de Québec-Centre, Hospitalier de L’Université Laval, Université Laval, Quebec City, QC Canada
| | - Louise A. Stephen
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG UK
| | - Anteneh Argaw
- Centre de Recherche du Centre Hospitalier, Universitaire de Québec-Centre, Hospitalier de L’Université Laval, Université Laval, Quebec City, QC Canada
| | - Carmen Huesa
- School of Infection and Immunity, University of Glasgow, Glasgow, UK
| | - Shuko Joseph
- Royal Hospital for Children Glasgow, School of Medicine, Dentistry and Nursing, Child Health, Queen Elizabeth University Hospital, Glasgow, UK
| | - Sze Choong Wong
- University of Glasgow/Royal Hospital for Children Glasgow, School of Medicine, Dentistry & Nursing, Child Health, Queen Elizabeth University Hospital, Glasgow, UK
| | - Jérôme Frenette
- Centre de Recherche du Centre Hospitalier, Universitaire de Québec-Centre, Hospitalier de L’Université Laval, Université Laval, Quebec City, QC Canada
| | - Colin Farquharson
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG UK
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14
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Grabarczyk M, Ksiazek-Winiarek D, Glabinski A, Szpakowski P. Dietary Polyphenols Decrease Chemokine Release by Human Primary Astrocytes Responding to Pro-Inflammatory Cytokines. Pharmaceutics 2023; 15:2294. [PMID: 37765263 PMCID: PMC10537369 DOI: 10.3390/pharmaceutics15092294] [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: 06/21/2023] [Revised: 08/26/2023] [Accepted: 09/01/2023] [Indexed: 09/29/2023] Open
Abstract
Astrocytes are considered to be the dominant cell fraction of the central nervous system. They play a supportive and protective role towards neurons, and regulate inflammatory processes; they thus make suitable targets for drugs and supplements, such as polyphenolic compounds. However, due to their wide range, knowledge of their anti-inflammatory potential remains relatively incomplete. The aim of this study was therefore to determine whether myricetin and chrysin are able to decrease chemokine release in reactive astrocytes. To assess the antioxidant and anti-inflammatory potential of polyphenols, human primary astrocytes were cultured in the presence of a reactive and neurotoxic astrocyte-inducing cytokine mixture (TNF-α, IL-1a, C1q), either alone or in the presence of myricetin or chrysin. The examined polyphenols were able to modify the secretion of chemokines by human cortical astrocytes, especially CCL5 (chrysin), CCL1 (myricetin) and CCL2 (both), while cell viability was not affected. Surprisingly, the compounds did not demonstrate any antioxidant properties in the astrocyte cultures.
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15
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Ismail OM, El-Omar OM, Said UN. Exploring the Role of Urocortin in Osteoporosis. Cureus 2023; 15:e38978. [PMID: 37313093 PMCID: PMC10259878 DOI: 10.7759/cureus.38978] [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] [Accepted: 05/13/2023] [Indexed: 06/15/2023] Open
Abstract
Osteoporosis is a debilitating disease that affects over 200 million people worldwide. Overactive osteoclast activity leads to micro-architectural defects and low bone mass. This culminates in fragility fractures, such as femoral neck fractures. Treatments currently available either are not completely effective or have considerable side effects; thus, there is a need for more effective treatments. The urocortin (Ucn) family, composed of urocortin 1 (Ucn1), urocortin 2 (Ucn2), urocortin 3 (Ucn3), corticotropin-releasing factor (CRF) and corticotropin-releasing factor-binding protein (CRF-BP), exerts a wide range of effects throughout the body. Ucn1 has been shown to inhibit murine osteoclast activity. This review article will aim to bridge the gap between existing knowledge of Ucn and whether it can affect human osteoclasts.
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Affiliation(s)
- Omar M Ismail
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, GBR
| | - Omar M El-Omar
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, GBR
| | - Umar N Said
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, GBR
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16
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Onji M, Penninger JM. RANKL and RANK in Cancer Therapy. Physiology (Bethesda) 2023; 38:0. [PMID: 36473204 DOI: 10.1152/physiol.00020.2022] [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: 12/12/2022] Open
Abstract
Receptor activator of nuclear factor-κB (RANK) and its ligand (RANKL) are key regulators of mammalian physiology such as bone metabolism, immune tolerance and antitumor immunity, and mammary gland biology. Here, we explore the multiple functions of RANKL/RANK in physiology and pathophysiology and discuss underlying principles and strategies to modulate the RANKL/RANK pathway as a therapeutic target in immune-mediated cancer treatment.
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Affiliation(s)
- Masahiro Onji
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences, VBC-Vienna BioCenter, Vienna, Austria
| | - Josef M Penninger
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences, VBC-Vienna BioCenter, Vienna, Austria.,Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
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17
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Euxanthone Suppresses the Proliferation, Migration and Invasion of Human Medulloblastoma Cells by Inhibiting the RANK/RANKL Pathway. Pharmacogn Mag 2023. [DOI: 10.1177/09731296221138649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2023] Open
Abstract
Background: Euxanthone is a plant-based flavonoid that is mostly isolated from a Chinese medicinal plant, Polygala caudate. This study was designed to evaluate the anticancer effects of euxanthone against human medulloblastoma cells. Materials and Methods: Cell viability was evaluated by CCK-8 and EdU assays. Apoptotic cell percentage was determined by annexin V/PI assay. The mRNA expression was determined by qRT-PCR. Wound healing and transwell assays were used to assess cell migration and invasion. Results: The results revealed aberrant activation of RANK/RANKL pathway in human medulloblastoma tissues and cell lines. Euxanthone suppressed the proliferation of the D425 medulloblastoma cells with comparatively lower cytotoxic effects against the normal human cerebellar granule cells. The IC50 of euxanthone against the D425 cells was found to be 10 µM. Interestingly, silencing of receptor activator of nuclear factor kβ (RANK) could also suppress the proliferation of the D425 cells via induction of apoptosis. Nonetheless, overexpression of RANK could abolish the cytotoxic effects of euxanthone on the D425 cells. Finally, wound-heal and transwell assay showed that euxanthone suppressed the migration and invasion of the D425 medulloblastoma cells. Conclusion: Collectively, the results revealed the anticancer effects of euxanthone against human medulloblastoma cells via RANK/RANKL pathway. These results suggest the potential of euxanthone as a lead molecule in the development of chemotherapy for medulloblastoma.
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18
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Fávaro WJ, Alonso JCC, de Souza BR, Reis IB, Gonçalves JM, Deckmann AC, Oliveira G, Dias QC, Durán N. New synthetic nano-immunotherapy (OncoTherad®) for non-muscle invasive bladder cancer: Its synthesis, characterization and anticancer property. Tissue Cell 2023; 80:101988. [PMID: 36521234 DOI: 10.1016/j.tice.2022.101988] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 11/16/2022] [Accepted: 11/23/2022] [Indexed: 12/12/2022]
Abstract
Bacillus Calmette-Guérin (BCG)-based intravesical immunotherapy has been applied as gold standard treatment for high-risk non-muscle invasive bladder cancer (NMIBC) for almost half a century. However, several patients with high-risk disease experience relapse, including those whose condition has worsened and who failed to respond to BCG. Non-significant therapeutic options have been developed for these at-risk patients, for many years. Immunotherapies have shown promising outcomes for bladder cancer treatment. Accordingly, our research group developed the OncoTherad® (MRB-CFI-1) immunotherapy, which has shown positive outcomes in NMIBC treatment. The aim of the current study is to describe, in details, the physicochemical features and potential action mechanisms of OncoTherad® nano-immunotherapy, based on toll-like receptor 4 (TLR4)-mediated interferon and on RANK/RANKL signaling pathways, in animal model with NMIBC. Based on the current findings, OncoTherad® nano-immunotherapy did not have genotoxic effect on the investigated model and did not show signs of limiting local and/or systemic toxicity at therapeutic doses. OncoTherad® nano-immunotherapy was more effective than the BCG treatment, since it reduced by 70% the malignancy rate. Furthermore, it was possible identifying an important action mechanism of OncoTherad®, which was based on the modulation of TLR4-mediated interferon and RANK/RANKL signaling pathways that, altogether, were essential to reduce malignancy rate. OncoTherad® mechanisms in these pathways helped preventing tumor recurrence.
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Affiliation(s)
- W J Fávaro
- Laboratory of Urogenital Carcinogenesis and Immunotherapy (LCURGIN), University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
| | - J C C Alonso
- Laboratory of Urogenital Carcinogenesis and Immunotherapy (LCURGIN), University of Campinas (UNICAMP), Campinas, São Paulo, Brazil; Paulínia Municipal Hospital, Paulínia, São Paulo, Brazil
| | - B R de Souza
- Laboratory of Urogenital Carcinogenesis and Immunotherapy (LCURGIN), University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - I B Reis
- Laboratory of Urogenital Carcinogenesis and Immunotherapy (LCURGIN), University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - J M Gonçalves
- Laboratory of Urogenital Carcinogenesis and Immunotherapy (LCURGIN), University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - A C Deckmann
- Laboratory of Urogenital Carcinogenesis and Immunotherapy (LCURGIN), University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - G Oliveira
- Laboratory of Urogenital Carcinogenesis and Immunotherapy (LCURGIN), University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Q C Dias
- Laboratory of Urogenital Carcinogenesis and Immunotherapy (LCURGIN), University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - N Durán
- Laboratory of Urogenital Carcinogenesis and Immunotherapy (LCURGIN), University of Campinas (UNICAMP), Campinas, São Paulo, Brazil; Nanomedicine Research Unit (Nanomed), Federal University of ABC (UFABC), Santo André, São Paulo, Brazil.
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19
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Choi H, Yang L, Liu Y, Jeong JK, Cho ES. Inactivation of Sufu in cementoblasts accelerates external tooth root resorption. J Cell Physiol 2023; 238:447-458. [PMID: 36598878 DOI: 10.1002/jcp.30943] [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: 09/28/2022] [Revised: 12/20/2022] [Accepted: 12/24/2022] [Indexed: 01/05/2023]
Abstract
Cementum has been empirically regarded as an antiresorptive barrier against tooth roots. However, little is known about the factors of homeostasis and resistant mechanisms of tooth roots against resorption. Here, we investigated cementum factors and their interaction against resorption using transgenic mice exhibiting external cervical root resorption (ECRR). Ectopically thickened cervical cementum caused by functional inactivation of ectonucleotide pyrophosphotase/phosphodiesterase 1 (Enpp1) was susceptible to ECRR with aging. In addition, the inactivation of the suppressor of fused (Sufu), a Hedgehog signaling inhibitor, in cementoblasts led to ECRR. Interestingly, concurrent inactivation of Sufu and Enpp1 in cementoblasts remarkably exacerbated ECRR with higher Rankl expression. Cellular and molecular analyses using cementoblasts and bone marrow-derived macrophages indicated that Dickkopf-related protein 1 (Dkk1) induced by the inactivation of Sufu in cementoblasts has roles in the acceleration of ECRR triggered by Enpp1 inactivation. Using compound mutant mice for concurrent Wntless and Enpp1 inactivation, this synergistic cooperation of Dkk1 and Npp1 for resorption found in double mutant Sufu and Enpp1 mice was confirmed by the reproduction of amplified ECRR. On the basis of these findings, we conclude that proper Npp1 function and sustained Wnt activity in the cervical cementum are essential for the homeostasis of tooth roots against resorption in a physiological state.
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Affiliation(s)
- Hwajung Choi
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Jeonbuk National University School of Dentistry, Jeonju, South Korea
| | - Liu Yang
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Jeonbuk National University School of Dentistry, Jeonju, South Korea
| | - Yudong Liu
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Jeonbuk National University School of Dentistry, Jeonju, South Korea
| | - Ju-Kyung Jeong
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Jeonbuk National University School of Dentistry, Jeonju, South Korea
| | - Eui-Sic Cho
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, Jeonbuk National University School of Dentistry, Jeonju, South Korea
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20
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Bone Metastasis of Breast Cancer: Molecular Mechanisms and Therapeutic Strategies. Cancers (Basel) 2022; 14:cancers14235727. [PMID: 36497209 PMCID: PMC9738274 DOI: 10.3390/cancers14235727] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/07/2022] [Accepted: 11/17/2022] [Indexed: 11/24/2022] Open
Abstract
Bone metastasis is a common complication of many types of advanced cancer, including breast cancer. Bone metastasis may cause severe pain, fractures, and hypercalcemia, rendering clinical management challenging and substantially reducing the quality of life and overall survival (OS) time of breast cancer patients. Studies have revealed that bone metastasis is related to interactions between tumor cells and the bone microenvironment, and involves complex molecular biological mechanisms, including colonization, osteolytic destruction, and an immunosuppressive bone microenvironment. Agents inhibiting bone metastasis (such as bisphosphate and denosumab) alleviate bone destruction and improve the quality of life of breast cancer patients with bone metastasis. However, the prognosis of these patients remains poor, and the specific biological mechanism of bone metastasis is incompletely understood. Additional basic and clinical studies are urgently needed, to further explore the mechanism of bone metastasis and develop new therapeutic drugs. This review presents a summary of the molecular mechanisms and therapeutic strategies of bone metastasis of breast cancer, aiming to improve the quality of life and prognosis of breast cancer patients and provide a reference for future research directions.
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Lorencetti-Silva F, Arnez MFM, Thomé JPDQ, de Carvalho MS, de Carvalho FK, de Queiroz AM, Faccioli LH, Paula-Silva FWG. Leukotriene B4 Loaded in Microspheres Inhibits Osteoclast Differentiation and Activation. Braz Dent J 2022; 33:35-45. [PMID: 36287497 PMCID: PMC9645171 DOI: 10.1590/0103-6440202204827] [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: 09/14/2021] [Accepted: 07/28/2022] [Indexed: 11/23/2022] Open
Abstract
To investigate osteoclast formation in vivo and if leukotriene B4 (LTB4) loaded in microspheres (MS) could be used as a therapeutical strategy to promote a sustained delivery of the mediator and prevent osteoclast differentiation. Methods: In vivo, apical periodontitis was induced in mice to investigate osteoclast differentiation and signaling in absence of 5-lipoxygenase (5-LO). In vitro, LTB4-MS were prepared using an oil-in-water emulsion solvent extraction-evaporation process. Characterization and efficiency of LTB4 encapsulation were investigated. J774A.1 macrophages were cultured in the presence of monocyte colony-stimulating factor (M-CSF) and ligand for receptor activator of nuclear factor kappa B (RANKL) and then stimulated with LTB4-MS. Cytotoxicity, in vitro MS-LTB4 uptake, osteoclast formation and gene expression were measured. Results: We found that 5-LO negatively regulates osteoclastic formation in vivo during apical periodontitis development. In vitro, LTB4-MS were up-taken by macrophages and were not cytotoxic to the cells. LTB4-MS inhibited osteoclast formation and the synthesis of osteoclastogenic genes Acp5, Mmp9, Calcr and Ctsk. LTB4-MS inhibited differentiation of macrophages into an osteoclastic phenotype and cell activation under M-CSF and RANKL stimulus.
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Affiliation(s)
- Francine Lorencetti-Silva
- Departamento de Clínica Infantil, Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil., Universidade de Rio Verde, Rio Verde, Goiás, Brasil
| | - Maya Fernanda Manfrin Arnez
- Departamento de Clínica Infantil, Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil
| | - João Pedro de Queiroz Thomé
- Departamento de Clínica Infantil, Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil., Faculdade de Ciências da Saúde de Barretos Dr. Paulo Prata, Barretos, SP, Brazil
| | - Marcio Santos de Carvalho
- Departamento de Clínica Infantil, Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil
| | - Fabrício Kitazono de Carvalho
- Departamento de Clínica Infantil, Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil
| | - Alexandra Mussolino de Queiroz
- Departamento de Clínica Infantil, Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil
| | - Lúcia Helena Faccioli
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas da Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Francisco Wanderley Garcia Paula-Silva
- Departamento de Clínica Infantil, Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil.,Departamento de Análises Clínicas, Toxicológicas e Bromatológicas da Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
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22
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Wang R, Zhang W, Ma H, Zou D, Zhang Z, Wang S. Structural insights into the binding of zoledronic acid with RANKL via computational simulations. Front Mol Biosci 2022; 9:992473. [PMID: 36200071 PMCID: PMC9527314 DOI: 10.3389/fmolb.2022.992473] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 09/05/2022] [Indexed: 12/03/2022] Open
Abstract
Zoledronic acid (ZOL) inhibits receptor activator of nuclear factor-κB ligand (RANKL) and reduces bone turnover. This plays an important role in the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Previous reports have shown that ZOL binds to the enzyme farnesyl pyrophosphate synthase (FPPS) to block its activity. However, the mechanism of action of ZOL and its interaction with RANKL is still unclear. In this study, we confirmed that ZOL significantly suppressed the bone remodeling in ZOL-treated rats, investigated whether ZOL could bind to RANKL and examined the interactions between these molecules at the atomic level. Surface plasmon resonance (SPR) assay was performed to validate that ZOL could directly bind to RANKL in a dose dependent manner, and the equilibrium constant was calculated (KD = 2.28 × 10−4 M). Then, we used molecular docking simulation to predict the binding site and analyze the binding characteristics of ZOL and RANKL. Through molecular dynamics simulation, we confirmed the stable binding between ZOL and RANKL and observed their dynamic interactions over time. Binding free energy calculations and its decomposition were conducted to obtain the binding free energy −70.67 ± 2.62 kJ/mol for the RANKL–ZOL complex. We identified the key residues of RANKL in the binding region, and these included Tyr217(A), Val277(A), Gly278(A), Val277(B), Gly278(B), and Tyr215(C). Taken together, our results demonstrated the direct interaction between ZOL and RANKL, indicating that the pharmacological action of ZOL might be closely related to RANKL. The design of novel small molecules targeting RANKL might reduce the occurrence of BRONJ.
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Affiliation(s)
- Ruijie Wang
- Department of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Research Unit of Oral and Maxillofacial Regenerative Medicine, National Center for Stomatology, National Clinical Research Center for Oral Diseases, College of Stomatology, Chinese Academy of Medical Sciences, Shanghai Jiao Tong University, Shanghai, China
| | - Wenjie Zhang
- Shanghai Key Laboratory of Stomatology, Research Unit of Oral and Maxillofacial Regenerative Medicine, National Center for Stomatology, National Clinical Research Center for Oral Diseases, College of Stomatology, Chinese Academy of Medical Sciences, Shanghai Jiao Tong University, Shanghai, China
- Department of Prosthodontics, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hailong Ma
- Shanghai Key Laboratory of Stomatology, Research Unit of Oral and Maxillofacial Regenerative Medicine, National Center for Stomatology, National Clinical Research Center for Oral Diseases, College of Stomatology, Chinese Academy of Medical Sciences, Shanghai Jiao Tong University, Shanghai, China
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Duohong Zou
- Department of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Research Unit of Oral and Maxillofacial Regenerative Medicine, National Center for Stomatology, National Clinical Research Center for Oral Diseases, College of Stomatology, Chinese Academy of Medical Sciences, Shanghai Jiao Tong University, Shanghai, China
| | - Zhiyuan Zhang
- Shanghai Key Laboratory of Stomatology, Research Unit of Oral and Maxillofacial Regenerative Medicine, National Center for Stomatology, National Clinical Research Center for Oral Diseases, College of Stomatology, Chinese Academy of Medical Sciences, Shanghai Jiao Tong University, Shanghai, China
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Zhiyuan Zhang, ; Shaoyi Wang,
| | - Shaoyi Wang
- Department of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Research Unit of Oral and Maxillofacial Regenerative Medicine, National Center for Stomatology, National Clinical Research Center for Oral Diseases, College of Stomatology, Chinese Academy of Medical Sciences, Shanghai Jiao Tong University, Shanghai, China
- *Correspondence: Zhiyuan Zhang, ; Shaoyi Wang,
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23
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Yang M, Wang F, Lu G, Cheng M, Zhao W, Zou C. Single-cell transcriptome analysis reveals T-cell exhaustion in denosumab-treated giant cell tumor of bone. Front Immunol 2022; 13:934078. [PMID: 36172351 PMCID: PMC9510370 DOI: 10.3389/fimmu.2022.934078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/19/2022] [Indexed: 12/05/2022] Open
Abstract
Denosumab (DMAB), a human monoclonal antibody against the receptor activator of the nuclear factor-kappa B ligand, is used for the treatment for unresectable giant cell tumor of bone (GCTB). However, little is known about the molecular and functional characteristics of GCTB-infiltrating lymphocytes after DMAB treatment. Here, we performed single-cell RNA sequencing and immunostaining assays to delineate the immune landscape of GCTB in the presence and absence of DMAB. We found that exhausted CD8+ T cells were preferentially enriched in DMAB-treated GCTB. A distinct M2-skewed type of tumor-associated macrophages (TAMs) comprises the majority of GCTB TAMs. We identified cytokines, including interleukin-10, and inhibitory receptors of M2 TAMs as important mediators of CD8+ T cell exhaustion. We further revealed that DMAB treatment notably increased the expression levels of periostin (POSTN) in GCTB cells. Furthermore, POSTN expression was transcriptionally regulated by c-FOS signaling and correlated with GCTB recurrence in patients after DMAB treatment. Collectively, our findings reveal that CD8+ T-cells undergo unappreciated exhaustion during DMAB therapy and that GCTB cell-derived POSTN educates TAMs and establishes a microenvironmental niche that facilitates GCTB recurrence.
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Affiliation(s)
- Meiling Yang
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Fen Wang
- Pathologica Department, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Guohao Lu
- Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-Sen University), Ministry of Education, Guangzhou, China
| | - Mingzhe Cheng
- Musculoskeletal Oncology Department, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Wei Zhao
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-Sen University), Ministry of Education, Guangzhou, China
- *Correspondence: Wei Zhao, ; Changye Zou,
| | - Changye Zou
- Musculoskeletal Oncology Department, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- *Correspondence: Wei Zhao, ; Changye Zou,
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Eichberger J, Weber F, Spanier G, Gerken M, Schreml S, Schulz D, Fiedler M, Ludwig N, Bauer RJ, Reichert TE, Ettl T. Loss of MMP-27 Predicts Mandibular Bone Invasion in Oral Squamous Cell Carcinoma. Cancers (Basel) 2022; 14:cancers14164044. [PMID: 36011038 PMCID: PMC9406335 DOI: 10.3390/cancers14164044] [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: 07/21/2022] [Revised: 08/13/2022] [Accepted: 08/17/2022] [Indexed: 12/24/2022] Open
Abstract
Simple Summary The growth of oral squamous cell carcinoma into the mandible poses significant challenges to head and neck surgery. The resulting need for extensive procedures has a decisive influence on subsequent esthetics and function and therefore also on the patient’s quality of life. The molecular mechanism behind this remains obscure to date. Hence, we investigated the influence of MMP-27, Osteoprotegerin and RANKL, three proteins with importance in bone remodeling. The results showed that tumors exhibited less bone-invasive behavior in the presence of MMP-27. This may be an incentive for further studies to elucidate the molecular mechanisms of mandibular bone invasion in OSCC. Abstract Invasion of the mandibular bone is frequent in oral squamous cell carcinoma (OSCC), which often results in extensive ablative and reconstructive procedures for the patient. The purpose of this single-center, retrospective study was to identify and evaluate potential biomarkers and risk factors for bone invasion in OSCC. Initially, in silico gene expression analysis was performed for different HNSCC tumor T-stages to find factors associated with invasive (T4a) tumor growth. Afterwards, the protein expression of bone-metabolizing MMP-27, TNFRSF11B (Osteoprotegerin, OPG), and TNFSF11 (RANKL) was investigated via Tissue Microarrays (TMAs) for their impact on mandibular bone invasion. TMAs were assembled from the bone–tumor interface of primary OSCCs of the floor of the mouth and gingiva from 119 patients. Sixty-four carcinomas with patho-histological jaw invasion (pT4a) were compared to 55 carcinomas growing along the mandible without invasion (pT2, pT3). Tissue samples were additionally evaluated for patterns of invasion using the WPOI grading system. Statistical analysis of in silico data revealed decreased MMP-27 mRNA expression to be strongly associated with the pT4a-stage in OSCC, indicating invasive tumor growth with infiltration of adjacent anatomical structures. Our own clinico-pathological data on OSCCs presented a significant decrease of MMP-27 in tumors invading the nearby mandible (pT4a), compared to pT2 and pT3 tumors without bone invasion. Loss of MMP27 evolved as the strongest predictor of mandibular bone invasion in binary logistic regression analysis. To our knowledge, this is the first study investigating the role of MMP-27 expression in OSCC and demonstrating the importance of the loss of MMP-27 in mandibular bone invasion.
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Affiliation(s)
- Jonas Eichberger
- Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, 93053 Regensburg, Germany
- Department of Oral and Maxillofacial Surgery and Center for Medical Biotechnology, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Florian Weber
- Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany
| | - Gerrit Spanier
- Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Michael Gerken
- Tumor Center Regensburg, Institute for Quality Assurance and Health Services Research, University of Regensburg, 93053 Regensburg, Germany
| | - Stephan Schreml
- Department of Dermatology, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Daniela Schulz
- Department of Oral and Maxillofacial Surgery and Center for Medical Biotechnology, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Mathias Fiedler
- Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, 93053 Regensburg, Germany
- Department of Oral and Maxillofacial Surgery and Center for Medical Biotechnology, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Nils Ludwig
- Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, 93053 Regensburg, Germany
- Department of Oral and Maxillofacial Surgery and Center for Medical Biotechnology, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Richard Josef Bauer
- Department of Oral and Maxillofacial Surgery and Center for Medical Biotechnology, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Torsten Eugen Reichert
- Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Tobias Ettl
- Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, 93053 Regensburg, Germany
- Correspondence:
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25
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Weng W, Li H, Zhu S. An Overlooked Bone Metabolic Disorder: Cigarette Smoking-Induced Osteoporosis. Genes (Basel) 2022; 13:genes13050806. [PMID: 35627191 PMCID: PMC9141076 DOI: 10.3390/genes13050806] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 12/19/2022] Open
Abstract
Cigarette smoking (CS) leads to significant bone loss, which is recognized as an independent risk factor for osteoporosis. The number of smokers is continuously increasing due to the addictive nature of smoking. Therefore it is of great value to effectively prevent CS-induced osteoporosis. However, there are currently no effective interventions to specifically counteract CS-induced osteoporosis, owing to the fact that the specific mechanisms by which CS affects bone metabolism are still elusive. This review summarizes the latest research findings of important pathways between CS exposure and bone metabolism, with the aim of providing new targets and ideas for the prevention of CS-induced osteoporosis, as well as providing theoretical directions for further research in the future.
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Affiliation(s)
- Weidong Weng
- Department of Trauma and Reconstructive Surgery, BG Trauma Clinic, Siegfried Weller Institute for Trauma Research, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany;
| | - Hongming Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, China;
| | - Sheng Zhu
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, China;
- Correspondence:
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26
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Kuo CH, Zhang BH, Huang SE, Hsu JH, Wang YH, Nguyen TTN, Lai CH, Yeh JL. Xanthine Derivative KMUP-1 Attenuates Experimental Periodontitis by Reducing Osteoclast Differentiation and Inflammation. Front Pharmacol 2022; 13:821492. [PMID: 35571109 PMCID: PMC9097136 DOI: 10.3389/fphar.2022.821492] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 03/21/2022] [Indexed: 11/24/2022] Open
Abstract
Periodontitis is an inflammatory disease of gum that may predispose to serious systemic complications such as diabetes and cardiovascular diseases. Activation of macrophages and osteoclasts around periodontal tissue can accelerate gum inflammation. In addition, alteration of cyclic nucleotide levels is associated with the severity of periodontitis. Our previous study has shown that KMUP-1, a xanthine derivative exhibiting phosphodiesterase inhibition and soluble guanylyl cyclase activation, can inhibit lipopolysaccharide (LPS)-induced inflammation and receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced osteoclastogenesis. This study was aimed to investigate whether KMUP-1 could attenuate periodontitis both in vitro and in vivo. In vitro, the protective effect of KMUP-1 on inflammation and osteoclastogenesis was investigated in RANKL-primed RAW264.7 cells treated by Porphyromonas gingivalis LPS (PgLPS). The results showed that KMUP-1 attenuated PgLPS-induced osteoclast differentiation as demonstrated by decreased TRAP-positive multinuclear cells and TRAP activity. This reduction of osteoclast differentiation by KMUP-1 was reversed by KT5823, a protein kinase G inhibitor. Similarly, pro-inflammatory cytokine levels induced by PgLPS were inhibited by KMUP-1 in a dose-dependent manner whereas reversed by KT5823. Mechanistically, suppression of MAPKs, PI3K/Akt, and NF-κB signaling pathways and decrease of c-Fos and NFATc1 expression in osteoclast precursors by KMUP-1 may mediate its protective effect. In vivo, two models of periodontitis in rats were induced by gingival injections of PgLPS and ligature placement around molar teeth, respectively. Our results showed that KMUP-1 inhibited alveolar bone loss in both rat models, and this effect mediated at least partly by reduced osteoclastogenesis. In conclusion, our study demonstrated the therapeutic potential of KMUP-1 on periodontitis through suppression of inflammation and osteoclast differentiation.
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Affiliation(s)
- Cheng-Hsiang Kuo
- International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
| | - Ban-Hua Zhang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shang-En Huang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jong-Hau Hsu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Pediatrics, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yan-Hsiung Wang
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Thi Tuyet Ngan Nguyen
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chao-Han Lai
- Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Jwu-Lai Yeh
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Pharmacology, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- *Correspondence: Jwu-Lai Yeh,
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27
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Li B, Wang P, Jiao J, Wei H, Xu W, Zhou P. Roles of the RANKL-RANK Axis in Immunity-Implications for Pathogenesis and Treatment of Bone Metastasis. Front Immunol 2022; 13:824117. [PMID: 35386705 PMCID: PMC8977491 DOI: 10.3389/fimmu.2022.824117] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 02/16/2022] [Indexed: 12/13/2022] Open
Abstract
A substantial amount patients with cancer will develop bone metastases, with 70% of metastatic prostate and breast cancer patients harboring bone metastasis. Despite advancements in systemic therapies for advanced cancer, survival remains poor for those with bone metastases. The interaction between bone cells and the immune system contributes to a better understanding of the role that the immune system plays in the bone metastasis of cancer. The immune and bone systems share various molecules, including transcription factors, signaling molecules, and membrane receptors, which can stimulate the differentiation and activation of bone-resorbing osteoclasts. The process of cancer metastasis to bone, which deregulates bone turnover and results in bone loss and skeletal-related events (SREs), is also controlled by primary cancer-related factors that modulate the intratumoral microenvironment as well as cellular immune process. The nuclear factor kappa B ligand (RANKL) and the receptor activator of nuclear factor kappa B (RANK) are key regulators of osteoclast development, bone metabolism, lymph node development, and T-cell/dendritic cell communication. RANKL is an osteoclastogenic cytokine that links the bone and the immune system. In this review, we highlight the role of RANKL and RANK in the immune microenvironment and bone metastases and review data on the role of the regulatory mechanism of immunity in bone metastases, which could be verified through clinical efficacy of RANKL inhibitors for cancer patients with bone metastases. With the discovery of the specific role of RANK signaling in osteoclastogenesis, the humanized monoclonal antibody against RANKL, such as denosumab, was available to prevent bone loss, SREs, and bone metastases, providing a unique opportunity to target RANKL/RANK as a future strategy to prevent bone metastases.
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Affiliation(s)
- Bo Li
- Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Pengru Wang
- Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jian Jiao
- Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Haifeng Wei
- Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Wei Xu
- Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Pingting Zhou
- Department of Radiation Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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28
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Pin F, Jones AJ, Huot JR, Narasimhan A, Zimmers TA, Bonewald LF, Bonetto A. RANKL Blockade Reduces Cachexia and Bone Loss Induced by Non-Metastatic Ovarian Cancer in Mice. J Bone Miner Res 2022; 37:381-396. [PMID: 34904285 PMCID: PMC8940654 DOI: 10.1002/jbmr.4480] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 11/18/2021] [Accepted: 11/20/2021] [Indexed: 12/13/2022]
Abstract
Tumor- and bone-derived soluble factors have been proposed to participate in the alterations of skeletal muscle size and function in cachexia. We previously showed that mice bearing ovarian cancer (OvCa) exhibit cachexia associated with marked bone loss, whereas bone-targeting agents, such as bisphosphonates, are able to preserve muscle mass in animals exposed to anticancer drugs. De-identified CT images and plasma samples from female patients affected with OvCa were used for body composition assessment and quantification of circulating cross-linked C-telopeptide type I (CTX-I) and receptor activator of NF-kB ligand (RANKL), respectively. Female mice bearing ES-2 tumors were used to characterize cancer- and RANKL-associated effects on muscle and bone. Murine C2C12 and human HSMM myotube cultures were used to determine the OvCa- and RANKL-dependent effects on myofiber size. To the extent of isolating new regulators of bone and muscle in cachexia, here we demonstrate that subjects affected with OvCa display evidence of cachexia and increased bone turnover. Similarly, mice carrying OvCa present high RANKL levels. By using in vitro and in vivo experimental models, we found that elevated circulating RANKL is sufficient to cause skeletal muscle atrophy and bone resorption, whereas bone preservation by means of antiresorptive and anti-RANKL treatments concurrently benefit muscle mass and function in cancer cachexia. Altogether, our data contribute to identifying RANKL as a novel therapeutic target for the treatment of musculoskeletal complications associated with RANKL-expressing non-metastatic cancers. © 2021 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Fabrizio Pin
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Alexander J Jones
- Department of Otolaryngology-Head & Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Joshua R Huot
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Ashok Narasimhan
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Teresa A Zimmers
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.,Department of Otolaryngology-Head & Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.,Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.,Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.,Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Lynda F Bonewald
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.,Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.,Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Andrea Bonetto
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.,Department of Otolaryngology-Head & Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.,Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.,Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.,Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA
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Jin X, Li Y, Yang Y, Shen H, Chen J, Xu B, Xu J. Thioacetamide promotes osteoclast transformation of bone marrow macrophages by influencing PI3K/AKT pathways. J Orthop Surg Res 2022; 17:53. [PMID: 35093114 PMCID: PMC8800259 DOI: 10.1186/s13018-022-02938-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 01/12/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Osteoclast cell increase is a major risk factor for osteoporosis and degenerative bone and joint diseases. At present, RANKL and M-CSF are commonly used to induce osteoclastogenesis. Thioacetamide (TAA) can lead to many types of liver and kidney damage, but less attention has been paid to the association of TAA with bone damage. In this work, we investigated the effects of TAA on the osteoclastogenesis and differentiation of bone marrow macrophages (BMMs).
Methods
BMMs of SD rat suckling mice were taken for primary culture. CCK-8 was used to detect the toxic effects of TAA on BMMs, and flow cytometry was used to detect the effects of TAA on the cell cycle, cell viability, apoptosis and intracytoplasmic Ca2+ concentration of BMMs. TRAP staining was used to detect the effect of RANKL and M-CSF and TAA on osteoclast differentiation of BMMs. Western Blot was used to detect the expression level of PI3K/AKT pathway and osteoclast-specific proteins (TRAP and cathepsin K).
Results
The results suggested that TAA inhibited the proliferation of BMMs, while enhancing osteoclastogenesis at 0.5 mg/mL and 1 mg/mL as assayed by TRAP staining. Exposed to TAA, BMMs could differentiate into osteoclast-like cells with overexpression of cathepsin K and TRAP proteins. Western blot results showed that TAA can activate the expression levels of P-PI3K, P-AKT, P-P38, and P-JNK, accompanied by apoptosis of BMMs and increase in intracellular Ca2+.
Conclusion
TAA may induce osteoclast formation in BMMs by activating the expression of PI3K/AKT pathway proteins, which is comparable to the classic osteoclast differentiation inducer RANKL and M-CSF. This suggests that we may find a cheap osteoclast inducer.
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30
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Li Y, Yang C, Jia K, Wang J, Wang J, Ming R, Xu T, Su X, Jing Y, Miao Y, Liu C, Lin N. Fengshi Qutong capsule ameliorates bone destruction of experimental rheumatoid arthritis by inhibiting osteoclastogenesis. JOURNAL OF ETHNOPHARMACOLOGY 2022; 282:114602. [PMID: 34492323 DOI: 10.1016/j.jep.2021.114602] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 09/01/2021] [Accepted: 09/02/2021] [Indexed: 05/28/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Bone destruction plays a key role in damaging the joint function of rheumatoid arthritis (RA). Fengshi Qutong capsule (FSQTC) consisting of 19 traditional Chinese medicines has been used for treating RA in China for many years. Preliminary studies show that FSQTC has analgesic activity and inhibits synovial angiogenesis of collagen-induced arthritis (CIA), but its role on bone destruction of RA is still unclear. AIM OF THE STUDY To explore the effect of FSQTC on bone destruction of RA and the possible mechanism of osteoclastogenesis in vivo and in vitro. MATERIALS AND METHODS LC-MS system was used to detect the quality control components of FSQTC. The anti-arthritic effect of FSQTC on CIA rats was evaluated by arthritis score, arthritis incidence and histopathology evaluation of inflamed joints. The effect of treatment with FSQTC on bone destruction of joint tissues was determined with X-ray and micro-CT quantification, and on bone resorption marker CTX-I and formation marker osteocalcin in sera were detected by ELISA. Then, osteoclast differentiation and mature were evaluated by TRAP staining, actin ring immunofluorescence and bone resorption assay both in joints and RANKL-induced RAW264.7 cells. In addition, RANKL, OPG, IL-1β and TNFα in sera were evaluated by ELISA. The molecular mechanisms of the inhibitions were elucidated by analyzing the protein and gene expression of osteoclastic markers CTSK, MMP-9 and β3-Integrin, transcriptional factors c-Fos and NFATc1, as well as phosphorylation of ERK1/2, JNK and P38 in joints and in RANKL-induced RAW264.7 cells using western blot and/or qPCR. RESULTS In this study, 12 major quality control components were identified. Our data showed that FSQTC significantly increased bone mineral density, volume fraction, trabecular thickness, and decreased trabecular separation of inflamed joints both at periarticular and extra-articular locations in CIA rats. FSQTC also diminished the level of CTX-I and simultaneously increased osteocalcin in sera of CIA rats. The effects were accompanied by reductions of osteoclast differentiation, bone resorption, and expression of osteoclastic markers (CTSK, MMP-9 and β3-Integrin) in joints. Interestingly, FSQTC treatment could reduce the protein level of RANKL, increase the expression of OPG, and decrease the ratio of RANKL to OPG in inflamed joints and sera of CIA rats. In addition, FSQTC inhibited the levels of pro-inflammatory cytokines implicated in bone resorption, such as IL-1β and TNFα in sera. When RAW264.7 cells were treated with RANKL, FSQTC inhibited the formation of TRAP + multinucleated cells, actin ring and the bone-resorbing activity in dose-dependent manners. Furthermore, FSQTC reduced the RANKL-induced expression of osteoclastic genes and proteins and transcriptional factors (c-Fos and NFATc1), as well as phosphorylation of mitogen-activated protein kinases (MAPKs). CONCLUSION FSQTC may inhibit bone destruction of RA by its anti-osteoclastogenic activity both in vivo and in vitro.
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Affiliation(s)
- Yiqun Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Chao Yang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Kexin Jia
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Jinxia Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Jingxia Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Ruirui Ming
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Tengteng Xu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Xiaohui Su
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Yu Jing
- Tonghua Golden-Horse Pharmaceutical Industry Co.,Ltd, Beijing, 100028, China
| | - Yandong Miao
- Tonghua Golden-Horse Pharmaceutical Industry Co.,Ltd, Beijing, 100028, China
| | - Chunfang Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Na Lin
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
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[Tumor necrosis factor-α promotes osteoclast differentiation via sialylation in mice]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2021; 41:1773-1779. [PMID: 35012907 PMCID: PMC8752434 DOI: 10.12122/j.issn.1673-4254.2021.12.03] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
OBJECTIVE To explore the mechanism through which tumor necrosis factor-α (TNF-α) promotes osteoclast differentiation. METHODS Bilateral knee joint samples were collected from 4-month-old wild-type mice and TNF-α transgenic mice for CT scan analysis, TRAP staining and sialic acid staining analysis. The osteoclast precursor (RAW264.7) cells were cultured for 3 days in induction medium in the presence of vehicle, TNF-α, or TNF-α and sialidase, and were then examined with RT-qPCR, TRAP staining, and sialic acid immunofluorescence co-localization staining. Bone marrow-derived macrophages isolated from the wild-type mice and TNF-α transgenic mouse and cultured in induction medium with or without the addition of sialidase, and TRAP and sialic acid staining was performed after 3 days of cell culture. RESULTS TRAP staining showed that the number of osteoclasts increased significantly in TNF-α transgenic mice as compared with the wild-type mice (P < 0.0001), and micro-CT analysis revealed significant reductions of BV/TV, Tb.N, and Tb.Th in TNF-α transgenic mice (P < 0.001). The osteoclasts in TNF-α transgenic mice also showed a significantly increased expression of sialic acid (P=0.004). In the cell experiment, RAW264.7 cells cultured with TNF-α showed a significantly higher expression of sialic acid (P < 0.0001) and a greater osteoclast formation rate (P=0.0007) than the the control cells, while the addition of sialidase significantly reduced sialic acid expression, osteoclast formation rate and TRAP mRNA level in TNF-α-treated cells (P < 0.0001). Similarly, in the bone marrow-derived macrophages, sialic acid expression and osteoclast formation rate were significantly increased by incubation with TNF-α (P < 0.0001), but the increments were obviously reduced by addition of sialidase in the medium (P < 0.0001). CONCLUSION TNF-α can promote the differentiation and activity of osteoclasts by increasing the sialylation level in the osteoclasts.
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Padala SR, Kashyap B, Dekker H, Mikkonen JJW, Palander A, Bravenboer N, Kullaa AM. Irradiation affects the structural, cellular and molecular components of jawbones. Int J Radiat Biol 2021; 98:136-147. [PMID: 34855558 DOI: 10.1080/09553002.2022.2013568] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE Emerging evidence shows that changes in the bone and its microenvironment following radiotherapy are associated with either an inhibition or a state of low bone formation. Ionizing radiation is damaging to the jawbone as it increases the complication rate due to the development of hypovascular, hypocellular, and hypoxic tissue. This review summarizes and correlates the current knowledge on the effects of irradiation on the bone with an emphasis on jawbone, as these have been a less extensively studied area. CONCLUSIONS The stringent regulation of bone formation and bone resorption can be influenced by radiation, causing detrimental effects at structural, cellular, vascular, and molecular levels. It is also associated with a high risk of damage to surrounding healthy tissues and an increased risk of fracture. Technological advances and research on animal models as well as a few human bone tissue studies have provided novel insights into the ways in which bone can be affected by high, low and sublethal dose of radiation. The influence of radiation on bone metabolism, cellular properties, vascularity, collagen, and other factors like inflammation, reactive oxygen species are discussed.
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Affiliation(s)
- Sridhar Reddy Padala
- Institute of Dentistry, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Bina Kashyap
- Institute of Dentistry, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Hannah Dekker
- Amsterdam University Medical Centers, Academic Centre for Dentistry Amsterdam (ACTA), Department of Oral and Maxillofacial Surgery/Oral Pathology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Jopi J W Mikkonen
- Institute of Dentistry, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Anni Palander
- Institute of Dentistry, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Nathalie Bravenboer
- Amsterdam UMC, Department of Clinical Chemistry, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.,Department of Internal Medicine, Division of Endocrinology and Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands
| | - Arja M Kullaa
- Institute of Dentistry, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
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Al-Rawaf HA, Alghadir AH, Gabr SA. Circulating MicroRNA Expression, Vitamin D, and Hypercortisolism as Predictors of Osteoporosis in Elderly Postmenopausal Women. DISEASE MARKERS 2021; 2021:3719919. [PMID: 34938374 PMCID: PMC8687791 DOI: 10.1155/2021/3719919] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 11/20/2021] [Accepted: 11/30/2021] [Indexed: 11/18/2022]
Abstract
BACKGROUND MicroRNAs (miRNA) identified as critical molecular regulators for bone development, function, and modeling/remodeling process and could be predictable for osteoporotic fractures in postmenopausal elderly women. AIM The potential diagnostic role of circulating miRNAs, miR-148a and miR-122-5p, in the pathogenesis of osteoporosis and its association with bone markers, hypercortisolism, and vitamin D deficiency were explored in postmenopausal elderly women with osteoporosis. METHODS A total of 120 elderly women aged 50-80 years old were recruited in this study, of which only 100 eligible women with amenorrhea of at least 12 consecutive months or surgical menopause participated in this study. Based upon bone mineral density (BMD) measurements, the participants were classified according into two groups: normal (n = 45; T score of ≥-1.0) and osteoporosis (n = 55; T score: ≤-2.5). Circulating miRNAs, miR-148a and miR-122-5p, were estimated by real-time RT-PCR analysis. In addition, bone markers, hypercortisolism, and vitamin D deficiency were colorimetrically and ELISA immune assay estimated. The potential role of miR-148a, miR-122-5p, cortisol, and vitamin D in the diagnosis of osteoporosis was predicted using the analysis of the respective area under the receiver operating characteristic curve (AUC-ROC). RESULTS The expressed level of miR-148a significantly increased and miR-122-5p significantly decreased in the serum of osteoporotic patients compared to healthy controls. In addition, a significant increase in the levels of cortisol, s-BAP, and CTx and significant decrease in the levels of T-BMD, the levels of OC, and s-Ca were also identified. All parameters significantly correlated with fracture risk parameters; BMD, and T score lumbar spine (L2-L4). Thus, the data showed AUC cut off values (miR-148a; 0.876, miR-122-5p; 0.761) were best evaluated for clinical diagnosis of patients with osteoporosis and that AUC cut off values of 0.748 for cortisol and 0.635 for vitamin D were the best cut off values, respectively, reported for the prediction of osteoporosis clinical diagnosis. CONCLUSION In this study, expressed miRNAs miR-148a and miR-122-5p and changes in the levels of both cortisol and vitamin D status are significantly associated with bone loss or osteoporosis. Thus, circulation miRNAs alone or in combination with cortisol and vitamin D status might be considered predictable biomarkers in the diagnosis or the pathogenesis of osteoporosis in elderly postmenopausal women; however, more studies are recommended.
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Affiliation(s)
- Hadeel A. Al-Rawaf
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Ahmad H. Alghadir
- Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Sami A. Gabr
- Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
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Ana ID, Barlian A, Hidajah AC, Wijaya CH, Notobroto HB, Kencana Wungu TD. Challenges and strategy in treatment with exosomes for cell-free-based tissue engineering in dentistry. Future Sci OA 2021; 7:FSO751. [PMID: 34840808 PMCID: PMC8609983 DOI: 10.2144/fsoa-2021-0050] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 09/21/2021] [Indexed: 12/11/2022] Open
Abstract
In dentistry, problems of craniofacial, osteochondral, periodontal tissue, nerve, pulp or endodontics injuries, and osteoarthritis need regenerative therapy. The use of stem cells in dental tissue engineering pays a lot of increased attention, but there are challenges for its clinical applications. Therefore, cell-free-based tissue engineering using exosomes isolated from stem cells is regarded an alternative approach in regenerative dentistry. However, practical use of exosome is restricted by limited secretion capability of cells. For future regenerative treatment with exosomes, efficient strategies for large-scale clinical applications are being studied, including the use of ceramics-based scaffold to enhance exosome production and secretion which can resolve limited exosome secretory from the cells when compared with the existing methods available. Indeed, more research needs to be done on these strategies going forward.
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Affiliation(s)
- Ika Dewi Ana
- Department of Dental Biomedical Sciences, Faculty of Dentistry, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia
| | - Anggraini Barlian
- School of Life Sciences & Technology, Institut Teknologi Bandung, Bandung, 40132, Indonesia
| | - Atik Choirul Hidajah
- Department of Epidemiology, Biostatistics, Population Studies, & Health Promotion, Faculty of Public Health, Universitas Airlangga, Surabaya, 60115, Indonesia
| | - Christofora Hanny Wijaya
- Department of Food Science & Technology, Faculty of Agricultural Engineering & Technology, IPB University, Bogor, 16002, Indonesia
| | - Hari Basuki Notobroto
- Department of Epidemiology, Biostatistics, Population Studies, & Health Promotion, Faculty of Public Health, Universitas Airlangga, Surabaya, 60115, Indonesia
| | - Triati Dewi Kencana Wungu
- Department of Physics, Faculty of Mathematics & Natural Sciences, Institut Teknologi Bandung, Bandung, 40132, Indonesia
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Simões D, Craveiro V, Santos MP, Camões M, Pires B, Ramos E. The effect of impact exercise on bone mineral density: A longitudinal study on non-athlete adolescents. Bone 2021; 153:116151. [PMID: 34391957 DOI: 10.1016/j.bone.2021.116151] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 08/09/2021] [Accepted: 08/10/2021] [Indexed: 11/19/2022]
Abstract
PURPOSE High impact exercise is known to induce osteogenic effects in the skeleton. However, less is known about the systemic effect of exercise practice in a potential adaptive mechanism of the skeletal accrual. This research aimed to assess the effect of impact exercise on bone mineral density (BMD) in the radius throughout adolescence. METHODS This study evaluated 1137 adolescents, at 13 and 17 years old, as part of the population-based cohort EPITeen. BMD (g/cm2) was measured at the ultradistal and proximal radius of the non-dominant forearm by dual-energy X-ray absorptiometry (DXA) using a Lunar® Peripheral Instantaneous X-ray Image device. The practice of (extra-curricular) exercise was categorized as: no exercise, exercise with high impact and exercise with low impact. Regression coefficients (β) and respective 95% confidence intervals (CI95%) were used to estimate the association between exercise practice categories at 13 years old and BMD at 13 and 17 years old and BMD gain between evaluations. RESULTS In boys, at 13 years, BMD was similar between the ones not practicing exercise and those practicing exercise with low impact, and the gain of BMD was also similar in both groups. Still in boys, at 13 years, those who practiced exercise with high impact presented higher mean (standard-deviation) of BMD, comparing to the other two groups (no exercise and low impact exercise), and also significantly increased the BMD gain between 13 and 17 years (β = 0.013; CI95%0.003;0.023). In girls, no statistically significant differences on BMD were found between the categories of exercise at 13 years and BMD at 17 years of age. CONCLUSION This research shows that the practice of high impact exercise could help to increase BMD more than low impact exercise even in a nonweight-bearing bone during adolescence.
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Affiliation(s)
- Daniela Simões
- EPIUnit - Institute of Public Health, University of Porto, 4050-600, Porto, Portugal; Santa Maria Health School, 4049-024 Porto, Portugal
| | - Vanda Craveiro
- EPIUnit - Institute of Public Health, University of Porto, 4050-600, Porto, Portugal; Laboratory for Integrative and Translational Research in Population Health (ITR), 4050-600 Porto, Portugal
| | - Maria Paula Santos
- Laboratory for Integrative and Translational Research in Population Health (ITR), 4050-600 Porto, Portugal; CIAFEL - Research Centre in Physical Activity, Health and Leisure, University of Porto, 4200-450 Porto, Portugal
| | - Miguel Camões
- EPIUnit - Institute of Public Health, University of Porto, 4050-600, Porto, Portugal
| | - Bruno Pires
- EPIUnit - Institute of Public Health, University of Porto, 4050-600, Porto, Portugal
| | - Elisabete Ramos
- EPIUnit - Institute of Public Health, University of Porto, 4050-600, Porto, Portugal; Laboratory for Integrative and Translational Research in Population Health (ITR), 4050-600 Porto, Portugal; Department of Public Health and Forensic Sciences, Medical Education, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.
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Luong A, Tawfik AN, Islamoglu H, Gobriel HS, Ali N, Ansari P, Shah R, Hung T, Patel T, Henson B, Thankam F, Lewis J, Mintline M, Boehm T, Tumur Z, Seleem D. Periodontitis and diabetes mellitus co-morbidity: A molecular dialogue. J Oral Biosci 2021; 63:360-369. [PMID: 34728373 DOI: 10.1016/j.job.2021.10.006] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 10/21/2021] [Accepted: 10/26/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) and periodontitis are two biologically linked diseases that often coexist in complex interaction. While periodontitis may lead to insulin receptor desensitization, diabetes may increase the expression of inflammatory cytokines, such as Tumor Necrosis Factor-α (TNF-α) and Interleukin 6 (IL-6), in the gingival crevicular fluid and activate osteoclasts via Receptor activator of nuclear factor kappa-Β ligand (RANK-L) production, leading to bone resorption. However, the association between the two diseases processes, where one may exacerbate the progression of the other, is unclear. In addition, both diseases have similar mechanistic themes, such as chronic inflammation and oxidative stress. This review aimed to investigate the pathophysiological and molecular mechanisms underlying T2DM and periodontitis. HIGHLIGHT Uncontrolled diabetes is often associated with severe periodontitis, measured by clinical attachment loss. Alteration in the oral microbiome composition, which may activate the host inflammatory response and lead to irreversible oxidative stress, is a common finding in both diseases. An understanding of the molecular crosstalk between the two disease processes is crucial for developing therapeutic targets that inhibit bone resorption and halt the progression of periodontitis in patients with diabetes. CONCLUSION The Oral microbiome composition in T2DM and periodontitis shifts toward dysbiosis, favoring bacterial pathogens, such as Fusobacteria and Porphyromonas species. Both conditions are marked by pro-inflammatory immune activity via the activation of Interleukin 17 (IL-17), Interleukin 1 (IL-1), TNF-α, and Nuclear Factor Kappa Beta (NF-κB). Common molecular crosstalk signaling appears to involve advanced glycation end products (AGEs) and oxidative stress. Thus, future drug targets are multifactorial, ranging from modulatory of host inflammatory response to preventing the accumulation of AGEs and oxidative free radicals.
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Affiliation(s)
- Anthony Luong
- College of Dental Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA
| | - Andy Nassif Tawfik
- College of Dental Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA
| | - Hicret Islamoglu
- College of Dental Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA
| | - Hanaa Selim Gobriel
- College of Dental Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA
| | - Nada Ali
- College of Dental Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA
| | - Pouya Ansari
- College of Dental Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA
| | - Ruchita Shah
- College of Dental Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA
| | - Tiffany Hung
- College of Dental Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA
| | - Tanusha Patel
- College of Dental Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA
| | - Bradley Henson
- College of Dental Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA
| | - Finosh Thankam
- College of Osteopathic Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA
| | - Jill Lewis
- College of Dental Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA
| | - Mark Mintline
- College of Dental Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA
| | - Tobias Boehm
- College of Dental Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA
| | - Zohra Tumur
- College of Dental Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA
| | - Dalia Seleem
- College of Dental Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA.
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Tran MT, Okusha Y, Feng Y, Sogawa C, Eguchi T, Kadowaki T, Sakai E, Tsukuba T, Okamoto K. A novel role of HSP90 in regulating osteoclastogenesis by abrogating Rab11b-driven transport. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1868:119096. [PMID: 34242681 DOI: 10.1016/j.bbamcr.2021.119096] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 07/01/2021] [Accepted: 07/02/2021] [Indexed: 12/16/2022]
Abstract
Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone that plays a pivotal role in folding, activating and assembling a variety of client proteins. In addition, HSP90 has recently emerged as a crucial regulator of vesicular transport of cellular proteins. In our previous study, we revealed Rab11b negatively regulated osteoclastogenesis by promoting the lysosomal proteolysis of c-fms and RANK surface receptors via the axis of early endosome-late endosome-lysosomes. In this study, using an in vitro model of osteoclasts differentiated from murine macrophage-like RAW-D cells, we revealed that Rab11b interacted with both HSP90 isoforms, HSP90 alpha (HSP90α) and HSP90 beta (HSP90β), suggesting that Rab11b is an HSP90 client. Using at specific blocker for HSP90 ATPase activity, 17-allylamino-demethoxygeldanamycin (17-AAG), we found that the HSP90 ATPase domain is indispensable for maintaining the interaction between HSP90 and Rab11b in osteoclasts. Nonetheless, its ATPase activity is not required for regulating the turnover of endogenous Rab11b. Interestingly, blocking the interaction between HSP90 and Rab11b by either HSP90-targeting small interfering RNA (siHSP90) or 17-AAG abrogated the inhibitory effects of Rab11b on osteoclastogenesis by suppressing the Rab11b-mediated transport of c-fms and RANK surface receptors to lysosomes via the axis of early endosome-late endosome-lysosomes, alleviating the Rab11b-mediated proteolysis of these surface receptors in osteoclasts. Based on our observations, we propose a HSP90/Rab11b-mediated regulatory mechanism for osteoclastogenesis by directly modulating the c-fms and RANK surface receptors in osteoclasts, thereby contributing to the maintenance of bone homeostasis.
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Affiliation(s)
- Manh Tien Tran
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8525, Japan
| | - Yuka Okusha
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8525, Japan; Division of Molecular and Cellular Biology, Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
| | - Yunxia Feng
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8525, Japan; College of Basic Medicine, China Medical University, Shenyang 1110112, China
| | - Chiharu Sogawa
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8525, Japan
| | - Takanori Eguchi
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8525, Japan; Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8525, Japan
| | - Tomoko Kadowaki
- Department of Frontier Oral Science, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan
| | - Eiko Sakai
- Department of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan
| | - Takayuki Tsukuba
- Department of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan
| | - Kuniaki Okamoto
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8525, Japan.
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38
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Xue F, Zhao Z, Gu Y, Han J, Ye K, Zhang Y. 7,8-Dihydroxyflavone modulates bone formation and resorption and ameliorates ovariectomy-induced osteoporosis. eLife 2021; 10:e64872. [PMID: 34227467 PMCID: PMC8285109 DOI: 10.7554/elife.64872] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 07/05/2021] [Indexed: 12/20/2022] Open
Abstract
Imbalances in bone formation and resorption cause osteoporosis. Mounting evidence supports that brain-derived neurotrophic factor (BDNF) implicates in this process. 7,8-Dihydroxyflavone (7,8-DHF), a plant-derived small molecular TrkB agonist, mimics the functions of BDNF. We show that both BDNF and 7,8-DHF promoted the proliferation, osteogenic differentiation, and mineralization of MC3T3-E1 cells. These effects might be attributed to the activation of the Wnt/β-catenin signaling pathway as the expression of cyclin D1, phosphorylated-glycogen synthase kinase-3β (p-GSK3β), β-catenin, Runx2, Osterix, and osteoprotegerin (OPG) was all significantly up-regulated. Knockdown of β-catenin restrained the up-regulation of Runx2 and Osterix stimulated by 7,8-DHF. In particular, blocking TrkB by its specific inhibitor K252a suppressed 7,8-DHF-induced osteoblastic proliferation, differentiation, and expression of osteoblastogenic genes. Moreover, BDNF and 7,8-DHF repressed osteoclastic differentiation of RAW264.7 cells. The transcription factor c-fos and osteoclastic genes such as tartrate-resistant acid phosphatase (TRAP), matrix metalloprotein-9 (MMP-9), Adamts5 were inhibited by 7,8-DHF. More importantly, 7,8-DHF attenuated bone loss, improved trabecular microarchitecture, tibial biomechanical properties, and bone biochemical indexes in an ovariectomy (OVX) rat model. The current work highlights the dual regulatory effects that 7,8-DHF exerts on bone remodeling.
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Affiliation(s)
- Fan Xue
- Department of Food Science and Nutrition, College of Biosystems Engineering and Food Science, Zhejiang Key Laboratory for Agro-Food Processing; Zhejiang Engineering Center for Food Technology and Equipment, Zhejiang UniversityHangzhouChina
| | - Zhenlei Zhao
- Department of Food Science and Nutrition, College of Biosystems Engineering and Food Science, Zhejiang Key Laboratory for Agro-Food Processing; Zhejiang Engineering Center for Food Technology and Equipment, Zhejiang UniversityHangzhouChina
| | - Yanpei Gu
- Department of Food Science and Nutrition, College of Biosystems Engineering and Food Science, Zhejiang Key Laboratory for Agro-Food Processing; Zhejiang Engineering Center for Food Technology and Equipment, Zhejiang UniversityHangzhouChina
| | - Jianxin Han
- Department of Food Science and Nutrition, College of Biosystems Engineering and Food Science, Zhejiang Key Laboratory for Agro-Food Processing; Zhejiang Engineering Center for Food Technology and Equipment, Zhejiang UniversityHangzhouChina
| | - Keqiang Ye
- Department of Pathology and Laboratory Medicine, Emory University School of MedicineAtlantaUnited States
| | - Ying Zhang
- Department of Food Science and Nutrition, College of Biosystems Engineering and Food Science, Zhejiang Key Laboratory for Agro-Food Processing; Zhejiang Engineering Center for Food Technology and Equipment, Zhejiang UniversityHangzhouChina
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39
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Zhou B, Peng K, Wang G, Chen W, Kang Y. Silencing Proteasome 26S Subunit ATPase 2 (PSMC2) Protects the Osteogenic Differentiation In Vitro and Osteogenesis In Vivo. Calcif Tissue Int 2021; 109:44-54. [PMID: 33625534 DOI: 10.1007/s00223-021-00819-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 01/30/2021] [Indexed: 12/17/2022]
Abstract
Osteoporosis is a commonly seen degenerative bone disorder in the elderly and postmenopausal women, with a low bone mineral density as a major risk factor. The osteogenic potential of bone marrow stromal cells (BMSCs) showed to be impaired during osteoporosis. We established a postmenopausal osteoporosis model in ovariectomized (OVX) mice and found the upregulation of proteasome 26S subunit ATPase 2 (PSMC2) in OVX mice. PSMC2 silencing improved OVX-impaired biomechanical properties of mice femur, OVX-decreased BMD, and OVX-destroyed bone structure. Histopathological analysis indicated that PSMC2 silencing improved bone trabecular structure and increased the contents of collagen fibers and newly formed bone or cartilage in OVX mice. In the meantime, PSMC2 silencing increased Runx2, PI3K, Wnt3a, and β-catenin protein contents while reduced CTSK protein. Within BMSCs isolated from OVX mice, PSMC2 silencing promoted BMSC osteogenic differentiation and elevated osteogenic markers' protein contents, including HOXA10, Runx2, OCN, OPN, and COL1A2. In conclusion, PSMC2 expression is upregulated in the postmenopausal osteoporosis model in OVX mice. PSMC2 silencing promotes the osteogenic differentiation of BMSCs in vitro, promotes bone formation, and inhibits bone resorption in vivo.
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Affiliation(s)
- Bin Zhou
- Department of Spine Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Kun Peng
- Department of Spine Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Guoqiang Wang
- Department of Spine Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Weihua Chen
- Department of Spine Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Yijun Kang
- Department of Spine Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
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40
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Lu C, Chen J, Yi C, Han J, Shi Q, Li J, Liu B, Zhou J, Su X. Gut microbiota mediated the protective effects of tuna oil on collagen-induced arthritis in mice. Food Funct 2021; 12:5387-5398. [PMID: 33983361 DOI: 10.1039/d1fo00709b] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Rheumatoid arthritis is emerging as a chronic autoimmune disease worldwide. In this study, the beneficial effects of tuna oil (TO) on collagen-induced arthritis (CIA) mice were investigated. Dietary administration of TO relieved arthritis severity and joint bone erosion, and ameliorated systemic inflammation. Furthermore, TO treatments regulated the phosphorylation of nuclear factor-kappa B (NF-κB) and Wnt1/β-catenin signaling pathways in the joint, enhanced osteoblastogenesis biomarkers and suppressed osteoclastogenesis biomarkers, and subsequently re-balanced bone remodeling. Moreover, the impaired intestinal epithelial barrier was repaired after TO treatments, along with gut microbiota modulation. By employing fecal microbiota transplantation, we clarified that the beneficial effects of TO in CIA alleviation were mediated by the modulated gut microbiota. These results indicated that gut microbiota mediated the protective effects of tuna oil on collagen-induced arthritis in mice.
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Affiliation(s)
- Chenyang Lu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China. and School of Marine Science, Ningbo University, Ningbo, China
| | - Ju Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China.
| | - Congmin Yi
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China.
| | - Jiaojiao Han
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China. and School of Marine Science, Ningbo University, Ningbo, China
| | - Qiuyue Shi
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China.
| | - Jingjing Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China.
| | - Bing Liu
- Vigor Technology Group, Shenzhen, China
| | - Jun Zhou
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China. and School of Marine Science, Ningbo University, Ningbo, China
| | - Xiurong Su
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China. and School of Marine Science, Ningbo University, Ningbo, China
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Tarantino U, Cariati I, Greggi C, Gasbarra E, Belluati A, Ciolli L, Maccauro G, Momoli A, Ripanti S, Falez F, Brandi ML. Skeletal System Biology and Smoke Damage: From Basic Science to Medical Clinic. Int J Mol Sci 2021; 22:ijms22126629. [PMID: 34205688 PMCID: PMC8234270 DOI: 10.3390/ijms22126629] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/15/2021] [Accepted: 06/16/2021] [Indexed: 01/03/2023] Open
Abstract
Cigarette smoking has a negative impact on the skeletal system, as it reduces bone mass and increases fracture risk through its direct or indirect effects on bone remodeling. Recent evidence demonstrates that smoking causes an imbalance in bone turnover, making bone vulnerable to osteoporosis and fragility fractures. Moreover, cigarette smoking is known to have deleterious effects on fracture healing, as a positive correlation between the daily number of cigarettes smoked and years of exposure has been shown, even though the underlying mechanisms are not fully understood. It is also well known that smoking causes several medical/surgical complications responsible for longer hospital stays and a consequent increase in the consumption of resources. Smoking cessation is, therefore, highly advisable to prevent the onset of bone metabolic disease. However, even with cessation, some of the consequences appear to continue for decades afterwards. Based on this evidence, the aim of our review was to evaluate the impact of smoking on the skeletal system, especially on bone fractures, and to identify the pathophysiological mechanisms responsible for the impairment of fracture healing. Since smoking is a major public health concern, understanding the association between cigarette smoking and the occurrence of bone disease is necessary in order to identify potential new targets for intervention.
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Affiliation(s)
- Umberto Tarantino
- Department of Clinical Sciences and Translational Medicine, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy; (U.T.); (I.C.); (C.G.); (E.G.)
- Department of Orthopaedics and Traumatology, “Policlinico Tor Vergata” Foundation, Viale Oxford 81, 00133 Rome, Italy
| | - Ida Cariati
- Department of Clinical Sciences and Translational Medicine, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy; (U.T.); (I.C.); (C.G.); (E.G.)
- Medical-Surgical Biotechnologies and Translational Medicine, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy
| | - Chiara Greggi
- Department of Clinical Sciences and Translational Medicine, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy; (U.T.); (I.C.); (C.G.); (E.G.)
- Medical-Surgical Biotechnologies and Translational Medicine, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy
| | - Elena Gasbarra
- Department of Clinical Sciences and Translational Medicine, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy; (U.T.); (I.C.); (C.G.); (E.G.)
- Department of Orthopaedics and Traumatology, “Policlinico Tor Vergata” Foundation, Viale Oxford 81, 00133 Rome, Italy
| | - Alberto Belluati
- Orthopaedic and Traumatology Department, Hospital Santa Maria delle Croci–AUSL Romagna, Viale Randi 5, 48121 Ravenna, Italy;
| | - Luigi Ciolli
- Orthopaedic and Traumatology Department, S. Spirito Hospital, Lungotevere in Sassia 1, 00193 Rome, Italy; (L.C.); (F.F.)
| | - Giulio Maccauro
- Department of Orthopaedics and Traumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168 Rome, Italy;
| | - Alberto Momoli
- Orthopedic and Traumatology Department, San Bortolo Hospital-AULSS 8 Berica, Viale Rodolfi 37, 36100 Vicenza, Italy;
| | - Simone Ripanti
- Department of Orthopaedics and Traumatology, San Giovanni-Addolorata Hospital, Via dell’Amba Aradam 8, 00184 Rome, Italy;
| | - Francesco Falez
- Orthopaedic and Traumatology Department, S. Spirito Hospital, Lungotevere in Sassia 1, 00193 Rome, Italy; (L.C.); (F.F.)
| | - Maria Luisa Brandi
- FIRMO Foundation, 50141 Florence, Italy
- Correspondence: ; Tel.: +39-55-5097-755
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Pawelczyk-Madalińska M, Benedicenti S, Sălăgean T, Bordea IR, Hanna R. Impact of Adjunctive Diode Laser Application to Non-Surgical Periodontal Therapy on Clinical, Microbiological and Immunological Outcomes in Management of Chronic Periodontitis: A Systematic Review of Human Randomized Controlled Clinical Trials. J Inflamm Res 2021; 14:2515-2545. [PMID: 34163210 PMCID: PMC8214554 DOI: 10.2147/jir.s304946] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 04/01/2021] [Indexed: 12/17/2022] Open
Abstract
Background Due to the limitations of scaling and root planing (SRP) in chronic periodontitis (CP) management, research has been focused on utilising additional therapies to enhance conventional treatment methods. The present systematic review is aimed to appraise the accessible scientific evidence of in vivo human studies to establish the effectiveness of adjunctive diode (λ 808- λ 980nm) laser treatment to SRP in CP. Methodology This systematic review was conducted following the PRISMA statement guidelines. The review protocol is registered in PROSPERO (CRD 42021227695). The search strategies were based on structured electronic and manual (with appropriate keywords) and were conducted to collect the applicable published data on RCTs studies (in vivo human), spanning over ten years between August 2010 and August 2020. The articles were selected to address the following research focus question: “Does diode laser (λ 808- λ 980nm) therapy have superior effects as an adjunct to SPR, compared to SRP alone, in terms of clinical or microbiological or immunological profiles in the management of CP?” Results Fifteen articles met the eligibility criteria and are included in this review. A wide range of discrepancies and inconsistencies were shown in the outcomes of the laser and SPR treatment modality, compared to SRP alone. The data on standardised study protocol, optimal laser parameters and outcome measurements were inconclusive, and a high risk of bias in the majority of the studies observed, which are crucial in establishing a homogenous and reproducible protocol. Conclusion In light of the confined evidence-based data and critical evaluation of this systematic review, the efficacy of adjunctive diode laser treatment ranging between 808 and 980nm to SRP remains debatable. The observational quality of the present systematic review was emphasised after scrutinising the available data, and an attempt to propose a laser protocol for future RCTs consideration was a great challenge due to an absence of clear and standardised recommendations in delivering a reliable laser protocol which can be replicable by future investigators. RCTs with robust methodology are warranted.
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Affiliation(s)
- Magdalena Pawelczyk-Madalińska
- Department of Surgical Sciences and Integrated Diagnostics, Laser Therapy Centre, University of Genoa, Genoa, Italy.,Department of Periodontology, Pomeranian Medical University, Szczecin, 70-204, Poland.,FAN-DENT Centrum Stomatologii i Periodontologii, Gdańsk, 80-257, Poland
| | - Stefano Benedicenti
- Department of Surgical Sciences and Integrated Diagnostics, Laser Therapy Centre, University of Genoa, Genoa, Italy
| | - Tudor Sălăgean
- Department of Land Measurements and Exact Sciences, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Cluj-Napoca, Romania
| | - Ioana Roxana Bordea
- Department of Oral Rehabilitation, "Iuliu Hațieganu" University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
| | - Reem Hanna
- Department of Surgical Sciences and Integrated Diagnostics, Laser Therapy Centre, University of Genoa, Genoa, Italy.,Department of Oral Surgery, King's College Hospital NHS Foundation Trust, London, UK
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He MC, Zhang J, Chen XJ, Shen YS, Fang B, Qin YX, He W, Wei QS. Osteoclastic activity was associated with the development of steroid-induced osteonecrosis of femoral head. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2021; 48:1036-1046. [PMID: 32667225 DOI: 10.1080/21691401.2020.1774596] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
This study is focussed on evaluating and comparing two mediators of osteoclast, osteoprotegerin (OPG) and nuclear factor-κB ligand (RANKL), in plasma and tissue levels in patients with steroid-induced osteonecrosis of femoral head (SIONFH). Subjects were included in this cross-sectional case-control study in 2016. Bone histomorphology, immunohistochemistry, Western blotting, OPG and RANKL plasma levels, post-hoc statistical power and receiver-operating characteristic (ROC) curves were evaluated. Eighty-six patients diagnosed with SIONFH and 51 healthy subjects were included. OPG expression levels in bone samples increased with ARCO stage, and RANKL expression levels decreased with ARCO stages. Plasma OPG and RANKL levels were significantly higher in the SIONFH group compared with the healthy control group. The plasma OPG level and ratio of OPG and RANKL were positively associated with ARCO stages and significantly higher in stages III and IV. Plasma RANKL levels were negatively associated with ARCO stage and were significantly higher in ARCO stages II and III. Plasma OPG and RANKL may represent potential biomarkers during SIONFH at different stages. Higher plasma OPG levels indicated late-stage SIONFH, and higher plasma RANKL levels indicated early stage. Our findings may provide a clue for the development of diagnostic tools and therapies for SIONFH.
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Affiliation(s)
- Min-Cong He
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, PR China
| | - Jin Zhang
- Department of Anatomy, Guangzhou University of Chinese Medicine, Guangzhou, PR China
| | - Xiao-Jun Chen
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, PR China
| | - Ying-Shan Shen
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, PR China
| | - Bin Fang
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, PR China
| | - Yi-Xian Qin
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA
| | - Wei He
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, PR China.,Institute of Hip Joint, Guangzhou University of Chinese Medicine, Guangzhou, PR China
| | - Qiu-Shi Wei
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, PR China.,Institute of Hip Joint, Guangzhou University of Chinese Medicine, Guangzhou, PR China
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Choi JH, Jang AR, Park MJ, Kim DI, Park JH. Melatonin Inhibits Osteoclastogenesis and Bone Loss in Ovariectomized Mice by Regulating PRMT1-Mediated Signaling. Endocrinology 2021; 162:6169647. [PMID: 33713122 DOI: 10.1210/endocr/bqab057] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Indexed: 12/16/2022]
Abstract
Melatonin, a pineal gland hormone, has been suggested to treat postmenopausal osteoporosis due to its inhibitory effect on osteoclast differentiation. We previously reported that protein arginine methyltransferase 1 (PRMT1) was an important mediator of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. However, the relationship between melatonin and PRMT1 in osteoclast differentiation and estrogen deficiency-induced osteoporosis is unclear. In this study, we investigated the inhibitory mechanisms of melatonin in vitro and in vivo by focusing on PRMT1. Melatonin treatment effectively blocked RANKL-induced osteoclastogenesis by inhibiting PRMT1 and asymmetric dimethylarginine (ADMA) expression. RANKL-induced tumor necrosis factor receptor-associated factor 6 (TRAF6) and the phosphorylation of JNK were also suppressed by melatonin, and TRAF6 siRNA attenuated RANKL-induced p-JNK and PRMT1 production. Melatonin inhibited the transcriptional activity of NF-κB by interfering with the binding of PRMT1 and NF-κB subunit p65 in RANKL-treated bone marrow-derived macrophages. Our results also revealed that melatonin inhibits RANKL-induced PRMT1 expression through receptors-independent pathway. Thus, the anti-osteoclastogenic effect of melatonin was mediated by a cascade of inhibition of RANKL-induced TRAF6, JNK, PRMT1, and NF-κB signaling in melatonin receptors-independent pathway. In vivo, ovariectomy caused significant decreases in bone mineral density, but melatonin treatment alleviated the ovariectomized (OVX)-induced bone loss by inhibiting bone resorption. Furthermore, the expression PRMT1 and TRAP mRNA was upregulated in OVX-femurs, but effectively suppressed by melatonin injection. These findings suggest that melatonin inhibited osteoclast differentiation and estrogen deficiency-induced osteoporosis by suppressing RANKL-induced TRAF6, JNK, PRMT1, and NF-κB signaling cascades in melatonin receptors-independent pathway.
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Affiliation(s)
- Joo-Hee Choi
- Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea
- Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Republic of Korea
| | - Ah-Ra Jang
- Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Min-Jung Park
- Department of Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Dong-Il Kim
- Department of Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Jong-Hwan Park
- Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea
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Xiao W, Wei Y, Yang F, Lu X, Liu S, Long Y, Yu Y. Cistanche deserticola polysaccharide inhibits OVX-induced bone loss in mice and RANKL-induced osteoclastogenesis. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104464] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
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Peng JX, Guan XY, Li GH, Zhong JL, Song JK, Xiao LL, Jin SH, Liu JG. Recombinant human insulin-like growth factor-1 promotes osteoclast formation and accelerates orthodontic tooth movement in rats. J Appl Oral Sci 2021; 29:e20200791. [PMID: 34008748 PMCID: PMC8128321 DOI: 10.1590/1678-7757-2020-0791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 03/12/2021] [Indexed: 11/21/2022] Open
Abstract
Background: IGF-1 may be an important factor in bone remodeling, but its mechanism of action on osteoclasts during orthodontic tooth movement is complex and unclear. Methodology: The closed-coil spring was placed between the left maxillary first molar and upper incisors with a force of 50 g to establish an orthodontic movement model. Eighty SD rats were randomized to receive phosphate buffer saline or 400 ng rhIGF-1 in the lateral buccal mucosa of the left maxillary first molar every two days. Tissue sections were stained for tartrate-resistant acidic phosphatase (TRAP), the number of TRAP-positive cells was estimated and tooth movement measured. Results: The rhIGF-1 group exhibited evidential bone resorption and lacuna appeared on the alveolar bone compared to the control group. Moreover, the number of osteoclasts in compression side of the periodontal ligament in the rhIGF-1 group peaked at day 4 (11.37±0.95 compared to 5.28±0.47 in the control group) after the orthodontic force was applied and was significantly higher than that of the control group (p<0.01). Furthermore, the distance of tooth movement in the rhIGF-1 group was significantly larger than that of the control group from day 4 to day 14 (p<0.01), suggesting that rhIGF-1 accelerated orthodontic tooth movement. Conclusion: Our study has showed that rhIGF-1 could stimulate the formation of osteoclasts in the periodontal ligament, and accelerate bone remodeling and orthodontic tooth movement.
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Affiliation(s)
- Ju-Xiang Peng
- Guiyang Stomatological Hospital Affiliated to Zunyi Medical University, Guiyang Hospital of Stomatology, Department of Orthodontic, Guiyang, China
| | - Xiao-Yan Guan
- Guiyang Stomatological Hospital Affiliated to Zunyi Medical University, Guiyang Hospital of Stomatology, Department of Orthodontic, Guiyang, China
| | - Gao-Hua Li
- Shenzhen Ai Kang Jian Stomatological Hospital, Outpatient Department of Stomatology, Shenzhen, China
| | - Jian-Li Zhong
- Guangdong Province Stomatological Hospital, Department of Orthodontic, Guangzhou, China
| | - Ju-Kun Song
- Guizhou Province People's Hospital, Department of Oral and Maxillofacial Surgery, Guiyang, China
| | - Lin-Lin Xiao
- Zunyi Medical University, School of Stomatology, Department of Orthodontic, Zunyi, China
| | - Su-Han Jin
- Zunyi Medical University, School of Stomatology, Department of Orthodontic, Zunyi, China
| | - Jian-Guo Liu
- Special Key Laboratory of Oral Diseases Research from Higher Education Institution of Guizhou Province & Zunyi Key Laboratory of Oral Disease Research, Zunyi, China
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Shen Z, Silva RM. MicroRNAs: emerging players in apical periodontitis. J Appl Oral Sci 2021; 29:e20201058. [PMID: 33886945 PMCID: PMC8054647 DOI: 10.1590/1678-7757-2020-1058] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 01/20/2021] [Indexed: 12/13/2022] Open
Abstract
Apical periodontitis is an inflammatory disorder of periradicular tissues developed from endodontic infections. Understanding its pathophysiology and the underlying molecular mechanisms is key to the advancement of endodontics. MicroRNAs (miRNAs), a group of evolutionarily conserved small non-coding RNAs, may be phenotypically and functionally associated with the pathogenesis of apical periodontitis. Several studies have focused on the role of miRNAs in the pulp and periradicular biology, and they have demonstrated their essential functions, such as initiating odontogenic differentiation and promoting pro- or anti-inflammatory responses in pulpitis. Up to date, over 2,000 miRNAs have been discovered in humans; however, only few have been reported to associate with apical periodontitis. Therefore, identifying miRNAs involved in diseased apical tissues and conducting functional studies are important in expanding our current knowledge of pulp and periradicular biology and exploring novel therapeutic avenues. In this review, we revisit current models of apical periodontitis and miRNA biogenesis, analyze existing evidence of the involvement of miRNAs in diseased apical tissues, and discuss their diverse functions and potential values. Based on their sheer abundance, prolonged stability in biofluid, and relative ease of sampling, miRNAs may be a useful tool to be developed as diagnostic biomarkers for apical periodontitis. Furthermore, it can be used as therapeutic targets in conjunction with conventional endodontic therapies.
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Affiliation(s)
- Zhen Shen
- The University of Texas Health Science Center at Houston, Department of Endodontics, Houston, TX, United States
| | - Renato Menezes Silva
- The University of Texas Health Science Center at Houston, Department of Endodontics, Houston, TX, United States.,The University of Texas Health Science Center at Houston, Center for Craniofacial Research, Houston, TX, United States
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Liu W, Li CJ, Li LJ. [Advances in molecular mechanisms of bone invasion by oral cancer]. HUA XI KOU QIANG YI XUE ZA ZHI = HUAXI KOUQIANG YIXUE ZAZHI = WEST CHINA JOURNAL OF STOMATOLOGY 2021; 39:221-226. [PMID: 33834679 DOI: 10.7518/hxkq.2021.02.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Bone invasion by oral cancer is a common clinical problem, which affects the choice of treatment and predicts a poor prognosis. Unfortunately, the molecular mechanism of this phenomenon has not been fully elucidated. Current studies have revealed that oral cancer cells modulate the formation and function of osteoclasts through the expression of a series of signal molecules. Many signal pathways are involved in this process, of which receptor activator of nuclear factor-κB ligand/receptor activator of nuclear factor-κB/osteoprotegerin signaling pathway attracted much attention. In this review, we introduce recent progress in molecular mechanisms of bone invasion by oral cancer.
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Affiliation(s)
- Wei Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Dept. of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Chun-Jie Li
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Dept. of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Long-Jiang Li
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Dept. of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
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Kalkitoxin Reduces Osteoclast Formation and Resorption and Protects against Inflammatory Bone Loss. Int J Mol Sci 2021; 22:ijms22052303. [PMID: 33669069 PMCID: PMC7956546 DOI: 10.3390/ijms22052303] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 02/19/2021] [Accepted: 02/22/2021] [Indexed: 11/17/2022] Open
Abstract
Osteoclasts, bone-specified multinucleated cells produced by monocyte/macrophage, are involved in numerous bone destructive diseases such as arthritis, osteoporosis, and inflammation-induced bone loss. The osteoclast differentiation mechanism suggests a possible strategy to treat bone diseases. In this regard, we recently examined the in vivo impact of kalkitoxin (KT), a marine product obtained from the marine cyanobacterium Moorena producens (previously Lyngbya majuscula), on the macrophage colony-stimulating factor (M-CSF) and on the receptor activator of nuclear factor κB ligand (RANKL)-stimulated in vitro osteoclastogenesis and inflammation-mediated bone loss. We have now examined the molecular mechanism of KT in greater detail. KT decreased RANKL-induced bone marrow-derived macrophages (BMMs) tartrate-resistant acid phosphatase (TRAP)-multinucleated cells at a late stage. Likewise, KT suppressed RANKL-induced pit area and actin ring formation in BMM cells. Additionally, KT inhibited several RANKL-induced genes such as cathepsin K, matrix metalloproteinase (MMP-9), TRAP, and dendritic cell-specific transmembrane protein (DC-STAMP). In line with these results, RANKL stimulated both genes and protein expression of c-Fos and nuclear factor of activated T cells (NFATc1), and this was also suppressed by KT. Moreover, KT markedly decreased RANKL-induced p-ERK1/2 and p-JNK pathways at different time points. As a result, KT prevented inflammatory bone loss in mice, such as bone mineral density (BMD) and osteoclast differentiation markers. These experiments demonstrated that KT markedly inhibited osteoclast formation and inflammatory bone loss through NFATc1 and mitogen-activated protein kinase (MAPK) signaling pathways. Therefore, KT may have potential as a treatment for destructive bone diseases.
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Shi J, Gu Y, Wang Y, Bai J, Xiong L, Tao Y, Xue Y, Xu Y, Yang H, Ye H, Geng D. Inhibitory effect of acetyl-11-keto-β-boswellic acid on titanium particle-induced bone loss by abrogating osteoclast formation and downregulating the ERK signaling pathway. Int Immunopharmacol 2021; 94:107459. [PMID: 33611061 DOI: 10.1016/j.intimp.2021.107459] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 01/27/2021] [Accepted: 01/31/2021] [Indexed: 10/22/2022]
Abstract
Wear debris-induced osteoclast accumulation around implants plays a crucial role during the progression of periprosthetic osteolysis (PPO). We have confirmed that acetyl-11-keto-β-boswellic acid (AKBA) promotes bone formation and protects against particle-induced bone destruction in vivo. However, the effect of AKBA on titanium-induced bone resorption is unknown. In this study, we detected the inhibitory effect of AKBA on titanium-induced bone erosion in vivo and used RAW264.7 cells and bone marrow macrophages (BMMs) to investigate the effect and underlying mechanism of AKBA on the differentiation and resorptive function of osteoclasts. Our findings revealed that AKBA inhibited particle-induced bone loss and osteoclast formation in vivo. Furthermore, AKBA exerted inhibitory effects on RANKL-induced osteoclastogenesis, osteoclastic ring-dependent resorption and the expression of osteoclast marker genes via the ERK signaling pathway in vitro. Our data further established the protective effect of AKBA on titanium particle-induced bone erosion from a new perspective of bone erosion prevention, strongly confirming that AKBA is an appropriate agent for protection against PPO.
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Affiliation(s)
- Jiawei Shi
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Ye Gu
- Department of Orthopedics, Changshu Hospital Affiliated to Soochow University, First People's Hospital of Changshu City, Changshu 215500, China
| | - Yong Wang
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China
| | - Jiaxiang Bai
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Longbin Xiong
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Yunxia Tao
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Yi Xue
- Department of Orthopedics, Changshu Hospital Affiliated to Nanjing University of Traditional Chinese Medicine, Changshu 215000, China
| | - Yaozeng Xu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Huilin Yang
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
| | - Hongwei Ye
- Department of Orthopedics, Changshu Hospital Affiliated to Soochow University, First People's Hospital of Changshu City, Changshu 215500, China.
| | - Dechun Geng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
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