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Liu G, Xue J, Zhou X, Gui M, Xia R, Zhang Y, Cai Y, Li S, Shi S, Mao X, Chen Z. The paradigm shifts of periodontal regeneration strategy: From reparative manipulation to developmental engineering. Bioact Mater 2025; 49:418-436. [PMID: 40165829 PMCID: PMC11957753 DOI: 10.1016/j.bioactmat.2025.03.009] [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: 11/02/2024] [Revised: 02/07/2025] [Accepted: 03/10/2025] [Indexed: 04/02/2025] Open
Abstract
Ideal periodontal regeneration requires the integration of alveolar bone, periodontal ligament, and cementum, along with Sharpey's fibers for occlusal force resistance. However, physiological regeneration remains rare due to its intricate structure, making clinical regeneration a challenge. Periodontal ligament stem cells (PDLSCs), first isolated in 2004, hold the key to multi-directional differentiation into cementoblasts, fibroblasts, and osteoblasts. While traditional therapies like guided tissue regeneration (GTR) aim to activate PDLSCs, clinical outcomes are inconsistent, suggesting the need for additional strategies to enhance PDLSCs' functions. Advancements in molecular biotechnology have introduced the use of recombinant growth factors for tissue regeneration. However, maintaining their efficacy requires high doses, posing cost and safety issues. Multi-layered scaffolds combined with cell sheet technology offer new insights, but face production, ethical, and survival challenges. Immune regulation plays a crucial role in PDLSC-mediated regeneration. The concept of "coagulo-immunomodulation" has emerged, emphasizing the coupling of blood coagulation and immune responses for periodontal regeneration. Despite its potential, the clinical translation of immune-based strategies remains elusive. The "developmental engineering" approach, which mimics developmental events using embryonic-stage cells and microenvironments, shows promise. Our research group has made initial strides, indicating its potential as a viable solution for periodontal complex regeneration. However, further clinical trials and considerations are needed for successful clinical application. This review aims to summarize the strategic transitions in the development of periodontal regenerative materials and to propose prospective avenues for future development.
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Affiliation(s)
- Guanqi Liu
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- Guangdong Research Center for Dental and Cranial Rehabilitation and Material Engineering, Guangzhou, 510055, China
| | - Junlong Xue
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- Guangdong Research Center for Dental and Cranial Rehabilitation and Material Engineering, Guangzhou, 510055, China
| | - Xuan Zhou
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- Guangdong Research Center for Dental and Cranial Rehabilitation and Material Engineering, Guangzhou, 510055, China
| | - Mixiao Gui
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- Guangdong Research Center for Dental and Cranial Rehabilitation and Material Engineering, Guangzhou, 510055, China
| | - Ruidi Xia
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- Guangdong Research Center for Dental and Cranial Rehabilitation and Material Engineering, Guangzhou, 510055, China
| | - Yanshu Zhang
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- Guangdong Research Center for Dental and Cranial Rehabilitation and Material Engineering, Guangzhou, 510055, China
| | - Yihua Cai
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- Guangdong Research Center for Dental and Cranial Rehabilitation and Material Engineering, Guangzhou, 510055, China
| | - Shuhua Li
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- Guangdong Research Center for Dental and Cranial Rehabilitation and Material Engineering, Guangzhou, 510055, China
| | - Songtao Shi
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- South China Center of Craniofacial Stem Cell Research, Guangzhou, 510055, China
| | - Xueli Mao
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- South China Center of Craniofacial Stem Cell Research, Guangzhou, 510055, China
| | - Zetao Chen
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, and Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055, China
- Guangdong Research Center for Dental and Cranial Rehabilitation and Material Engineering, Guangzhou, 510055, China
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Liu D, Xiang Y, Sun M, Hu J, Chen Q, Liao L, Liu Y, Wei Y. Transcriptome and metabolome analysis of osteoblasts identifies disrupted purine metabolism and parathyroid hormone associated pathway induced by P. gingivalis infection. Bone 2025; 193:117401. [PMID: 39832660 DOI: 10.1016/j.bone.2025.117401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 01/17/2025] [Accepted: 01/17/2025] [Indexed: 01/22/2025]
Abstract
Porphyromonas gingivalis (P. gingivalis), a major pathogenic bacterium of chronic periodontitis and central player in the onset and subsequent progression of periodontitis, can cause alveolar bone resorption. The osteoblast dysfunction induced by P. gingivalis infection is a crucial pathological process causing bone loss. However, the comprehensive responses of osteoblasts, especially metabolism processes involved in osteoblast dysfunction under P. gingivalis invasion are largely unknown. In the present study, to profile the molecules switched in osteoblast dysfunction caused by P. gingivalis infection, the effect of P. gingivalis invasion on osteoblast differentiation was assessed and investigated through transcriptomics and metabolomics approaches. We found that P. gingivalis infection dramatically impaired osteoblast function. P. gingivalis invasion disrupted homeostasis of phosphorus (Pi)/calcium (Ca2+) and induced robust oxidative stress, cell apoptosis and massive activation of inflammatory response in osteoblasts. Notably, the exposure to P. gingivalis induced the inactivation of endocrines pathways, involved in bone formation, which is characterized by downregulated genes and less accumulated metabolites in "Parathyroid hormone synthesis, secretion and action", its downstream "Wnt signaling pathway" and related Pi/Ca2+ transport. Furthermore, we found that disrupted purine metabolism produced less ATP in P. gingivalis-infected osteoblasts and the reduced ATP may directly inhibit phosphorus transport. Collectively, these results provide a new insight into the molecular changes in P. gingivalis-infected osteoblasts in a comprehensive way.
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Affiliation(s)
- Dianbin Liu
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology/School of Stomatology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Yaoyao Xiang
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology/School of Stomatology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Mengxin Sun
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology/School of Stomatology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Jiayi Hu
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology/School of Stomatology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Qiuchong Chen
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology/School of Stomatology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Longxiang Liao
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology/School of Stomatology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Yan Liu
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology/School of Stomatology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
| | - Yanxia Wei
- Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology/School of Stomatology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
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Zhang R, Jo JI, Tsuda S, Li R, Nishiura A, Honda Y, Hashimoto Y, Matsumoto N. Sustained Fisetin Release Prevents Orthodontic Ti-6Al-4V Screw Failure by Suppressing Peri-Implantitis and Alveolar Bone Resorption. ACS Biomater Sci Eng 2025; 11:1472-1485. [PMID: 39928042 DOI: 10.1021/acsbiomaterials.4c01818] [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] [Indexed: 02/11/2025]
Abstract
In clinical practice, mini-screws of titanium-6-aluminum-4-vanadium alloy with an extra low interstitial (ELI) grade (Ti-6Al-4V ELI) are widely used as orthodontic anchorages. However, in orthodontic treatment, Ti-6Al-4V mini-screw failure because of peri-implantitis is a major challenge. To prevent damage caused by peri-implantitis, we developed a novel Ti-6Al-4V disc/screw coated with poly(lactide-co-glycolide) incorporating fisetin, a naturally occurring flavonoid with anti-inflammatory and antiosteoclastogenic/osteogenic properties. Sustained fisetin release from the Ti-6Al-4V disc and its anti-inflammatory and antiosteoclastogenic/osteogenic differentiation properties were demonstrated using in vitro cell culture experiment. In addition, in a rat model of peri-implantitis, sustained fisetin release from the Ti-6Al-4V screw suppressed inflammation progression, reduced alveolar bone resorption, and stabilized screw movement. These findings highlight sustained fisetin-release Ti-6Al-4V screws as a promising strategy for enhancing orthodontic mini-screw stability and success through peri-implantitis prevention.
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Affiliation(s)
- Ruonan Zhang
- Department of Orthodontics, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata 573-1121, Osaka, Japan
| | - Jun-Ichiro Jo
- Department of Biomaterials, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata 573-1121, Osaka, Japan
| | - Susumu Tsuda
- Department of Chemistry, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata 573-1121, Osaka, Japan
| | - Runbo Li
- Department of Biomaterials, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata 573-1121, Osaka, Japan
| | - Aki Nishiura
- Department of Orthodontics, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata 573-1121, Osaka, Japan
| | - Yoshitomo Honda
- Department of Oral Anatomy, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata 573-1121, Osaka, Japan
| | - Yoshiya Hashimoto
- Department of Biomaterials, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata 573-1121, Osaka, Japan
| | - Naoyuki Matsumoto
- Department of Orthodontics, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata 573-1121, Osaka, Japan
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Valencia J, Yáñez RM, Muntión S, Fernández-García M, Martín-Rufino JD, Zapata AG, Bueren JA, Vicente Á, Sánchez-Guijo F. Improving the therapeutic profile of MSCs: Cytokine priming reduces donor-dependent heterogeneity and enhances their immunomodulatory capacity. Front Immunol 2025; 16:1473788. [PMID: 40034706 PMCID: PMC11872697 DOI: 10.3389/fimmu.2025.1473788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 01/28/2025] [Indexed: 03/05/2025] Open
Abstract
Introduction MSCs exhibit regenerative, anti-inflammatory and immunomodulatory properties due to the large amount of cytokines, chemokines and growth factors they secrete. MSCs have been extensively evaluated in clinical trials, however, in some cases their therapeutic effects are variable. Therefore, strategies to improve their therapeutic potential, such as preconditioning with proinflammatory factors, have been proposed. Several priming approaches have provided non-conclusive results, and the duration of priming effects on MSC properties or their response to a second inflammatory stimulus have not been fully addressed. Methods We have investigated the impact of triple cytokine priming in MSCs on their characterization and viability, their transcriptomic profile, the functionality of innate and acquired immune cells, as well as the maintenance of the response to priming over time, their subsequent responsiveness to a second inflammatory stimulus. Results Priming MSCs with proinflammatory cytokines (CK-MSCs) do not modify the differentiation capacity of MSCs, nor their immunophenotype and viability. Moreover, cytokine priming enhances the anti-inflammatory and immunomodulatory properties of MSCs against NK and dendritic cells, while maintaining the same T cell immunomodulatory capacity as unstimulated MSCs. Thus, they decrease T-lymphocytes and NK cell proliferation, inhibit the differentiation and allostimulatory capacity of dendritic cells and promote the differentiation of monocytes with an immunosuppressive profile. In addition, we have shown for the first time that proinflammatory priming reduces the variability between different donors and MSC origins. Finally, the effect on CK-MSC is maintained over time and even after a secondary inflammatory stimulus. Conclusions Cytokine-priming improves the therapeutic potential of MSCs and reduces inter-donor variability.
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Affiliation(s)
- Jaris Valencia
- Department of Cell Biology, School of Medicine, Complutense University of Madrid, Madrid, Spain
- Heath Research Institute Hospital Clínico San Carlos (IdISSC), Madrid, Spain
- RICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Rosa M. Yáñez
- RICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
- Heath Research Institute-Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain
| | - Sandra Muntión
- RICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Department of Medicine, University of Salamanca and Cell Therapy Area and Hematology Department, IBSAL-University Hospital of Salamanca, Salamanca, Spain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y León, Salamanca, Spain
| | - María Fernández-García
- RICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
- Heath Research Institute-Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain
| | - Jorge Diego Martín-Rufino
- Division of Hematology/Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Agustín G. Zapata
- RICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Department of Cell Biology, Faculty of Biology, Complutense University of Madrid, Madrid, Spain
- Heath Research Institute Hospital 12 de Octubre (I+12), Madrid, Spain
| | - Juan A. Bueren
- RICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
- Heath Research Institute-Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain
| | - Ángeles Vicente
- Department of Cell Biology, School of Medicine, Complutense University of Madrid, Madrid, Spain
- RICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Heath Research Institute Hospital 12 de Octubre (I+12), Madrid, Spain
| | - Fermín Sánchez-Guijo
- RICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Department of Medicine, University of Salamanca and Cell Therapy Area and Hematology Department, IBSAL-University Hospital of Salamanca, Salamanca, Spain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y León, Salamanca, Spain
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Graue J, Timmen M, Schmitz K, Kronenberg D, Böhm M, Sivaraj KK, Bixel MG, Stange R. Anti-inflammatory treatment using alpha melanocyte stimulating hormone (α-MSH) does not alter osteoblasts differentiation and fracture healing. BMC Musculoskelet Disord 2025; 26:123. [PMID: 39915758 PMCID: PMC11800508 DOI: 10.1186/s12891-025-08374-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 01/29/2025] [Indexed: 02/11/2025] Open
Abstract
BACKGROUND Alpha-melanocyte-stimulating-hormone (α-MSH) has been identified as a new anti-inflammatory treatment compound in rheumatoid arthritis (RA) and other inflammatory diseases. However, its direct effect on bone cell differentiation or on bone regeneration, which is an inflammatory process, too, has not been investigated, yet. Bone tissue is significantly affected in inflammatory joint diseases. Additionally, inflammatory signaling is essential -in bone regeneration during fracture healing. Therefore, we evaluated the impact of α-MSH-treatment on bone forming cells in an inflammatory setting in vitro and as a treatment approach in a murine fracture healing model in vivo. METHODS The influence of α-MSH treatment and melanocortin-receptor expression patterns was investigated in vitro in the presence of either IL-1β or/and TNF-α as an inflammatory stimulus. Osteoblast cell function was evaluated by analyzing proliferation and mineralisation capacities. Using quantitative real time PCR, we analyzed mRNA expression of receptors. To explore the impact of α-MSH on bone regeneration in vivo, treatment with α-MSH or NaCl (control) was performed in a murine fracture-healing model using a closed femur fracture stabilized with an intramedullary implant (female, n = 6-8 mice per group). RESULTS α-MSH-treatment did not impair either proliferation nor mineralisation of osteoblastic cells under native or inflammatory conditions (no significant differences found). All four melanocortin receptor-molecules were expressed in murine osteoblastic cells but in very limited amounts and this did not change upon treatment with inflammatory cytokines or α-MSH or both at the same time. Callus formation in fractured femurs of α-MSH-treated mice was slightly delayed at day 14 post fracture with regard to less cartilage formation (NaCl: 19.9%; α-MSH: 13.5%) and soft tissue remodeling (NaCl: 15.2%; α-MSH: 19.5%) but these results were not significantly different and fracture healing overall occurred in a regular way. CONCLUSION α-MSH has no negative impact on bone or bone-forming cells in native, inflammatory, or regenerative contexts. We can conclude from our results, that treatment of inflammatory diseases using α-MSH does not interfere significantly with bone regeneration in a murine fracture model and therefore treatment with α-MSH could be continued without negative effects on bone formation and bone regeneration in patients. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Johanna Graue
- Department of Regenerative Musculoskeletal Medicine, Institute of Musculoskeletal Medicine, University of Muenster, Albert-Schweitzer-Campus 1, D3, 48149, Muenster, Germany
| | - Melanie Timmen
- Department of Regenerative Musculoskeletal Medicine, Institute of Musculoskeletal Medicine, University of Muenster, Albert-Schweitzer-Campus 1, D3, 48149, Muenster, Germany
| | - Katharina Schmitz
- Department of Regenerative Musculoskeletal Medicine, Institute of Musculoskeletal Medicine, University of Muenster, Albert-Schweitzer-Campus 1, D3, 48149, Muenster, Germany
| | - Daniel Kronenberg
- Department of Regenerative Musculoskeletal Medicine, Institute of Musculoskeletal Medicine, University of Muenster, Albert-Schweitzer-Campus 1, D3, 48149, Muenster, Germany
| | - Markus Böhm
- Department of Dermatology, University Hospital Muenster, Von-Esmarch-Str. 58, 48149, Muenster, Germany
| | - Kishor K Sivaraj
- Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, 48149, Muenster, Germany
| | - M Gabriele Bixel
- Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, 48149, Muenster, Germany
| | - Richard Stange
- Department of Regenerative Musculoskeletal Medicine, Institute of Musculoskeletal Medicine, University of Muenster, Albert-Schweitzer-Campus 1, D3, 48149, Muenster, Germany.
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Zhang Y, Zhou C, Xie Q, Xia L, Liu L, Bao W, Lin H, Xiong X, Zhang H, Zheng Z, Zhao J, Liang W. Dual release scaffolds as a promising strategy for enhancing bone regeneration: an updated review. Nanomedicine (Lond) 2025; 20:371-388. [PMID: 39891431 PMCID: PMC11812394 DOI: 10.1080/17435889.2025.2457317] [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: 10/25/2024] [Accepted: 01/20/2025] [Indexed: 02/03/2025] Open
Abstract
Advancements in tissue regeneration, particularly bone regeneration is key area of research due to potential of novel therapeutic approaches. Efforts to reduce reliance on autologous and allogeneic bone grafts have led to the development of biomaterials that promote synchronized and controlled bone healing. However, the use of growth factors is limited by their short half-life, slow tissue penetration, large molecular size and potential toxicity. These factors suggest that traditional delivery methods may be inadequate hence, to address these challenges, new strategies are being explored. These novel approaches include the use of bioactive substances within advanced delivery systems that enable precise spatiotemporal control. Dual-release composite scaffolds offer a promising solution by reducing the need for multiple surgical interventions and simplifying the treatment process. These scaffolds allow for sustained and controlled drug release, enhancing bone repair while minimizing the drawbacks of conventional methods. This review explores various dual-drug release systems, discussing their modes of action, types of drugs used and release mechanisms to improve bone regeneration.
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Affiliation(s)
- Yongtao Zhang
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
| | - Chao Zhou
- Department of Orthopedics, Zhoushan Guanghua Hospital, Zhoushan, Zhejiang, China
| | - Qiong Xie
- Medical Research Center, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
| | - Linying Xia
- Medical Research Center, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
| | - Lu Liu
- Medical Research Center, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
| | - Wenwen Bao
- Medical Research Center, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
| | - Hongming Lin
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
| | - Xiaochun Xiong
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
| | - Hao Zhang
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
| | - Zeping Zheng
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
| | - Jiayi Zhao
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
| | - Wenqing Liang
- Department of Orthopedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
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Jeong H, Subramanian K, Lee JB, Byun H, Shin H, Yun JH. Anti-inflammatory and osteoconductive multi-functional nanoparticles for the regeneration of an inflamed alveolar bone defect. Biomater Sci 2025; 13:810-825. [PMID: 39749408 DOI: 10.1039/d4bm01280a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Infected alveolar bone defects pose challenging clinical issues due to disrupted intrinsic healing mechanisms. Thus, the employment of advanced biomaterials enabling the modulation of several aspects of bone regeneration is necessary. This study investigated the effect of multi-functional nanoparticles on anti-inflammatory/osteoconductive characteristics and bone repair in the context of inflamed bone abnormalities. Tannic-acid mineral nanoparticles (TMPs) were prepared by the supramolecular assembly of tannic acid with bioactive calcium and phosphate ions, which were subsequently incorporated into collagen plugs via molecular interactions. Under physiological conditions, in vitro analysis confirmed that tannic acid was dissociated and released, which significantly reduced the expression of pro-inflammatory genes in lipopolysaccharide (LPS)-activated RAW264.7 cells. Meanwhile, the bioactive ions of Ca2+ and PO43- synergistically increased the gene and protein expressions of osteogenic markers of bone marrow-derived stem cells. For in vivo studies, combined endodontic-periodontal lesions were induced in beagle dogs where the plugs were readily implanted. After 2 months of the implantation, analysis of micro-computed tomography and histomorphometry revealed that groups of dogs implanted with the plug incorporating TMPs exhibited a significant decrease in bone surface density as well as structural model index, and significant increase in the mineralized bone content, respectively, with positive OPN expression being observed in reversal lines. Notably, the profound improvement in bone regeneration relied on the concentration of TMPs in the implants, underscoring the promise of multi-functional nanoparticles for treating infected alveolar bones.
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Affiliation(s)
- Hyewoo Jeong
- Department of Bioengineering, Hanyang University, Seoul, Republic of Korea.
- BK21 FOUR, Education and Research Group for Biopharmaceutical Innovation Leader, Department of Bioengineering, Hanyang University, Seoul, Republic of Korea
| | - Keerthana Subramanian
- Department of Periodontology, College of Dentistry and Institute of Oral Bioscience, Jeonbuk National University, Jeonju, Republic of Korea.
| | - Jong-Bin Lee
- Department of Periodontology, College of Dentistry and Research Institute of Oral Sciences, Gangneung-Wonju National University, Gangneung, Republic of Korea
| | - Hayeon Byun
- Department of Bioengineering, Hanyang University, Seoul, Republic of Korea.
- BK21 FOUR, Education and Research Group for Biopharmaceutical Innovation Leader, Department of Bioengineering, Hanyang University, Seoul, Republic of Korea
| | - Heungsoo Shin
- Department of Bioengineering, Hanyang University, Seoul, Republic of Korea.
- BK21 FOUR, Education and Research Group for Biopharmaceutical Innovation Leader, Department of Bioengineering, Hanyang University, Seoul, Republic of Korea
- Institute of Nano Science and Technology, Hanyang University, Seoul, Republic of Korea
| | - Jeong-Ho Yun
- Department of Periodontology, College of Dentistry and Institute of Oral Bioscience, Jeonbuk National University, Jeonju, Republic of Korea.
- Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Republic of Korea
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Tyrina E, Yakubets D, Markina E, Buravkova L. Hippo Signaling Pathway Involvement in Osteopotential Regulation of Murine Bone Marrow Cells Under Simulated Microgravity. Cells 2024; 13:1921. [PMID: 39594669 PMCID: PMC11592674 DOI: 10.3390/cells13221921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/02/2024] [Accepted: 11/16/2024] [Indexed: 11/28/2024] Open
Abstract
The development of osteopenia is one of the most noticeable manifestations of the adverse effects of space factors on crew members. The Hippo signaling pathway has been shown to play a central role in regulating the functional activity of cells through their response to mechanical stimuli. In the present study, the components of the Hippo pathway and the protective properties of osteodifferentiation inducers were investigated under simulated microgravity (smg) using a heterotypic bone marrow cell culture model, which allows for the maintenance of the close interaction between the stromal and hematopoietic compartments, present in vivo and of great importance for both the fate of osteoprogenitors and hematopoiesis. After 14 days of smg, the osteopotential and osteodifferentiation of bone marrow stromal progenitor cells, the expression of Hippo cascade genes and the immunocytochemical status of the adherent fraction of bone marrow cells, as well as the paracrine profile in the conditioned medium and the localization of Yap1 and Runx2 in mechanosensitive cells of the bone marrow were obtained. Simulated microgravity negatively affects stromal and hematopoietic cells when interacting in a heterotypic murine bone marrow cell culture. This is evidenced by the decrease in cell proliferation and osteopotential. Changes in the production of pleiotropic cytokines IL-6, GROβ and MCP-1 were revealed. Fourteen days of simulated microgravity induced a decrease in the nuclear translocation of Yap1 and the transcription factor Runx2 in the stromal cells of the intact group. Exposure to osteogenic induction conditions partially compensated for the negative effect of simulated microgravity. The data obtained will be crucial for understanding the effects of spaceflight on osteoprogenitor cell growth and differentiation via Hippo-Yap signaling.
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Affiliation(s)
- Ekaterina Tyrina
- Cell Physiology Laboratory, Institute of Biomedical Problems, Russian Academy of Sciences, 123007 Moscow, Russia; (D.Y.); (L.B.)
| | | | - Elena Markina
- Cell Physiology Laboratory, Institute of Biomedical Problems, Russian Academy of Sciences, 123007 Moscow, Russia; (D.Y.); (L.B.)
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9
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Omar O, Rydén L, Wamied AR, Al-Otain I, Alhawaj H, Abuohashish H, Al-Qarni F, Emanuelsson L, Johansson A, Palmquist A, Thomsen P. Molecular mechanisms of poor osseointegration in irradiated bone: In vivo study in a rat tibia model. J Clin Periodontol 2024; 51:1236-1251. [PMID: 38798064 DOI: 10.1111/jcpe.14021] [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: 09/06/2023] [Revised: 04/30/2024] [Accepted: 05/15/2024] [Indexed: 05/29/2024]
Abstract
AIM Radiotherapy is associated with cell depletion and loss of blood supply, which are linked to compromised bone healing. However, the molecular events underlying these effects at the tissue-implant interface have not been fully elucidated. This study aimed to determine the major molecular mediators associated with compromised osseointegration due to previous exposure to radiation. MATERIALS AND METHODS Titanium implants were placed in rat tibiae with or without pre-exposure to 20 Gy irradiation. Histomorphometric, biomechanical, quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay analyses were performed at 1 and 4 weeks after implantation. RESULTS The detrimental effects of irradiation were characterized by reduced bone-implant contact and removal torque. Furthermore, pre-exposure to radiation induced different molecular dysfunctions such as (i) increased expression of pro-inflammatory (Tnf) and osteoclastic (Ctsk) genes and decreased expression of the bone formation (Alpl) gene in implant-adherent cells; (ii) increased expression of bone formation (Alpl and Bglap) genes in peri-implant bone; and (iii) increased expression of pro-inflammatory (Tnf) and pro-fibrotic (Tgfb1) genes in peri-implant soft tissue. The serum levels of pro-inflammatory, bone formation and bone resorption proteins were greater in the irradiated rats. CONCLUSIONS Irradiation causes the dysregulation of multiple biological activities, among which perturbed inflammation seems to play a common role in hindering osseointegration.
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Affiliation(s)
- Omar Omar
- Department of Biomedical Dental Sciences, College of Dentistry, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Louise Rydén
- Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | | | - Ibrahim Al-Otain
- Radiation Oncology, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Hussain Alhawaj
- Department of Environmental Health Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Hatem Abuohashish
- Department of Biomedical Dental Sciences, College of Dentistry, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Faisal Al-Qarni
- Department of Substitutive Dental Sciences, College of Dentistry, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Lena Emanuelsson
- Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anna Johansson
- Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anders Palmquist
- Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Peter Thomsen
- Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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10
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Rong Z, Xi Y, Zhang C, Dai W, Xue H, Luo F, Xu J, Dai F. Herpesvirus-Entry Mediator Inhibits the NF- κB Pathway Activated by IL-17 and Fosters the Osteogenic Differentiation of Allogeneic Mesenchymal Stem Cells. J Tissue Eng Regen Med 2024; 2024:8146991. [PMID: 40225753 PMCID: PMC11919193 DOI: 10.1155/2024/8146991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 08/09/2024] [Indexed: 04/15/2025]
Abstract
The challenge in developing tissue-engineered bones (TEBs) for clinical applications lies in the constraints associated with the source and availability of autologous mesenchymal stem cells (MSCs) derived from the bone marrow, which creates a bottleneck. While allogeneic MSCs have shown promise in TEB applications, their ability to promote bone growth is notably diminished because of the inflammatory reaction at the transplant site and the inherent immune response triggered by allogeneic MSCs. Hence, there is a pressing need to develop methods that enhance the osteogenic differentiation of allogeneic MSCs during transplantation. Previous studies have found that IL-17 is a key proinflammatory factor in initiating inflammation and cascade amplification in the early stages of an inflammatory response, and proinflammatory cytokines such as TNF-α and IL-17 can inhibit the osteogenic differentiation of MSCs in an immune environment. In this study, MSCs expressing HVEM were successfully constructed by viral transfection and further reconfirmed that IL-17 can inhibit the in vivo and in vitro osteogenesis of allogeneic MSCs through in vitro experiments and mouse calvarial bone defect (diameter about 3 mm) model, while MSCs that express herpesvirus-entry mediator (HVEM) exhibit the capacity to suppress immune responses and sustain strong osteogenic potential. We further pointed out that the mechanism by which HVEM promotes the osteogenesis of allogeneic MSCs is related to its inhibition of the IκB kinase (IKK)-NF-κB signaling pathway activated by IL-17 in the immune environment, which can significantly inhibit the ubiquitination and degradation of β-catenin in MSCs induced by the IKK-NF-κB pathway, upregulate the expression of β-catenin, and promote bone formation. Hence, this research provides an initial connection between the Wnt/β-catenin signaling pathway and the IKK-NF-κB pathway during allogeneic MSC transplantation, offering new avenues for investigation and establishing a theoretical foundation for the potential use of HVEM-expressing MSCs in clinical treatments for bone defects.
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Affiliation(s)
- Zhigang Rong
- Department of OrthopaedicsSouthwest HospitalThird Military Medical University (Army Medical University), Chongqing 400038, China
| | - Yuhang Xi
- Department of OrthopaedicsSouthwest HospitalThird Military Medical University (Army Medical University), Chongqing 400038, China
| | - Chengmin Zhang
- Department of OrthopaedicsSouthwest HospitalThird Military Medical University (Army Medical University), Chongqing 400038, China
| | - Wei Dai
- Department of OrthopaedicsSouthwest HospitalThird Military Medical University (Army Medical University), Chongqing 400038, China
| | - Hao Xue
- Department of OrthopaedicsSouthwest HospitalThird Military Medical University (Army Medical University), Chongqing 400038, China
| | - Fei Luo
- Department of OrthopaedicsSouthwest HospitalThird Military Medical University (Army Medical University), Chongqing 400038, China
| | - Jianzhong Xu
- Department of OrthopaedicsSouthwest HospitalThird Military Medical University (Army Medical University), Chongqing 400038, China
| | - Fei Dai
- Department of OrthopaedicsSouthwest HospitalThird Military Medical University (Army Medical University), Chongqing 400038, China
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11
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Hang K, Wang Y, Bai J, Wang Z, Wu W, Zhu W, Liu S, Pan Z, Chen J, Chen W. Chaperone-mediated autophagy protects the bone formation from excessive inflammation through PI3K/AKT/GSK3β/β-catenin pathway. FASEB J 2024; 38:e23646. [PMID: 38795328 DOI: 10.1096/fj.202302425r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 02/06/2024] [Accepted: 04/22/2024] [Indexed: 05/27/2024]
Abstract
Multiple regulatory mechanisms are in place to ensure the normal processes of bone metabolism, encompassing both bone formation and absorption. This study has identified chaperone-mediated autophagy (CMA) as a critical regulator that safeguards bone formation from the detrimental effects of excessive inflammation. By silencing LAMP2A or HSCA8, we observed a hindrance in the osteoblast differentiation of human bone marrow mesenchymal stem cells (hBMSCs) in vitro. To further elucidate the role of LAMP2A, we generated LAMP2A gene knockdown and overexpression of mouse BMSCs (mBMSCs) using adenovirus. Our results showed that LAMP2A knockdown led to a decrease in osteogenic-specific proteins, while LAMP2A overexpression favored the osteogenesis of mBMSCs. Notably, active-β-catenin levels were upregulated by LAMP2A overexpression. Furthermore, we found that LAMP2A overexpression effectively protected the osteogenesis of mBMSCs from TNF-α, through the PI3K/AKT/GSK3β/β-catenin pathway. Additionally, LAMP2A overexpression significantly inhibited osteoclast hyperactivity induced by TNF-α. Finally, in a murine bone defect model, we demonstrated that controlled release of LAMP2A overexpression adenovirus by alginate sodium capsule efficiently protected bone healing from inflammation, as confirmed by imaging and histological analyses. Collectively, our findings suggest that enhancing CMA has the potential to safeguard bone formation while mitigating hyperactivity in bone absorption.
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Affiliation(s)
- Kai Hang
- Department of Orthopaedics, the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Zhejiang, Hangzhou, China
| | - YiBo Wang
- Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - JinWu Bai
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
| | - ZhongXiang Wang
- Department of Orthopedic Surgery of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - WeiLiang Wu
- Department of Orthopaedics, the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Zhejiang, Hangzhou, China
| | - WeiWei Zhu
- Department of Orthopaedics, the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Zhejiang, Hangzhou, China
| | - ShuangAi Liu
- Department of Pediatric Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - ZhiJun Pan
- Department of Orthopedic Surgery of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - JianSong Chen
- Department of Orthopaedics, the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Zhejiang, Hangzhou, China
| | - WenHao Chen
- Department of Orthopaedics, the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Zhejiang, Hangzhou, China
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12
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Capobianco CA, Hankenson KD, Knights AJ. Temporal dynamics of immune-stromal cell interactions in fracture healing. Front Immunol 2024; 15:1352819. [PMID: 38455063 PMCID: PMC10917940 DOI: 10.3389/fimmu.2024.1352819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 02/06/2024] [Indexed: 03/09/2024] Open
Abstract
Bone fracture repair is a complex, multi-step process that involves communication between immune and stromal cells to coordinate the repair and regeneration of damaged tissue. In the US, 10% of all bone fractures do not heal properly without intervention, resulting in non-union. Complications from non-union fractures are physically and financially debilitating. We now appreciate the important role that immune cells play in tissue repair, and the necessity of the inflammatory response in initiating healing after skeletal trauma. The temporal dynamics of immune and stromal cell populations have been well characterized across the stages of fracture healing. Recent studies have begun to untangle the intricate mechanisms driving the immune response during normal or atypical, delayed healing. Various in vivo models of fracture healing, including genetic knockouts, as well as in vitro models of the fracture callus, have been implemented to enable experimental manipulation of the heterogeneous cellular environment. The goals of this review are to (1): summarize our current understanding of immune cell involvement in fracture healing (2); describe state-of-the art approaches to study inflammatory cells in fracture healing, including computational and in vitro models; and (3) identify gaps in our knowledge concerning immune-stromal crosstalk during bone healing.
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Affiliation(s)
- Christina A. Capobianco
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, United States
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
| | - Kurt D. Hankenson
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, United States
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
| | - Alexander J. Knights
- Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, United States
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13
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Zhang P, Feng Q, Chen W, Bai X. Catalpol antagonizes LPS-mediated inflammation and promotes osteoblast differentiation through the miR-124-3p/DNMT3b/TRAF6 axis. Acta Histochem 2024; 126:152118. [PMID: 38039796 DOI: 10.1016/j.acthis.2023.152118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 11/13/2023] [Indexed: 12/03/2023]
Abstract
BACKGROUND Dysregulated inflammation and osteoblast differentiation are implicated in osteoporosis. Exploring the activity of catalpol in inflammation and osteoblast differentiation deepens the understanding of osteoporosis pathogenesis. METHODS LPS was used to treated hFOB1.19 cells to induce inflammation and repress osteoblast differentiation. FOB1.19 cells were induced in osteoblast differentiation medium and treated with LPS and catalpol. Cell viability was assessed using CCK-8. ALP and Alizarin red S staining were conducted for analyzing osteoblast differentiation. The levels of IL-1β, TNF-α and IL-6 were examined by ELISA. The methylation of TRAF6 promoter was examined through MS-PCR. The binding of miR-124-3p to DNMT3b and DNMT3b to TRAF6 promoter was determined with dual luciferase reporter and ChIP assays. RESULTS LPS enhanced secretion of inflammatory cytokines and suppressed osteoblast differentiation. MiR-124-3p and TRAF6 were upregulated and DNMT3b was downregulated in LPS-induced hFOB1.19 cells. Catalpol protected hFOB1.19 cells against LPS via inhibiting inflammation and promoting osteoblast differentiation. MiR-124-3p targeted DNMT3b, and its overexpression abrogated catalpol-mediated protection in LPS-treated hFOB1.19 cells. In addition, DNMT3b methylated TRAF6 promoter to restrain its expression. Catalpol exerted protective effects through suppression of the miR-124-3p/DNMT3b/TRAF6 axis in hFOB1.19 cells. CONCLUSION Catalpol antagonizes LPS-mediated inflammation and suppressive osteoblast differentiation via controlling the miR-124-3p/DNMT3b/TRAF6 axis.
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Affiliation(s)
- Pan Zhang
- Department of Orthopaedics, The People's Hospital of Liaoning Province, Shenyang 110016, Liaoning, People's Republic of China
| | - Qun Feng
- Department of Orthopaedics, The People's Hospital of Liaoning Province, Shenyang 110016, Liaoning, People's Republic of China
| | - Wenxiao Chen
- Department of Orthopaedics, The People's Hospital of Liaoning Province, Shenyang 110016, Liaoning, People's Republic of China
| | - Xizhuang Bai
- Department of Orthopaedics, The People's Hospital of Liaoning Province, Shenyang 110016, Liaoning, People's Republic of China.
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14
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Han H, Chen BT, Liu Y, Wang Y, Xing L, Wang H, Zhou TJ, Jiang HL. Engineered stem cell-based strategy: A new paradigm of next-generation stem cell product in regenerative medicine. J Control Release 2024; 365:981-1003. [PMID: 38123072 DOI: 10.1016/j.jconrel.2023.12.024] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 12/06/2023] [Accepted: 12/16/2023] [Indexed: 12/23/2023]
Abstract
Stem cells have garnered significant attention in regenerative medicine owing to their abilities of multi-directional differentiation and self-renewal. Despite these encouraging results, the market for stem cell products yields limited, which is largely due to the challenges faced to the safety and viability of stem cells in vivo. Besides, the fate of cells re-infusion into the body unknown is also a major obstacle to stem cell therapy. Actually, both the functional protection and the fate tracking of stem cells are essential in tissue homeostasis, repair, and regeneration. Recent studies have utilized cell engineering techniques to modify stem cells for enhancing their treatment efficiency or imparting them with novel biological capabilities, in which advances demonstrate the immense potential of engineered cell therapy. In this review, we proposed that the "engineered stem cells" are expected to represent the next generation of stem cell therapies and reviewed recent progress in this area. We also discussed potential applications of engineered stem cells and highlighted the most common challenges that must be addressed. Overall, this review has important guiding significance for the future design of new paradigms of stem cell products to improve their therapeutic efficacy.
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Affiliation(s)
- Han Han
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Bi-Te Chen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Yang Liu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Yi Wang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Lei Xing
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China; College of Pharmacy, Yanbian University, Yanji 133002, China
| | - Hui Wang
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Tian-Jiao Zhou
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China.
| | - Hu-Lin Jiang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China; College of Pharmacy, Yanbian University, Yanji 133002, China.
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15
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Ali M, He Y, Chang ASN, Wu A, Liu J, Cao Y, Mohammad Y, Popat A, Walsh L, Ye Q, Xu C, Kumeria T. Osteoimmune-modulating and BMP-2-eluting anodised 3D printed titanium for accelerated bone regeneration. J Mater Chem B 2023; 12:97-111. [PMID: 37842835 DOI: 10.1039/d3tb01029e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2023]
Abstract
3D printing of titanium (Ti) metal has potential to transform the field of personalised orthopaedics and dental implants. However, the impacts of controlled surface topographical features of 3D printed Ti implants on their interactions with the cellular microenvironment and incorporation of biological growth factors, which are critical in guiding the integration of implants with bone, are not well studied. In the present study, we explore the role of surface topological features of 3D printed Ti implants using an anodised titania nanotube (TiNT) surface layer in guiding their immune cell interaction and ability to deliver bioactive form of growth factors. TiNT layers with precisely controlled pore diameter (between 21and 130 nm) were anodically grown on 3D printed Ti surfaces to impart a nano-micro rough topology. Immune biomarker profiles at gene and protein levels show that anodised 3D Ti surfaces with smaller pores resulted in classical activation of macrophages (M1-like), while larger pores (i.e., >100 nm) promoted alternate activation of macrophages (M2-like). The in vitro bone mineralisation studies using the conditioned media from the immunomodulatory studies elucidate a clear impact of pore diameter on bone mineralisation. The tubular structure of TiNTs was utilised as a container to incorporate recombinant human bone morphogenetic protein-2 (BMP-2) in the presence of various sugar and polymeric cryoprotectants. Sucrose offered the most sustainable release of preserved BMP-2 from TiNTs. Downstream effects of released BMP-2 on macrophages as well as bone mineralisation were assessed showing bioactivity retention of the released rhBMP-2. Overall, the TiNT surface topography in combination with controlled, sustained, and local release of bioactive growth factors can potentially enhance the osseointegration outcomes of custom 3D printed Ti implants in the clinic.
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Affiliation(s)
- Masood Ali
- Therapeutics Research Group, Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD 4102, Australia
| | - Yan He
- Institute of Regenerative and Translational Medicine, Wuhan University of Science and Technology, Wuhan 430040, China
| | - Anna Sze Ni Chang
- School of Pharmacy, The University of Queensland, Brisbane, Queensland 4102, Australia.
| | - Alice Wu
- School of Pharmacy, The University of Queensland, Brisbane, Queensland 4102, Australia.
| | - Jingyu Liu
- School of Mechanical, Medical and process Engineering, Queensland University of Technology, Brisbane, Queensland 4000, Australia
| | - Yuxue Cao
- School of Pharmacy, The University of Queensland, Brisbane, Queensland 4102, Australia.
| | - Yousuf Mohammad
- Therapeutics Research Group, Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD 4102, Australia
- School of Pharmacy, The University of Queensland, Brisbane, Queensland 4102, Australia.
| | - Amirali Popat
- School of Pharmacy, The University of Queensland, Brisbane, Queensland 4102, Australia.
| | - Laurie Walsh
- School of Dentistry, The University of Queensland, Herston, Queensland 4006, Australia.
| | - Qingsong Ye
- Centre of Regenerative Medicine, Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
| | - Chun Xu
- School of Dentistry, The University of Queensland, Herston, Queensland 4006, Australia.
| | - Tushar Kumeria
- School of Pharmacy, The University of Queensland, Brisbane, Queensland 4102, Australia.
- School of Materials Science and Engineering, University of New South Wales, Kensington, Sydney, New South Wales 2052, Australia
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Kuroyanagi G, Kamiya N, Yamaguchi R, Kim HK. Interleukin-6 receptor blockade improves bone healing following ischemic osteonecrosis in adolescent mice. OSTEOARTHRITIS AND CARTILAGE OPEN 2023; 5:100386. [PMID: 37600923 PMCID: PMC10432805 DOI: 10.1016/j.ocarto.2023.100386] [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: 10/19/2022] [Accepted: 07/13/2023] [Indexed: 08/22/2023] Open
Abstract
Objective Juvenile ischemic osteonecrosis (JIO) of the femoral head is one of the most serious hip disorders causing a permanent deformity of the femoral head in childhood. We recently reported that interleukin 6 (IL-6) is significantly increased in the hip synovial fluid of patients with JIO and that articular chondrocytes are primary source of IL-6. Adolescent JIO is particularly challenging to treat and has poor outcome. This study determined if IL-6 receptor blockade prevents bone loss and improves the bone healing in adolescent JIO. Method Adolescent mice (12-week-old) surgically induced with JIO were treated with either saline or MR16-1, an IL-6 receptor blocker. Results Micro-CT assessment showed significantly increased bone volume (p < 0.001, Cohen's d = 2.0) and trabecular bone thickness (p < 0.001, d = 2.3) after the MR16-1 treatment. Histomorphometric assessment showed significantly increased osteoblast number (p < 0.01, d = 2.3), bone formation rate (p < 0.01, d = 4.3), and mineral apposition rate (p < 0.01, d = 4.1) after the MR16-1 treatment. The number of osteoclasts was unchanged. Histologic assessment showed significantly increased revascularization (p < 0.01) and restoration of the necrotic marrow with new hematopoietic bone marrow (p < 0.01). Vascular endothelial growth factor (VEGF) expression was increased in the revascularized area and the articular cartilage, and in the cultured chondrocytes treated with IL-6 receptor inhibitor. Conclusion IL-6 blockade in adolescent mice with JIO enhanced bone formation and revascularization. The findings suggest IL-6 receptor blocker as a potential medical therapy for adolescent JIO.
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Affiliation(s)
- Gen Kuroyanagi
- Center for Excellence in Hip, Scottish Rite for Children, Dallas, TX 75219, USA
- Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Nobuhiro Kamiya
- Center for Excellence in Hip, Scottish Rite for Children, Dallas, TX 75219, USA
- Faculty of Budo and Sport Studies, Tenri University, Nara 6320071, Japan
| | - Ryosuke Yamaguchi
- Center for Excellence in Hip, Scottish Rite for Children, Dallas, TX 75219, USA
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Harry K.W. Kim
- Center for Excellence in Hip, Scottish Rite for Children, Dallas, TX 75219, USA
- Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390-8883, USA
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17
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Bianconi S, Oliveira KMC, Klein KL, Wolf J, Schaible A, Schröder K, Barker J, Marzi I, Leppik L, Henrich D. Pretreatment of Mesenchymal Stem Cells with Electrical Stimulation as a Strategy to Improve Bone Tissue Engineering Outcomes. Cells 2023; 12:2151. [PMID: 37681884 PMCID: PMC10487010 DOI: 10.3390/cells12172151] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 08/11/2023] [Accepted: 08/16/2023] [Indexed: 09/09/2023] Open
Abstract
Electrical stimulation (EStim), whether used alone or in combination with bone tissue engineering (BTE) approaches, has been shown to promote bone healing. In our previous in vitro studies, mesenchymal stem cells (MSCs) were exposed to EStim and a sustained, long-lasting increase in osteogenic activity was observed. Based on these findings, we hypothesized that pretreating MSC with EStim, in 2D or 3D cultures, before using them to treat large bone defects would improve BTE treatments. Critical size femur defects were created in 120 Sprague-Dawley rats and treated with scaffold granules seeded with MSCs that were pre-exposed or not (control group) to EStim 1 h/day for 7 days in 2D (MSCs alone) or 3D culture (MSCs + scaffolds). Bone healing was assessed at 1, 4, and 8 weeks post-surgery. In all groups, the percentage of new bone increased, while fibrous tissue and CD68+ cell count decreased over time. However, these and other healing features, like mineral density, bending stiffness, the amount of new bone and cartilage, and the gene expression of osteogenic markers, did not significantly differ between groups. Based on these findings, it appears that the bone healing environment could counteract the long-term, pro-osteogenic effects of EStim seen in our in vitro studies. Thus, EStim seems to be more effective when administered directly and continuously at the defect site during bone healing, as indicated by our previous studies.
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Affiliation(s)
- Santiago Bianconi
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany (K.-L.K.); (J.W.); (A.S.); (I.M.); (L.L.); (D.H.)
| | - Karla M. C. Oliveira
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany (K.-L.K.); (J.W.); (A.S.); (I.M.); (L.L.); (D.H.)
| | - Kari-Leticia Klein
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany (K.-L.K.); (J.W.); (A.S.); (I.M.); (L.L.); (D.H.)
| | - Jakob Wolf
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany (K.-L.K.); (J.W.); (A.S.); (I.M.); (L.L.); (D.H.)
| | - Alexander Schaible
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany (K.-L.K.); (J.W.); (A.S.); (I.M.); (L.L.); (D.H.)
| | - Katrin Schröder
- Vascular Research Centre, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany
| | - John Barker
- Frankfurt Initiative for Regenerative Medicine, Experimental Orthopedics and Trauma Surgery, Goethe University Frankfurt, 60528 Frankfurt am Main, Germany;
| | - Ingo Marzi
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany (K.-L.K.); (J.W.); (A.S.); (I.M.); (L.L.); (D.H.)
| | - Liudmila Leppik
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany (K.-L.K.); (J.W.); (A.S.); (I.M.); (L.L.); (D.H.)
| | - Dirk Henrich
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany (K.-L.K.); (J.W.); (A.S.); (I.M.); (L.L.); (D.H.)
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Sonmez Kaplan S, Sazak Ovecoglu H, Genc D, Akkoc T. TNF-α, IL-1B and IL-6 affect the differentiation ability of dental pulp stem cells. BMC Oral Health 2023; 23:555. [PMID: 37568110 PMCID: PMC10422753 DOI: 10.1186/s12903-023-03288-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 08/05/2023] [Indexed: 08/13/2023] Open
Abstract
BACKGROUND This in vitro study examined the effect of the inflammatory cytokines (tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6) on osteogenic, chondrogenic, and adipogenic differentiation of dental pulp stem cells (DPSCs) which have significant relevance in future regenerative therapies. METHODS DPSCs were isolated from the impacted third molar dental pulp and determined with flow cytometry analysis. DPSCs were divided into into 5 main groups with 3 subdivisions for each group making a total of 15 groups. Experimental groups were stimulated with TNF-α, IL-1β, IL-6, and a combination of all three to undergo osteogenic, chondrogenic, and adipogenic differentiation protocols. Next, the differentiation of each group was examined with different staining procedures under a light microscope. Histological analysis of osteogenic, chondrogenic, and adipogenic differentiated pellets was assessed using a modified Bern score. Statistical significance determined using one-way analysis of variance, and correlations were assessed using Pearson's test (two-tailed). RESULTS Stimulation with inflammatory cytokines significantly inhibited the osteogenic, chondrogenic and adipogenic differentiation of DPSCs in terms of matrix and cell formation resulting in weak staining than the unstimulated groups with inflammatory cytokines. On contrary, the unstimulated groups of MSCs have shown to be highly proliferative ability in terms of osteogenic, chondrogenic, and adipogenic differentiation. CONCLUSIONS DPSCs have high osteogenic, chondrogenic, and adipogenic differentiation capabilities. Pretreatment with inflammatory cytokines decreases the differentiation ability in vitro, thus inhibiting tissue formation.
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Affiliation(s)
- Sema Sonmez Kaplan
- Department of Endodontics, Faculty of Dentistry, Biruni University, 10. Yıl Caddesi Protokol Yolu No: 45, 34010, Topkapı, Istanbul, Turkey.
| | - Hesna Sazak Ovecoglu
- Faculty of Dentistry Department of Endodontics, Marmara University, Istanbul, Turkey
| | - Deniz Genc
- Department of Pediatric Health & Diseases Faculty of Health Sciences, Muğla Sıtkı Koçman University, Mugla, Turkey
- Research Laboratories Center, Immunology and Stem Cell Laboratory, Muğla Sıtkı Koçman University, Mugla, Turkey
| | - Tunc Akkoc
- Immunology Department, Marmara University Medical Faculty, Istanbul, Turkey
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Xu ZH, Xiong CW, Miao KS, Yu ZT, Zhang JJ, Yu CL, Huang Y, Zhou XD. Adipokines regulate mesenchymal stem cell osteogenic differentiation. World J Stem Cells 2023; 15:502-513. [PMID: 37424950 PMCID: PMC10324509 DOI: 10.4252/wjsc.v15.i6.502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 02/26/2023] [Accepted: 04/24/2023] [Indexed: 06/26/2023] Open
Abstract
Mesenchymal stem cells (MSCs) can differentiate into various tissue cell types including bone, adipose, cartilage, and muscle. Among those, osteogenic differentiation of MSCs has been widely explored in many bone tissue engineering studies. Moreover, the conditions and methods of inducing osteogenic differentiation of MSCs are continuously advancing. Recently, with the gradual recognition of adipokines, the research on their involvement in different pathophysiological processes of the body is also deepening including lipid metabolism, inflammation, immune regulation, energy disorders, and bone homeostasis. At the same time, the role of adipokines in the osteogenic differentiation of MSCs has been gradually described more completely. Therefore, this paper reviewed the evidence of the role of adipokines in the osteogenic differentiation of MSCs, emphasizing bone formation and bone regeneration.
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Affiliation(s)
- Zhong-Hua Xu
- Department of Orthopedics, Jintan Hospital Affiliated to Jiangsu University, Changzhou 213200, Jiangsu Province, China
| | - Chen-Wei Xiong
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
| | - Kai-Song Miao
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
| | - Zhen-Tang Yu
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
| | - Jun-Jie Zhang
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
| | - Chang-Lin Yu
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
| | - Yong Huang
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
| | - Xin-Die Zhou
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Department of Orthopedics, Gonghe County Hospital of Traditional Chinese Medicine, Hainan Tibetan Autonomous Prefecture 811800, Qinghai Province, China
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20
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Purwaningrum M, Giachelli CM, Osathanon T, Rattanapuchpong S, Sawangmake C. Dissecting specific Wnt components governing osteogenic differentiation potential by human periodontal ligament stem cells through interleukin-6. Sci Rep 2023; 13:9055. [PMID: 37270571 PMCID: PMC10239497 DOI: 10.1038/s41598-023-35569-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 05/20/2023] [Indexed: 06/05/2023] Open
Abstract
Periodontal ligament stem cells (PDLSCs) play a significant role on periodontal tissue and alveolar bone homeostasis. During inflammation, interleukin (IL)-6 serves as one of key cytokine players controlling tissue reaction as well as alveolar bone tissue remodeling. It is believed that periodontal tissue inflammation causes periodontium degradation, especially alveolar bone. However, in this study, we show that an inflammatory mediator, IL-6, may serve another direction on alveolar bone homeostasis during inflammatory condition. We found that, IL-6 at 10 and 20 ng/mL was not cytotoxic and dose-dependently exerted beneficial effects on osteogenic differentiation of human PDLSCs (hPDLSCs), as demonstrated by increased alkaline phosphatase activity, mRNA expression of osteogenic markers, and matrix mineralization. The presence of physiological and inflammatory level of IL-6, the osteogenic differentiation potential by hPDLSCs was enhanced by several possible mechanisms including transforming growth factor (TGF), Wnt, and Notch pathways. After in-depth and thorough exploration, we found that Wnt pathway serves as key regulator controlling osteogenic differentiation by hPDLSCs amid the IL-6 presentation. Surprisingly, apart from other mesenchymal stem cells, distinct Wnt components are employed by hPDLSCs, and both canonical and non-canonical Wnt pathways are triggered by different mechanisms. Further validation by gene silencing, treatment with recombinant Wnt ligands, and β-catenin stabilization/translocation confirmed that IL-6 governed the canonical Wnt/β-catenin pathway via either WNT2B or WNT10B and employed WNT5A to activate the non-canonical Wnt pathway. These findings fulfill the homeostasis pathway governing periodontal tissue and alveolar bone regeneration and may serve for further therapeutic regimen design for restoring the tissues.
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Affiliation(s)
- Medania Purwaningrum
- The International Graduate Program of Veterinary Science and Technology (VST), Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand
- Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand
- Department of Biochemistry, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia
- Veterinary Stem Cell and Bioengineering Research Unit, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Cecilia M Giachelli
- Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA
| | - Thanaphum Osathanon
- Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Bangkok, 10330, Thailand
- Dental Stem Cell Biology Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok, 10330, Thailand
- Center of Excellence in Regenerative Dentistry (CERD), Chulalongkorn University, Bangkok, 10330, Thailand
| | - Sirirat Rattanapuchpong
- Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand.
- Veterinary Stem Cell and Bioengineering Research Unit, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand.
- Academic Affairs, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand.
| | - Chenphop Sawangmake
- Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand.
- Veterinary Stem Cell and Bioengineering Research Unit, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand.
- Department of Pharmacology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand.
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21
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Grčević D, Sanjay A, Lorenzo J. Interactions of B-lymphocytes and bone cells in health and disease. Bone 2023; 168:116296. [PMID: 34942359 PMCID: PMC9936888 DOI: 10.1016/j.bone.2021.116296] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 12/01/2021] [Accepted: 12/08/2021] [Indexed: 02/09/2023]
Abstract
Bone remodeling occurs through the interactions of three major cell lineages, osteoblasts, which mediate bone formation, osteocytes, which derive from osteoblasts, sense mechanical force and direct bone turnover, and osteoclasts, which mediate bone resorption. However, multiple additional cell types within the bone marrow, including macrophages, T lymphocytes and B lymphocytes influence the process. The bone marrow microenvironment, which is supported, in part, by bone cells, forms a nurturing network for B lymphopoiesis. In turn, developing B lymphocytes influence bone cells. Bone health during homeostasis depends on the normal interactions of bone cells with other lineages in the bone marrow. In disease state these interactions become pathologic and can cause abnormal function of bone cells and inadequate repair of bone after a fracture. This review summarizes what is known about the development of B lymphocytes and the interactions of B lymphocytes with bone cells in both health and disease.
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Affiliation(s)
- Danka Grčević
- Department of Physiology and Immunology, Croatian Institute for Brain Research, School of Medicine University of Zagreb, Zagreb, Croatia.
| | - Archana Sanjay
- Department of Orthopaedics, UConn Health, Farmington, CT, USA.
| | - Joseph Lorenzo
- Departments of Medicine and Orthopaedics, UConn Health, Farmington, CT, USA.
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22
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Molecular Basis beyond Interrelated Bone Resorption/Regeneration in Periodontal Diseases: A Concise Review. Int J Mol Sci 2023; 24:ijms24054599. [PMID: 36902030 PMCID: PMC10003253 DOI: 10.3390/ijms24054599] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/19/2023] [Accepted: 02/06/2023] [Indexed: 03/02/2023] Open
Abstract
Periodontitis is the sixth most common chronic inflammatory disease, destroying the tissues supporting the teeth. There are three distinct stages in periodontitis: infection, inflammation, and tissue destruction, where each stage has its own characteristics and hence its line of treatment. Illuminating the underlying mechanisms of alveolar bone loss is vital in the treatment of periodontitis to allow for subsequent reconstruction of the periodontium. Bone cells, including osteoclasts, osteoblasts, and bone marrow stromal cells, classically were thought to control bone destruction in periodontitis. Lately, osteocytes were found to assist in inflammation-related bone remodeling besides being able to initiate physiological bone remodeling. Furthermore, mesenchymal stem cells (MSCs) either transplanted or homed exhibit highly immunosuppressive properties, such as preventing monocytes/hematopoietic precursor differentiation and downregulating excessive release of inflammatory cytokines. In the early stages of bone regeneration, an acute inflammatory response is critical for the recruitment of MSCs, controlling their migration, and their differentiation. Later during bone remodeling, the interaction and balance between proinflammatory and anti-inflammatory cytokines could regulate MSC properties, resulting in either bone formation or bone resorption. This narrative review elaborates on the important interactions between inflammatory stimuli during periodontal diseases, bone cells, MSCs, and subsequent bone regeneration or bone resorption. Understanding these concepts will open up new possibilities for promoting bone regeneration and hindering bone loss caused by periodontal diseases.
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23
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Cao Z, Wang H, Chen J, Zhang Y, Mo Q, Zhang P, Wang M, Liu H, Bao X, Sun Y, Zhang W, Yao Q. Silk-based hydrogel incorporated with metal-organic framework nanozymes for enhanced osteochondral regeneration. Bioact Mater 2023; 20:221-242. [PMID: 35702612 PMCID: PMC9163388 DOI: 10.1016/j.bioactmat.2022.05.025] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/02/2022] [Accepted: 05/19/2022] [Indexed: 11/17/2022] Open
Abstract
Osteochondral defects (OCD) cannot be efficiently repaired due to the unique physical architecture and the pathological microenvironment including enhanced oxidative stress and inflammation. Conventional strategies, such as the control of implant microstructure or the introduction of growth factors, have limited functions failing to manage these complex environments. Here we developed a multifunctional silk-based hydrogel incorporated with metal-organic framework nanozymes (CuTA@SF) to provide a suitable microenvironment for enhanced OCD regeneration. The incorporation of CuTA nanozymes endowed the SF hydrogel with a uniform microstructure and elevated hydrophilicity. In vitro cultivation of mesenchymal stem cells (MSCs) and chondrocytes showed that CuTA@SF hydrogel accelerated cell proliferation and enhanced cell viability, as well as had antioxidant and antibacterial properties. Under the inflammatory environment with the stimulation of IL-1β, CuTA@SF hydrogel still possessed the potential to promote MSC osteogenesis and deposition of cartilage-specific extracellular matrix (ECM). The proteomics analysis further confirmed that CuTA@SF hydrogel promoted cell proliferation and ECM synthesis. In the full-thickness OCD model of rabbit, CuTA@SF hydrogel displayed successfully in situ OCD regeneration, as evidenced by micro-CT, histology (HE, S/O, and toluidine blue staining) and immunohistochemistry (Col I and aggrecan immunostaining). Therefore, CuTA@SF hydrogel is a promising biomaterial targeted at the regeneration of OCD.
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Affiliation(s)
- Zhicheng Cao
- Department of Orthopaedic Surgery, Institute of Digital Medicine, Nanjing First Hospital, Nanjing Medical University, 210006, Nanjing, China
- School of Medicine, Southeast University, 210009, Nanjing, China
| | - Hongmei Wang
- School of Medicine, Southeast University, 210009, Nanjing, China
- Department of Pharmaceutical Sciences, Binzhou Medical University, 264003, Yantai, Shandong, China
| | - Jialin Chen
- School of Medicine, Southeast University, 210009, Nanjing, China
- Jiangsu Key Laboratory for Biomaterials and Devices, Southeast University, 210096, Nanjing, China
- China Orthopedic Regenerative Medicine Group (CORMed), China
| | - Yanan Zhang
- School of Medicine, Southeast University, 210009, Nanjing, China
| | - Qingyun Mo
- School of Medicine, Southeast University, 210009, Nanjing, China
| | - Po Zhang
- Department of Orthopaedic Surgery, Institute of Digital Medicine, Nanjing First Hospital, Nanjing Medical University, 210006, Nanjing, China
- School of Medicine, Southeast University, 210009, Nanjing, China
| | - Mingyue Wang
- School of Medicine, Southeast University, 210009, Nanjing, China
| | - Haoyang Liu
- School of Medicine, Southeast University, 210009, Nanjing, China
| | - Xueyang Bao
- School of Medicine, Southeast University, 210009, Nanjing, China
| | - Yuzhi Sun
- Department of Orthopaedic Surgery, Institute of Digital Medicine, Nanjing First Hospital, Nanjing Medical University, 210006, Nanjing, China
- School of Medicine, Southeast University, 210009, Nanjing, China
| | - Wei Zhang
- School of Medicine, Southeast University, 210009, Nanjing, China
- Jiangsu Key Laboratory for Biomaterials and Devices, Southeast University, 210096, Nanjing, China
- China Orthopedic Regenerative Medicine Group (CORMed), China
| | - Qingqiang Yao
- Department of Orthopaedic Surgery, Institute of Digital Medicine, Nanjing First Hospital, Nanjing Medical University, 210006, Nanjing, China
- China Orthopedic Regenerative Medicine Group (CORMed), China
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24
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Singhatanadgit W, Olsen I, Young A. ICAM-1-mediated osteoblast-T lymphocyte direct interaction increases mineralization through TGF-β1 suppression. J Cell Physiol 2023; 238:420-433. [PMID: 36602898 DOI: 10.1002/jcp.30939] [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: 08/08/2022] [Revised: 11/30/2022] [Accepted: 12/20/2022] [Indexed: 01/06/2023]
Abstract
Modulation of osteoblast functions by T lymphocytes is important in inflammation-associated mineralized tissue diseases. The study aimed to determine whether direct interaction between these two cell types affects osteoblast functions and mineralization. The results showed that direct contact between the two cell types was evident by scanning electron microscopy and transmission electron microscopy. Under osteogenic induction, higher hydroxyapatite precipitation was observed in cocultures with direct contact with T lymphocytes compared with that by osteoblasts cultured alone. Cocultures without direct cell contact caused a decrease in mineralization. Direct cell contact also upregulated intercellular adhesion molecule (ICAM)-1 and simultaneously downregulated transforming growth factor (TGF)-β1 in osteoblasts. However, the downregulation of TGF-β1 was reversed by ICAM-1 blocking. Exogenously added TGF-β1 in cocultures with direct cell contact suppressed mineralization. In conclusion, studies are consistent with ICAM-1-mediated direct contact between osteoblasts and T lymphocytes increasing mineralization via downregulation of TGF-β1 in osteoblasts in vitro. This suggests a possible unexpected, but crucial, role of T lymphocytes in enhancing matrix mineralization during the repair process in vivo. The study identifies ICAM-1/TGF-β1 as possible novel therapeutic targets for the treatment and prevention of inflammation-associated mineralized tissue diseases.
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Affiliation(s)
- Weerachai Singhatanadgit
- Research Unit in Mineralized Tissue Reconstruction and Faculty of Dentistry, Thammasat University, Khlong Luang, Pathum Thani, Thailand
| | - Irwin Olsen
- Division of Biomaterials & Tissue Engineering, UCL Eastman Dental Institute, Royal Free Hospital, London, UK
| | - Anne Young
- Division of Biomaterials & Tissue Engineering, UCL Eastman Dental Institute, Royal Free Hospital, London, UK
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25
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Neutralization of Staphylococcus aureus Protein A Prevents Exacerbated Osteoclast Activity and Bone Loss during Osteomyelitis. Antimicrob Agents Chemother 2023; 67:e0114022. [PMID: 36533935 PMCID: PMC9872667 DOI: 10.1128/aac.01140-22] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Osteomyelitis caused by Staphylococcus aureus is an important and current health care problem worldwide. Treatment of this infection frequently fails not only due to the increasing incidence of antimicrobial-resistant isolates but also because of the ability of S. aureus to evade the immune system, adapt to the bone microenvironment, and persist within this tissue for decades. We have previously demonstrated the role of staphylococcal protein A (SpA) in the induction of exacerbated osteoclastogenesis and increased bone matrix degradation during osteomyelitis. The aim of this study was to evaluate the potential of using anti-SpA antibodies as an adjunctive therapy to control inflammation and bone damage. By using an experimental in vivo model of osteomyelitis, we demonstrated that the administration of an anti-SpA antibody by the intraperitoneal route prevented excessive inflammatory responses in the bone upon challenge with S. aureus. Ex vivo assays indicated that blocking SpA reduced the priming of osteoclast precursors and their response to RANKL. Moreover, the neutralization of SpA was able to prevent the differentiation and activation of osteoclasts in vivo, leading to reduced expression levels of cathepsin K, reduced expression of markers associated with abnormal bone formation, and decreased trabecular bone loss during osteomyelitis. Taken together, these results demonstrate the feasibility of using anti-SpA antibodies as an antivirulence adjunctive therapy that may prevent the development of pathological conditions that not only damage the bone but also favor bacterial escape from antimicrobials and the immune system.
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26
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Chen L, Zhou X, Mo M. The response of RAW264.7 cells to dicalcium silicate nanoparticles and the effect of the nanoparticle-regulated immune environment on osteogenesis. JOURNAL OF MATERIALS RESEARCH 2022; 37:4268-4283. [DOI: 10.1557/s43578-022-00793-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 10/10/2022] [Indexed: 01/04/2025]
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Cui Y, Liu H, Tian Y, Fan Y, Li S, Wang G, Wang Y, Peng C, Wu D. Dual-functional composite scaffolds for inhibiting infection and promoting bone regeneration. Mater Today Bio 2022; 16:100409. [PMID: 36090611 PMCID: PMC9449864 DOI: 10.1016/j.mtbio.2022.100409] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/18/2022] [Accepted: 08/20/2022] [Indexed: 12/14/2022] Open
Abstract
The treatment of infected bone defects is an intractable problem in orthopedics. It comprises two critical parts, namely that of infection control and bone defect repair. According to these two core tasks during treatment, the ideal approach of simultaneously controlling infection and repairing bone defects is promising treatment strategy. Several engineered biomaterials and drug delivery systems with dual functions of anti-bacterial action and ostogenesis-promotion have been developed and demonstrated excellent therapeutic effects. Compared with the conventional treatment method, the dual-functional composite scaffold can provide one-stage treatment avoiding multiple surgeries, thereby remarkably simplifying the treatment process and reducing the treatment time, overcoming the disadvantages of conventional bone transplantation. In this review, the impaired bone repair ability and its specific mechanisms in the microenvironment of pathogen infection and excessive inflammation were analyzed, providing a theoretical basis for the treatment of infectious bone defects. Furthermore, we discussed the composite dual-functional scaffold composed of a combination of antibacterial and osteogenic material. Finally, a series of advanced drug delivery systems with antibacterial and bone-promoting capabilities were summarized and discussed. This review provides a comprehensive understanding for the microenvironment of infectious bone defects and leading-edge design strategies for the antibacterial and bone-promoting dual-function scaffold, thus providing clinically significant treatment methods for infectious bone defects.
Antibacterial and bone-promoting dual-function scaffolds are ideal strategies for treatment of infectious bone defects. The effect of infection on bone repair was summarized in detail from four important aspects. A variety of dual-function scaffolds based on antibacterial and osteogenic materials were discussed. Dual-function drug delivery systems promoting repair of infectious bone defects by locally releasing functional agents. Leading-edge design strategies, challenges and prospects for dual-functional biomaterials were provided.
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Peng J, Mao Z, Liu Y, Tian Y, Leng Q, Gu J, Tan R. 12-Epi-Napelline regulated TGF-β/BMP signaling pathway mediated by BMSCs paracrine acceleration against osteoarthritis. Int Immunopharmacol 2022; 113:109307. [DOI: 10.1016/j.intimp.2022.109307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 09/29/2022] [Accepted: 09/30/2022] [Indexed: 11/05/2022]
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29
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Harun NH, Froemming GRA, Mohd Ismail A, Nawawi H, Mokhtar SS, Abd Muid S. Osteoblast Demineralization Induced by Oxidized High-Density Lipoprotein via the Inflammatory Pathway Is Suppressed by Adiponectin. Int J Mol Sci 2022; 23:ijms232314616. [PMID: 36498945 PMCID: PMC9740717 DOI: 10.3390/ijms232314616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/15/2022] [Accepted: 09/28/2022] [Indexed: 11/24/2022] Open
Abstract
Low mineralization activity by human osteoblast cells (HOBs) indicates abnormal bone remodeling that potentially leads to osteoporosis. Oxidation, the most prominent form of high-density lipoprotein (HDL) modification, is suggested to affect bone mineralization through the inflammatory pathway. Adiponectin, which possesses anti-inflammatory activity, is postulated to have the ability to suppress the detrimental effects of oxidized HDL (oxHDL). This study aimed to investigate the effects of HDL before and after oxidation on markers of mineralization and inflammation. The protective effects of adiponectin on demineralization and inflammation induced by oxHDL were also investigated. OxHDL at 100 µg/mL protein had the highest inhibitory effect on mineralization, followed by lower calcium incorporation. OxHDL also had significantly lower expression of a mineralization marker (COL1A2) and higher expression of inflammatory markers (IL-6, TNF-α, and RELA proto-oncogene, NF-κβ (p65)) compared to the unstimulated control group. These findings suggest that oxHDL reduces the mineralization activity of HOBs by increasing the expression of inflammatory markers. Interestingly, co-incubation of adiponectin and oxHDL in HOBs resulted in higher expression of mineralization markers (ALPL, COL1A2, BGLAP, and RUNX2) and significantly reduced all targeted inflammatory markers compared to the oxHDL groups. On the contrary, HDL increased the expression of mineralization markers (COL1A2 and STAT-3) and exhibited lower expression of inflammatory cytokines (IL-6 and TNF-α), proving the protective effect of HDL beyond the reverse cholesterol transport activity.
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Affiliation(s)
- Noor Hanisa Harun
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh 47000, Selangor, Malaysia
| | - Gabriele Ruth Anisah Froemming
- Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Universiti Malaysia Sarawak, Kota Samarahan 94300, Sarawak, Malaysia
| | - Aletza Mohd Ismail
- Department of Pathology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh 47000, Selangor, Malaysia
| | - Hapizah Nawawi
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh 47000, Selangor, Malaysia
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerforM), Universiti Teknologi MARA, Sungai Buloh 47000, Selangor, Malaysia
| | - Siti Shuhada Mokhtar
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh 47000, Selangor, Malaysia
| | - Suhaila Abd Muid
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh 47000, Selangor, Malaysia
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerforM), Universiti Teknologi MARA, Sungai Buloh 47000, Selangor, Malaysia
- Correspondence: ; Tel.: +60-361267338
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Wang D, Chen MW, Wei YJ, Geng WB, Hu Y, Luo Z, Cai KY. Construction of Wogonin Nanoparticle-Containing Strontium-Doped Nanoporous Structure on Titanium Surface to Promote Osteoporosis Fracture Repair. Adv Healthc Mater 2022; 11:e2201405. [PMID: 36048734 DOI: 10.1002/adhm.202201405] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 08/25/2022] [Indexed: 01/28/2023]
Abstract
M2 polarization of macrophage is an important immunomodulatory event that attenuates inflammation. To regulate the immune microenvironment in osteoporotic conditions for enhancing bone healing, strontium-doped nano-structure is fabricated on the surface of titanium implant via microarc oxidation and electrochemical deposition technology, followed by the addition of multiplayer coatings embedded with silk fibroin-based wogonin nanoparticles (Ti-MAO/Sr/LBLWNP ) by layer-by-layer self-assembly technique (LBL). It is found that Ti-MAO/Sr/LBLWNP can release wogonin and Sr2+ in a sustainable manner for more than 7 and 21 days. In vitro studies show that Ti-MAO/Sr/LBLWNP significantly upregulates the expression of CD206 while reducing the expression of CD86. Meanwhile, Ti-MAO/Sr/LBLWNP can promote the expression level of M2 macrophage anti-inflammatory factor (TGF-β1, Arg-1), which improves the proliferation and osteogenic differentiation of osteoblasts through paracrine signaling. Compared to bare titanium, Ti-MAO/Sr/LBLWNP significantly inhibits the expression of inflammatory factors around the implant and effectively promotes new bone formation at pre-implant interface after implantation for 4 weeks. This study provides a simple and effective method to develop functional titanium alloy materials for osteoporotic fracture repair.
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Affiliation(s)
- Dong Wang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, P. R. China
| | - Mao-Wen Chen
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, P. R. China
| | - Yu-Jia Wei
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, P. R. China
| | - Wen-Bo Geng
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, P. R. China
| | - Yan Hu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, P. R. China
| | - Zhong Luo
- School of Life Science, Chongqing University, Chongqing, 400044, P. R. China
| | - Kai-Yong Cai
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, P. R. China
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Zhao DW, Fan XC, Zhao YX, Zhao W, Zhang YQ, Zhang RH, Cheng L. Biocompatible Nano-Hydroxyapatites Regulate Macrophage Polarization. MATERIALS (BASEL, SWITZERLAND) 2022; 15:ma15196986. [PMID: 36234325 PMCID: PMC9573195 DOI: 10.3390/ma15196986] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/06/2022] [Accepted: 10/05/2022] [Indexed: 05/27/2023]
Abstract
Research on regulation of the immune microenvironment based on bioactive materials is important to osteogenic regeneration. Hydroxyapatite (HAP) is believed to be a promising scaffold material for dental and orthopedic implantation due to its ideal biocompatibility and high osteoconductivity. However, any severe inflammation response can lead to loosening and fall of implantation, which cause implant failures in the clinic. Morphology modification has been widely studied to regulate the host immune environment and to further promote bone regeneration. Here, we report the preparation of nHAPs, which have uniform rod-like shape and different size (200 nm and 400 nm in length). The morphology, biocompatibility, and anti-inflammatory properties were evaluated. The results showed that the 400 nm nHAPs exhibited excellent biocompatibility and osteoimmunomodulation, which can not only induce M2-phenotype macrophages (M2) polarization to decrease the production of inflammatory cytokines, but also promote the production of osteogenic factor. The reported 400 nm nHAPs are promising for osteoimmunomodulation in bone regeneration, which is beneficial for clinical application of bone defects.
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Affiliation(s)
- Da-Wang Zhao
- Department of Orthopedics, Qilu Hospital of Shandong University, Jinan 250012, China
- Institute of Stomatology, Shandong University, Jinan 250012, China
| | - Xin-Cheng Fan
- Department of Orthopedics, Qilu Hospital of Shandong University, Jinan 250012, China
- Department of Orthopaedics, Taian City Central Hospital, Tai’an 271000, China
| | - Yi-Xiang Zhao
- Department of Orthopedics, Qilu Hospital of Shandong University, Jinan 250012, China
- Institute of Stomatology, Shandong University, Jinan 250012, China
| | - Wei Zhao
- Department of Orthopedics, Qilu Hospital of Shandong University, Jinan 250012, China
- Institute of Stomatology, Shandong University, Jinan 250012, China
| | - Yuan-Qiang Zhang
- Department of Orthopedics, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Ren-Hua Zhang
- Outpatient Department, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Lei Cheng
- Department of Orthopedics, Qilu Hospital of Shandong University, Jinan 250012, China
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Xu X, Wang M, Wang Z, Chen Q, Chen X, Xu Y, Dai M, Wu B, Li Y. The bridge of the gut-joint axis: Gut microbial metabolites in rheumatoid arthritis. Front Immunol 2022; 13:1007610. [PMID: 36275747 PMCID: PMC9583880 DOI: 10.3389/fimmu.2022.1007610] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 09/22/2022] [Indexed: 11/13/2022] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint destruction, synovitis, and pannus formation. Gut microbiota dysbiosis may exert direct pathogenic effects on gut homeostasis. It may trigger the host's innate immune system and activate the "gut-joint axis", which exacerbates the RA. However, although the importance of the gut microbiota in the development and progression of RA is widely recognized, the mechanisms regulating the interactions between the gut microbiota and the host immune system remain incompletely defined. In this review, we discuss the role of gut microbiota-derived biological mediators, such as short-chain fatty acids, bile acids, and tryptophan metabolites, in maintaining intestinal barrier integrity, immune balance and bone destruction in RA patients as the bridge of the gut-joint axis.
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Affiliation(s)
- Xiaoyu Xu
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China
- Department of Rheumatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Miao Wang
- Department of Rheumatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Zikang Wang
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China
| | - Qian Chen
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China
| | - Xixuan Chen
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China
| | - Yingyue Xu
- Department of Rheumatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Min Dai
- Department of Rheumatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Bin Wu
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China
- Department of Rheumatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Yanping Li
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China
- Department of Rheumatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
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V. K. AD, Ray S, Arora U, Mitra S, Sionkowska A, Jaiswal AK. Dual drug delivery platforms for bone tissue engineering. Front Bioeng Biotechnol 2022; 10:969843. [PMID: 36172012 PMCID: PMC9511792 DOI: 10.3389/fbioe.2022.969843] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 08/23/2022] [Indexed: 11/22/2022] Open
Abstract
The dual delivery platforms used in bone tissue engineering provide supplementary bioactive compounds that include distinct medicines and growth factors thereby aiding enhanced bone regeneration. The delivery of these compounds can be adjusted for a short or prolonged time based on the requirement by altering various parameters of the carrier platform. The platforms thus used are fabricated to mimic the niche of the bone microenvironment, either in the form of porous 3D structures, microspheres, or films. Thus, this review article focuses on the concept of dual drug delivery platform and its importance, classification of various platforms for dual drug delivery specific to bone tissue engineering, and finally highlights the foresight into the future direction of these techniques for better clinical applications.
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Affiliation(s)
- Anupama Devi V. K.
- Tissue Engineering Group, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology (VIT), Vellore, India
- School of Bio Sciences and Technology (SBST), Vellore Institute of Technology (VIT), Vellore, India
| | - Sarbajit Ray
- School of Bio Sciences and Technology (SBST), Vellore Institute of Technology (VIT), Vellore, India
| | - Udita Arora
- School of Bio Sciences and Technology (SBST), Vellore Institute of Technology (VIT), Vellore, India
| | - Sunrito Mitra
- School of Bio Sciences and Technology (SBST), Vellore Institute of Technology (VIT), Vellore, India
| | | | - Amit Kumar Jaiswal
- Tissue Engineering Group, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology (VIT), Vellore, India
- *Correspondence: Amit Kumar Jaiswal,
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Gutierrez-Camacho JR, Avila-Carrasco L, Martinez-Vazquez MC, Garza-Veloz I, Zorrilla-Alfaro SM, Gutierrez-Camacho V, Martinez-Fierro ML. Oral Lesions Associated with COVID-19 and the Participation of the Buccal Cavity as a Key Player for Establishment of Immunity against SARS-CoV-2. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:11383. [PMID: 36141654 PMCID: PMC9517300 DOI: 10.3390/ijerph191811383] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 09/01/2022] [Accepted: 09/06/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND Some oral lesions have been described in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); the possibility has been raised that the buccal lesions observed in patients with the coronavirus disease 2019 (COVID-19) are due to this virus and the patient's systemic condition. The aim of this review was to integrate the knowledge related to the oral lesions associated with COVID-19 and the participation of the buccal cavity in the establishment of immunity against SARS-CoV-2. METHODS A literature search on the manifestations of buccal lesions from the beginning of the pandemic until October 2021 was carried out by using the PubMed database. A total of 157 scientific articles were selected from the library, which included case reports and reports of lesions appearing in patients with COVID-19. RESULTS Oral lesions included erosions, ulcers, vesicles, pustules, plaques, depapillated tongue, and pigmentations, among others. The oral cavity is a conducive environment for the interaction of SARS-CoV-2 with the mucosal immune system and target cells; direct effects of the virus in this cavity worsen the antiviral inflammatory response of underlying oral disorders, immunodeficiencies, and autoimmunity primarily. CONCLUSIONS The oral cavity is an accessible and privileged environment for the interaction of SARS-CoV-2 with the mucosal immune system and target cells; the direct effects of the virus in this cavity worsen the antiviral inflammatory response of underlying oral disorders, in particular those related to immunodeficiencies and autoimmunity.
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Slavkova N, Nedevska M. Aseptic osteonecrosis of the maxilla after severe COVID-19 infection and its treatment. Radiol Case Rep 2022; 17:3228-3232. [PMID: 35801131 PMCID: PMC9250319 DOI: 10.1016/j.radcr.2022.06.009] [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: 04/16/2022] [Revised: 05/31/2022] [Accepted: 06/04/2022] [Indexed: 12/04/2022] Open
Abstract
The course of the new SARS-CoV-2 (COVID-19) is unpredictable and is still being investigated. Although the majority of complications are expected to affect the respiratory system, there have been reports in literature concerning the adverse effects of the infection on bone and joint tissue. Several complications have been observed in the maxillofacial area in people who suffered from the infection, including osteonecrosis and osteomyelitis of the jaw. These complications have been subject to various hypotheses. They may result either from the disease pathogenetic mechanism or from a response to the therapeutic modalities used to treat the underlying disease, and overuse of particular medications – glucocorticoids, antirheumatics, interleukin-6 inhibitors, and antibiotics. This article presents a case of osteonecrosis of the maxilla after severe COVID-19 infection.
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Regenerative and Anti-Inflammatory Potential of Regularly Fed, Starved Cells and Extracellular Vesicles In Vivo. Cells 2022; 11:cells11172696. [PMID: 36078106 PMCID: PMC9455002 DOI: 10.3390/cells11172696] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/20/2022] [Accepted: 08/25/2022] [Indexed: 11/17/2022] Open
Abstract
Background: Mesenchymal stem/stromal cells (MSC) have been employed successfully in immunotherapy and regenerative medicine, but their therapeutic potential is reduced considerably by the ischemic environment that exists after transplantation. The assumption that preconditioning MSC to promote quiescence may result in increased survival and regenerative potential upon transplantation is gaining popularity. Methods: The purpose of this work was to evaluate the anti-inflammatory and regenerative effects of human bone marrow MSC (hBM-MSC) and their extracellular vesicles (EVs) grown and isolated in a serum-free medium, as compared to starved hBM-MSC (preconditioned) in streptozotocin-induced diabetic fractured male C57BL/6J mice. Results: Blood samples taken four hours and five days after injection revealed that cells, whether starved or not, generated similar plasma levels of inflammatory-related cytokines but lower levels than animals treated with EVs. Nonetheless, starved cells prompted the highest production of IL-17, IL-6, IL-13, eotaxin and keratinocyte-derived chemokines and induced an earlier soft callus formation and mineralization of the fracture site compared to EVs and regularly fed cells five days after administration. Conclusions: Preconditioning may be crucial for refining and defining new criteria for future MSC therapies. Additionally, the elucidation of mechanisms underpinning an MSC’s survival/adaptive processes may result in increased cell survival and enhanced therapeutic efficacy following transplantation.
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Zhao X, Sun W, Guo B, Cui L. Circular RNA BIRC6 depletion promotes osteogenic differentiation of periodontal ligament stem cells via the miR-543/PTEN/PI3K/AKT/mTOR signaling pathway in the inflammatory microenvironment. Stem Cell Res Ther 2022; 13:417. [PMID: 35964136 PMCID: PMC9375426 DOI: 10.1186/s13287-022-03093-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 05/14/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Periodontal ligament stem cells (PDLSCs) are the ideal seed cells for periodontal tissue regeneration. It is well established that persistent inflammation significantly impairs the osteogenic differentiation capability of PDLSCs. Therefore, maintaining PDLSC osteogenic potential under the inflammatory microenvironment is important for treating bone loss in periodontitis. The aim of our study was to explore the potential role of circular RNA BIRC6 (circBIRC6) in regulating osteogenic differentiation of PDLSCs in the inflammatory conditions. METHODS Alkaline phosphatase staining, Alizarin Red staining, quantitative real-time polymerase chain reaction, western blotting and immunofluorescence staining were used to evaluated the effects of circBIRC6 on the osteogenic differentiation of PDLSCs. RNA pull-down and luciferase assays were performed to explore the interaction between circBIRC6 and miR-543. Then, the downstream signaling pathway affected by circBIRC6/miR-543 axis was further investigated. RESULTS The expression level of circBIRC6 was higher in PDLSCs exposed to inflammatory stimulus and in periodontitis tissues compared to the respective controls. Downregulation of circBIRC6 enhanced the osteogenic potential of PDLSCs under the inflammatory conditions, and upregulation of circBIRC6 led to opposite findings. Mechanistically, we found that circBIRC6 modulated PDLSC osteogenic differentiation through sponging miR-543. More importantly, we have demonstrated that circBIRC6/miR-543 axis regulated the mineralization capacity of PDLSCs via PTEN/PI3K/AKT/mTOR signaling pathway in the inflammatory microenvironment. CONCLUSIONS In summary, the expression of miR-543 is significantly increased following circBIRC6 downregulation, leading to inhibition of PTEN and subsequently activation of PI3K/AKT/mTOR signaling pathway. Therefore, targeting circBIRC6 might represent a potential therapeutic strategy for improving bone loss in periodontitis.
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Affiliation(s)
- Xinyuan Zhao
- Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Wenjuan Sun
- Department of Stomatology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China
| | - Bing Guo
- Department of Dentistry, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China.
| | - Li Cui
- Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China. .,School of Dentistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
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Won JE, Kim WJ, Ryu JJ, Shim JS. Guided Bone Regeneration with a Nitric-Oxide Releasing Polymer Inducing Angiogenesis and Osteogenesis in Critical-Sized Bone Defects. Macromol Biosci 2022; 22:e2200162. [PMID: 35895972 DOI: 10.1002/mabi.202200162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/09/2022] [Indexed: 11/07/2022]
Abstract
Synthetic scaffolds, as bone grafts, provide a favorable environment for the repair and growth of new bone tissue at defect sites. However, the lack of angio- and osteo-induction limits the usefulness of artificial scaffolds for bone regeneration. Nitric oxide (NO) performs essential roles in healing processes, such as regulating inflammation and addressing incomplete revascularization. In this study, we developed a polymer capable of controlled NO release to promote the osteogenic capacity in artificial scaffolds. The biological efficiency of the NO compound was assessed by its effect on pre-osteoblasts and macrophages in vitro and the extent of vascularization and bone formation in the calvaria defect model in vivo. The compound did not inhibit cell adhesion or proliferation. NO treatment significantly increased both alkaline phosphatase activity and mineralization in pre-osteoblasts. Macrophages treated with NO secreted high levels of anti-inflammatory factors and adopted the pro-regenerative M2 phenotype. In the critical-sized defect model, the collagen scaffold containing the NO compound enhanced neovascularization and bone formation. The developed NO-releasing system promoted osteogenesis and regeneration of damaged bone tissue. As the multiple functions of NO involve macrophage modulation and angiogenesis, such release systems may be valuable for guiding bone regeneration in critical-sized defects. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Jong-Eun Won
- Institute for Clinical Dental Research, Department of Dentistry, Korea University Guro Hospital, Seoul, 08308, Republic of Korea
| | - Won Jong Kim
- Department of Chemistry, Pohang University of Science and Technology (POSTECH), Pohang-si, 37673, Republic of Korea
| | - Jae Jun Ryu
- Department of Dentistry, Korea University Anam Hospital, Seoul, 02841, Republic of Korea
| | - Ji Suk Shim
- Institute for Clinical Dental Research, Department of Dentistry, Korea University Guro Hospital, Seoul, 08308, Republic of Korea
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Gu H, Ru Y, Wang W, Cai G, Gu L, Ye J, Zhang WB, Wang L. Orexin-A Reverse Bone Mass Loss Induced by Chronic Intermittent Hypoxia Through OX1R-Nrf2/HIF-1α Pathway. Drug Des Devel Ther 2022; 16:2145-2160. [PMID: 35818538 PMCID: PMC9270907 DOI: 10.2147/dddt.s363286] [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: 02/20/2022] [Accepted: 05/24/2022] [Indexed: 11/28/2022] Open
Abstract
Background Recent studies suggest that there is a potential connection between obstructive sleep apnea (OSA) and osteoporosis through dysregulation of bone metabolism. Orexin-A, a neuroprotective peptide secreted by the hypothalamus, is at a lower level in the plasma of OSA patients, which regulates appetite, energy expenditure and sleep-wake states. However, the protective effect of orexin-A on bone metabolism in OSA is unclear. Purpose To investigate whether the activation of OX1R by orexin-A can reverse bone mass loss induced by chronic intermittent hypoxia (CIH). Methods Mice were randomly divided into the normoxia group and CIH group. Within the CIH or normoxia groups, treatment groups were given a subcutaneous injection of either orexin-A or saline vehicle once every day for 4 weeks and then femurs were removed for micro-CT scans. Histology and immunohistochemical staining were performed to observe and calculate the changes in femurs as a result of hypoxia. Cell immunofluorescence and immunohistochemical staining were used to detect the expression of orexin receptors in MC3T3-E1 cells or in bones. CCK-8 assay, ALP assay kit and alizarin red staining were used to detect the viability, alkaline phosphatase (ALP) activity, and capacity of mineralization, respectively. The effect of orexin-A on osteogenic differentiation of MC3T3-E1 cells was evaluated using qRT-PCR, Western blot and cell staining. Results CIH led to a decrease in the amount and density of trabecular bone, downregulated OCN expression while increasing osteoclast numbers in femurs and inhibited the expression of RUNX2, OSX, OPN and Nrf2 in MC3T3-E1 cells. Orexin-A treatment alleviated these CIH-induced effects by combining to OX1R. The level of HIF-1α was elevated both in CIH and orexin-A treatment groups. Conclusion CIH environment inhibits osteogenesis and orexin-A can reverse bone mass loss induced by CIH through OX1R-Nrf2/HIF-1α pathway.
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Affiliation(s)
- Hong Gu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, People′s Republic of China
| | - Yiwen Ru
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, People′s Republic of China
| | - Wei Wang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, People′s Republic of China
- Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, People′s Republic of China
| | - Guanhui Cai
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, People′s Republic of China
| | - Lanxin Gu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, People′s Republic of China
| | - Junjie Ye
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, People′s Republic of China
| | - Wei-Bing Zhang
- Department of Stomatology, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, People′s Republic of China
- Department of Stomatology, Medical Center of Soochow University, Suzhou, People′s Republic of China
- Correspondence: Wei-Bing Zhang, Department of Stomatology, Dushu Lake Hospital Affiliated to Soochow University, 9 Chongwen Road, Suzhou, 215000, People′s Republic of China, Tel +86-512-67505200, Email
| | - Lin Wang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, People′s Republic of China
- Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, People′s Republic of China
- Lin Wang, Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, 136 Hanzhong Road, Nanjing, 210029, People′s Republic of China, Tel +86-025-69593060, Email
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Chai H, Zhang ZH, Fang JY, She C, Geng DC, Xu W. Osteocytic cells exposed to titanium particles increase sclerostin expression and inhibit osteoblastic cell differentiation mostly via direct cell-to-cell contact. J Cell Mol Med 2022; 26:4371-4385. [PMID: 35762300 PMCID: PMC9345295 DOI: 10.1111/jcmm.17460] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 04/21/2022] [Accepted: 06/06/2022] [Indexed: 12/01/2022] Open
Abstract
The mechanism underlying induction of periprosthetic osteolysis by wear particles remains unclear. In this study, cultured MLO‐Y4 osteocytic cells were exposed to different concentrations of titanium (Ti) particles. The results showed that Ti particles increased expression of the osteocytic marker SOST/sclerostin in a dose‐dependent manner, accelerated apoptosis of MLO‐Y4 cells, increased the expression of IL‐6, TNF‐α and connexin 43. SOST silence alleviated the increase of MLO‐Y4 cells apoptosis, decreased the expression of IL‐6, TNF‐α and connexin 43 caused by Ti particles. The different co‐culture systems of MLO‐Y4 cells with MC3T3‐E1 osteoblastic cells were further used to observe the effects of osteocytic cells' changes induced by Ti particles on osteoblastic cells. MLO‐Y4 cells treated with Ti particles inhibited dramatically differentiation of MC3T3‐E1 cells mostly through direct cell‐to‐cell contact. SOST silence attenuated the inhibition effects of Ti‐induced MLO‐Y4 on MC3T3‐E1 osteoblastic differentiation, which ALP level and mineralization of MC3T3‐E1 cells increased and the expression of ALP, OCN and Runx2 increased compared to the Ti‐treated group. Taken together, Ti particles had negative effects on MLO‐Y4 cells and the impact of Ti particles on osteocytic cells was extensive, which may further inhibit osteoblastic differentiation mostly through intercellular contact directly. SOST/sclerostin plays an important role in the process of mutual cell interaction. These findings may help to understand the effect of osteocytes in wear particle‐induced osteolysis.
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Affiliation(s)
- Hao Chai
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Zai Hang Zhang
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Jing Yi Fang
- The Experiment Center, The Medical College of Soochow University, Suzhou, Jiangsu Province, China
| | - Chang She
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - De Chun Geng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Wei Xu
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
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Genç D, Günaydın B, Sezgin S, Aladağ A, Tarhan EF. The Comparison of the Differentiation Potential of Periodontal Ligament and Dental Pulp Mesenchymal Stem Cells in the Inflammatory Synovium Microenvironment. CYPRUS JOURNAL OF MEDICAL SCIENCES 2022. [DOI: 10.4274/cjms.2022.2021-192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Mo Q, Zhang W, Zhu A, Backman LJ, Chen J. Regulation of osteogenic differentiation by the pro-inflammatory cytokines IL-1β and TNF-α: current conclusions and controversies. Hum Cell 2022; 35:957-971. [PMID: 35522425 DOI: 10.1007/s13577-022-00711-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 04/23/2022] [Indexed: 12/09/2022]
Abstract
Treatment of complex bone fracture diseases is still a complicated problem that is urged to be solved in orthopedics. In bone tissue engineering, the use of mesenchymal stromal/stem cells (MSCs) for tissue repair brings hope to the medical field of bone diseases. MSCs can differentiate into osteoblasts and promote bone regeneration. An increasing number of studies show that the inflammatory microenvironment affects the osteogenic differentiation of MSCs. It is shown that TNF-α and IL-1β play different roles in the osteogenic differentiation of MSCs via different signal pathways. The main factors that affect the role of TNF-α and IL-1β in osteogenic differentiation of MSCs include concentration and the source of stem cells (different species and different tissues). This review in-depth analyzes the roles of pro-inflammatory cytokines in the osteogenic differentiation of MSCs and reveals some current controversies to provide a reference of comprehensively understanding.
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Affiliation(s)
- Qingyun Mo
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Wei Zhang
- School of Medicine, Southeast University, Nanjing, 210009, China
- Jiangsu Key Laboratory for Biomaterials and Devices, Southeast University, Nanjing, 210096, China
- China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China
| | - Aijing Zhu
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Ludvig J Backman
- Department of Integrative Medical Biology, Anatomy, Umeå University, SE-901 87, Umeå, Sweden
- Department of Community Medicine and Rehabilitation, Physiotherapy, Umeå University, SE-901 87, Umeå, Sweden
| | - Jialin Chen
- School of Medicine, Southeast University, Nanjing, 210009, China.
- Jiangsu Key Laboratory for Biomaterials and Devices, Southeast University, Nanjing, 210096, China.
- China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China.
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He M, Wang Q, Feng Y, Gao X, He C, Li J, Zhao W, Tian W, Zhao C. Spatiotemporal Management of the Osteoimmunomodulation of Fibrous Scaffolds by Loading a Novel Amphiphilic Nanomedicine. ACS APPLIED MATERIALS & INTERFACES 2022; 14:13991-14003. [PMID: 35311248 DOI: 10.1021/acsami.1c20809] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Implanted bone scaffolds or their biodegradation products may disturb the sequential functions of distinct macrophage phenotypes and cause improper timing of macrophage activation, resulting in delayed or dysfunctional bone regeneration. Although spatiotemporal manipulation of the immune response has been recognized as a promising strategy to address this issue, developing satisfactory drug delivery systems with the function of proper timing control on the macrophage phenotype transformation from pro-inflammatory M1 to anti-inflammatory M2 phenotype still remains a challenge. Here, we propose an amphiphilic nanomedicine with dual anti-inflammatory functions and inflammation-responsive drug release properties to spatiotemporally manage the osteoimmunomodulation of the bone scaffold. The nanomedicine enables the modified scaffold to manipulate the immune response in a staged manner, not only avoiding the overinhibition of M1 macrophages in the initial phase but also facilitating its polarization to M2 phenotype, as well as exhibiting full-course inhibition on later biodegradation-induced inflammation. The described immunomodulatory manner attempts to conform to the principle of osteoimmunomodulation, consequently resulting in better in vivo osteogenesis compared with traditional drug delivery systems. We anticipate that this strategy might aid the development of advanced immunomodulatory bone biomaterials.
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Affiliation(s)
- Min He
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.,National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.,State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Qian Wang
- College of Polymer Science and Engineering, Sichuan University, Chengdu, Sichuan 610065, China
| | - Yunbo Feng
- College of Polymer Science and Engineering, Sichuan University, Chengdu, Sichuan 610065, China
| | - Xinghui Gao
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.,National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.,State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Chao He
- College of Polymer Science and Engineering, Sichuan University, Chengdu, Sichuan 610065, China
| | - Jiangge Li
- College of Biomedical Engineering, Sichuan University, Chengdu, Sichuan 610065, China
| | - Weifeng Zhao
- College of Polymer Science and Engineering, Sichuan University, Chengdu, Sichuan 610065, China
| | - Weidong Tian
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.,National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.,State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Changsheng Zhao
- College of Polymer Science and Engineering, Sichuan University, Chengdu, Sichuan 610065, China
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Choe H, Tatro JM, Hausman BS, Hujer KM, Marshall SH, Akkus O, Rather PN, Lee Z, Bonomo RA, Greenfield EM. Staphylococcus aureus and Acinetobacter baumannii Inhibit Osseointegration of Orthopedic Implants. Infect Immun 2022; 90:e0066921. [PMID: 35099267 PMCID: PMC8929340 DOI: 10.1128/iai.00669-21] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/06/2022] [Indexed: 11/20/2022] Open
Abstract
Bacterial infections routinely cause inflammation and thereby impair osseointegration of orthopedic implants. Acinetobacter spp., which cause osteomyelitis following trauma, on or off the battlefield, were, however, reported to cause neither osteomyelitis nor osteolysis in rodents. We therefore compared the effects of Acinetobacter strain M2 to those of Staphylococcus aureus in a murine implant infection model. Sterile implants and implants with adherent bacteria were inserted in the femur of mice. Bacterial burden, levels of proinflammatory cytokines, and osseointegration were measured. All infections were localized to the implant site. Infection with either S. aureus or Acinetobacter strain M2 increased the levels of proinflammatory cytokines and the chemokine CCL2 in the surrounding femurs, inhibited bone formation around the implant, and caused loss of the surrounding cortical bone, leading to decreases in both histomorphometric and biomechanical measures of osseointegration. Genetic deletion of TLR2 and TLR4 from the mice partially reduced the effects of Acinetobacter strain M2 on osseointegration but did not alter the effects of S. aureus. This is the first report that Acinetobacter spp. impair osseointegration of orthopedic implants in mice, and the murine model developed for this study will be useful for future efforts to clarify the mechanism of implant failure due to Acinetobacter spp. and to assess novel diagnostic tools or therapeutic agents.
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Affiliation(s)
- Hyonmin Choe
- Department of Orthopaedics, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Orthopaedics, Yokohama City University, Yokohama, Kanagawa, Japan
| | - Joscelyn M. Tatro
- Department of Orthopaedics, Case Western Reserve University, Cleveland, Ohio, USA
| | - Bryan S. Hausman
- Department of Orthopaedics, Case Western Reserve University, Cleveland, Ohio, USA
| | - Kristine M. Hujer
- CWRU–Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, Ohio, USA
| | - Steve H. Marshall
- CWRU–Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, Ohio, USA
| | - Ozan Akkus
- Department of Mechanical Engineering, Case Western Reserve University, Cleveland, Ohio, USA
| | - Phillip N. Rather
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA
- Research Service, Atlanta Veterans Affairs Medical Center, Decatur, Georgia, USA
| | - Zhenghong Lee
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Robert A. Bonomo
- CWRU–Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, Ohio, USA
- Medical Service and GRECC, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Center for Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Edward M. Greenfield
- Department of Orthopaedics, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
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LncRNA GACAT2 binds with protein PKM1/2 to regulate cell mitochondrial function and cementogenesis in an inflammatory environment. Bone Res 2022; 10:29. [PMID: 35296649 PMCID: PMC8927299 DOI: 10.1038/s41413-022-00197-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 10/31/2021] [Accepted: 12/21/2021] [Indexed: 12/17/2022] Open
Abstract
Periodontal ligament stem cells (PDLSCs) are a key cell type for restoring/regenerating lost/damaged periodontal tissues, including alveolar bone, periodontal ligament and root cementum, the latter of which is important for regaining tooth function. However, PDLSCs residing in an inflammatory environment generally exhibit compromised functions, as demonstrated by an impaired ability to differentiate into cementoblasts, which are responsible for regrowing the cementum. This study investigated the role of mitochondrial function and downstream long noncoding RNAs (lncRNAs) in regulating inflammation-induced changes in the cementogenesis of PDLSCs. We found that the inflammatory cytokine-induced impairment of the cementogenesis of PDLSCs was closely correlated with their mitochondrial function, and lncRNA microarray analysis and gain/loss-of-function studies identified GACAT2 as a regulator of the cellular events involved in inflammation-mediated mitochondrial function and cementogenesis. Subsequently, a comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS) and parallel reaction monitoring (PRM) assays revealed that GACAT2 could directly bind to pyruvate kinase M1/2 (PKM1/2), a protein correlated with mitochondrial function. Further functional studies demonstrated that GACAT2 overexpression increased the cellular protein expression of PKM1/2, the PKM2 tetramer and phosphorylated PKM2, which led to enhanced pyruvate kinase (PK) activity and increased translocation of PKM2 into mitochondria. We then found that GACAT2 overexpression could reverse the damage to mitochondrial function and cementoblastic differentiation of PDLSCs induced by inflammation and that this effect could be abolished by PKM1/2 knockdown. Our data indicated that by binding to PKM1/2 proteins, the lncRNA GACAT2 plays a critical role in regulating mitochondrial function and cementogenesis in an inflammatory environment.
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Seaweed Exhibits Therapeutic Properties against Chronic Diseases: An Overview. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12052638] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Seaweeds or marine macroalgae are known for producing potentially bioactive substances that exhibit a wide range of nutritional, therapeutic, and nutraceutical properties. These compounds can be applied to treat chronic diseases, such as cancer, cardiovascular disease, osteoporosis, neurodegenerative diseases, and diabetes mellitus. Several studies have shown that consumption of seaweeds in Asian countries, such as Japan and Korea, has been correlated with a lower incidence of chronic diseases. In this study, we conducted a review of published papers on seaweed consumption and chronic diseases. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method for this study. We identified and screened research articles published between 2000 and 2021. We used PubMed and ScienceDirect databases and identified 107 articles. This systematic review discusses the potential use of bioactive compounds of seaweed to treat chronic diseases and identifies gaps where further research in this field is needed. In this review, the therapeutic and nutraceutical properties of seaweed for the treatment of chronic diseases such as neurodegenerative diseases, obesity, diabetes, cancer, liver disease, cardiovascular disease, osteoporosis, and arthritis were discussed. We concluded that further study on the identification of bioactive compounds of seaweed, and further study at a clinical level, are needed.
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Liu P, Tu J, Wang W, Li Z, Li Y, Yu X, Zhang Z. Effects of Mechanical Stress Stimulation on Function and Expression Mechanism of Osteoblasts. Front Bioeng Biotechnol 2022; 10:830722. [PMID: 35252138 PMCID: PMC8893233 DOI: 10.3389/fbioe.2022.830722] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 01/10/2022] [Indexed: 12/13/2022] Open
Abstract
Osteoclasts and osteoblasts play a major role in bone tissue homeostasis. The homeostasis and integrity of bone tissue are maintained by ensuring a balance between osteoclastic and osteogenic activities. The remodeling of bone tissue is a continuous ongoing process. Osteoclasts mainly play a role in bone resorption, whereas osteoblasts are mainly involved in bone remodeling processes, such as bone cell formation, mineralization, and secretion. These cell types balance and restrict each other to maintain bone tissue metabolism. Bone tissue is very sensitive to mechanical stress stimulation. Unloading and loading of mechanical stress are closely related to the differentiation and formation of osteoclasts and bone resorption function as well as the differentiation and formation of osteoblasts and bone formation function. Consequently, mechanical stress exerts an important influence on the bone microenvironment and bone metabolism. This review focuses on the effects of different forms of mechanical stress stimulation (including gravity, continuously compressive pressure, tensile strain, and fluid shear stress) on osteoclast and osteoblast function and expression mechanism. This article highlights the involvement of osteoclasts and osteoblasts in activating different mechanical transduction pathways and reports changings in their differentiation, formation, and functional mechanism induced by the application of different types of mechanical stress to bone tissue. This review could provide new ideas for further microscopic studies of bone health, disease, and tissue damage reconstruction.
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Affiliation(s)
- Pan Liu
- School of Clinical Medicine, Chengdu Medical College, Chengdu, China
- The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Ji Tu
- Spine Labs, St. George & Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - Wenzhao Wang
- Department of Orthopedics, West China Hospital of Sichuan University, Chengdu, China
| | - Zheng Li
- People’s Hospital of Jiulongpo District, Chongqing, China
| | - Yao Li
- School of Clinical Medicine, Chengdu Medical College, Chengdu, China
- The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Xiaoping Yu
- School of Public Health, Chengdu Medical College, Chengdu, China
- Basic Medical College of Chengdu University, Chengdu, China
- *Correspondence: Xiaoping Yu, ; Zhengdong Zhang,
| | - Zhengdong Zhang
- School of Clinical Medicine, Chengdu Medical College, Chengdu, China
- The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
- Department of Orthopedics, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
- *Correspondence: Xiaoping Yu, ; Zhengdong Zhang,
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Łukowicz K, Zagrajczuk B, Wieczorek J, Millan-Ciesielska K, Polkowska I, Cholewa-Kowalska K, Osyczka AM. Molecular Indicators of Biomaterials Osteoinductivity - Cell Migration, BMP Production and Signalling Turns a Key. Stem Cell Rev Rep 2022; 18:672-690. [PMID: 34782949 PMCID: PMC8930966 DOI: 10.1007/s12015-021-10300-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/07/2021] [Indexed: 12/05/2022]
Abstract
In this work we dissected the osteoinductive properties of selected, PLGA-based scaffolds enriched with gel-derived bioactive glasses (SBGs) of either binary SiO2-CaO or ternary SiO2-CaO-P2O5 system, differing in CaO/SiO2 ratio (i.e. high -or low-calcium SBGs). To assess the inherent ability of the scaffolds to induce osteogenesis of human bone marrow stromal cells (BMSC), the study was designed to avoid any osteogenic stimuli beyond the putative osteogenic SBG component of the studied scaffolds. The bioactivity and porosity of scaffolds were confirmed by SBF test and porosimetry. Condition media (CM) from BMSC-loaded scaffolds exhibited increased Ca and decreased P content corresponding to SBGs CaO/SiO2 ratio, whereas Si content was relatively stable and overall lower in CM from scaffolds containing binary SBGs. CM from cell-loaded scaffolds containing high-calcium, binary SBGs promoted migration of BMSC and BMP-response in reporter osteoblast cell line. BMSC culture on these scaffolds or the ones containing ternary, low-calcium SBGs resulted in the activation of BMP-related signaling and expression of several osteogenic markers. Ectopic bone formation was induced by scaffolds containing binary SBGs, but high-calcium ones produced significantly more osteoid. Scaffolds containing ternary SBGs negatively influenced the expression of osteogenic transcription factors and Cx43, involved in cell-cell interactions. High-calcium scaffolds stimulated overall higher Cx43 expression. We believe the initial cell-cell communication may be crucial to induce and maintain osteogenesis and high BMP signaling on the studied scaffolds. The presented scaffolds' biological properties may also constitute new helpful markers to predict osteoinductive potential of other bioactive implant materials.
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Affiliation(s)
- Krzysztof Łukowicz
- Faculty of Biology, Institute of Zoology and Biomedical Research, Department of Biology and Cell Imaging, Jagiellonian University, 9 Gronostajowa St, 30-387, Krakow, Poland
| | - Barbara Zagrajczuk
- Faculty of Materials Science and Ceramics, Department of Glass Technology and Amorphous Coatings, AGH University of Science and Technology, 30 Mickiewicza Ave, 30-059, Krakow, Poland
| | - Jarosław Wieczorek
- University Centre of Veterinary Medicine UJ-UR, University of Agriculture in Krakow, 24/28 Mickiewicza Ave., 30-059, Krakow, Poland
| | - Katarzyna Millan-Ciesielska
- Faculty of Medicine, Department of Pathomorphology, Jagiellonian University Medical College, 2 Jakubowskiego St., 30-688, Krakow, Poland
| | - Izabela Polkowska
- Faculty of Veterinary Medicine, Department and Clinic of Animal Surgery, University of Life Sciences in Lublin, 13 Akademicka St., 20-950, Lublin, Poland
| | - Katarzyna Cholewa-Kowalska
- Faculty of Materials Science and Ceramics, Department of Glass Technology and Amorphous Coatings, AGH University of Science and Technology, 30 Mickiewicza Ave, 30-059, Krakow, Poland.
| | - Anna M Osyczka
- Faculty of Biology, Institute of Zoology and Biomedical Research, Department of Biology and Cell Imaging, Jagiellonian University, 9 Gronostajowa St, 30-387, Krakow, Poland.
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Chen R, Hao Z, Wang Y, Zhu H, Hu Y, Chen T, Zhang P, Li J. Mesenchymal Stem Cell-Immune Cell Interaction and Related Modulations for Bone Tissue Engineering. Stem Cells Int 2022; 2022:7153584. [PMID: 35154331 PMCID: PMC8825274 DOI: 10.1155/2022/7153584] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 01/03/2022] [Indexed: 12/11/2022] Open
Abstract
Critical bone defects and related delayed union and nonunion are still worldwide problems to be solved. Bone tissue engineering is mainly aimed at achieving satisfactory bone reconstruction. Mesenchymal stem cells (MSCs) are a kind of pluripotent stem cells that can differentiate into bone cells and can be used as one of the key pillars of bone tissue engineering. In recent decades, immune responses play an important role in bone regeneration. Innate immune responses provide a suitable inflammatory microenvironment for bone regeneration and initiate bone regeneration in the early stage of fracture repair. Adaptive immune responses maintain bone regeneration and bone remodeling. MSCs and immune cells regulate each other. All kinds of immune cells and secreted cytokines can regulate the migration, proliferation, and osteogenic differentiation of MSCs, which have a strong immunomodulatory ability to these immune cells. This review mainly introduces the interaction between MSCs and immune cells on bone regeneration and its potential mechanism, and discusses the practical application in bone tissue engineering by modulating this kind of cell-to-cell crosstalk. Thus, an in-depth understanding of these principles of bone immunology can provide a new way for bone tissue engineering.
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Affiliation(s)
- Renxin Chen
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Zhuowen Hao
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Yi Wang
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Hongzhen Zhu
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Yingkun Hu
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Tianhong Chen
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Peng Zhang
- Department of Orthopedics, Suzhou Science and Technology Town Hospital, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou 215153, China
| | - Jingfeng Li
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
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50
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Kitaura H, Marahleh A, Ohori F, Noguchi T, Nara Y, Pramusita A, Kinjo R, Ma J, Kanou K, Mizoguchi I. Role of the Interaction of Tumor Necrosis Factor-α and Tumor Necrosis Factor Receptors 1 and 2 in Bone-Related Cells. Int J Mol Sci 2022; 23:ijms23031481. [PMID: 35163403 PMCID: PMC8835906 DOI: 10.3390/ijms23031481] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/24/2022] [Accepted: 01/26/2022] [Indexed: 02/04/2023] Open
Abstract
Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine expressed by macrophages, monocytes, and T cells, and its expression is triggered by the immune system in response to pathogens and their products, such as endotoxins. TNF-α plays an important role in host defense by inducing inflammatory reactions such as phagocytes and cytocidal systems activation. TNF-α also plays an important role in bone metabolism and is associated with inflammatory bone diseases. TNF-α binds to two cell surface receptors, the 55kDa TNF receptor-1 (TNFR1) and the 75kDa TNF receptor-2 (TNFR2). Bone is in a constant state of turnover; it is continuously degraded and built via the process of bone remodeling, which results from the regulated balance between bone-resorbing osteoclasts, bone-forming osteoblasts, and the mechanosensory cell type osteocytes. Precise interactions between these cells maintain skeletal homeostasis. Studies have shown that TNF-α affects bone-related cells via TNFRs. Signaling through either receptor results in different outcomes in different cell types as well as in the same cell type. This review summarizes and discusses current research on the TNF-α and TNFR interaction and its role in bone-related cells.
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