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Mendelsohn DH, Walter N, Cheung WH, Wong RMY, Schönmehl R, Winter L, El Khassawna T, Heiss C, Brochhausen C, Rupp M. Targeting mitochondria in bone and cartilage diseases: A narrative review. Redox Biol 2025; 83:103667. [PMID: 40354767 DOI: 10.1016/j.redox.2025.103667] [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: 03/02/2025] [Revised: 04/28/2025] [Accepted: 05/06/2025] [Indexed: 05/14/2025] Open
Abstract
Mitochondria are essential regulators of bone health, controlling cell differentiation, cellular energy production, immune function, osteogenesis, and osteoclast activity. Their dysfunction is linked to orthopedic disorders such as osteoporosis, osteoarthritis, and osteomyelitis, contributing to impaired bone homeostasis and increased fracture risk. While mitochondrial research has been more advanced in fields such as cardiology and neurology, emerging therapeutic strategies from these areas are beginning to show potential for translation into orthopedics. These include mitochondrial biogenesis stimulation, mitochondrial fission inhibition, antioxidant therapies, mitochondrial transplantation, and photobiomodulation, which have demonstrated success in enhancing tissue repair, reducing oxidative stress, and improving overall cellular function in non-orthopedic applications. The novel inhibitor of mitochondrial fission and accumulation of reactive oxygen species Mdivi-1 offers potential to improve clinical outcomes of bone diseases by alleviating cellular dysfunction and preventing bone loss. While these treatments are still in the developmental phase, they present innovative approaches to address mitochondrial dysfunction in orthopedic conditions, potentially transforming bone disease management and enhancing patient outcomes. This report explores research regarding the involvement of mitochondrial health in bone and joint function and discusses possible future treatment strategies targeting mitochondria in orthopedic conditions.
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Affiliation(s)
- Daniel H Mendelsohn
- Institute of Pathology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Friedrich-Baur-Institute, Department of Neurology, LMU Clinic Munich, Germany
| | - Nike Walter
- Department of Psychosomatic Medicine, University Medical Center Regensburg, Regensburg, Germany
| | - Wing-Hoi Cheung
- Department of Orthopedics and Traumatology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China
| | - Ronald Man Yeung Wong
- Department of Orthopedics and Traumatology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China
| | - Rebecca Schönmehl
- Institute of Pathology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Lina Winter
- Institute of Pathology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | | | - Christian Heiss
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital Giessen, Germany; Biruni University, Istanbul, Türkiye
| | - Christoph Brochhausen
- Institute of Pathology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Markus Rupp
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital Giessen, Germany.
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Wang C, Li H, Li F, Yang Y, Xu Z, Gao T, Li R, Zhang R, Mu Y, Guo Z, Guo Q, Liu S. The mitochondrial protectant SS31 optimized decellularized Wharton's jelly scaffold improves allogeneic chondrocyte implantation-mediated articular cartilage repair. J Orthop Translat 2025; 52:126-137. [PMID: 40291636 PMCID: PMC12032180 DOI: 10.1016/j.jot.2025.03.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 03/24/2025] [Accepted: 03/31/2025] [Indexed: 04/30/2025] Open
Abstract
Background The process of allogeneic chondrocyte implantation entails obtaining donor chondrocytes, culturing them in a medium enriched with growth factors, and then introducing them-either individually or in conjunction with biocompatible scaffolds-into areas of cartilage damage. While promising, this approach is hindered by mitochondrial dysfunction in the implanted chondrocytes. Methods This research introduced an innovative approach by creating a new type of scaffold derived from Decellularized Umbilical Cord Wharton's Jelly (DUCWJ) extracted from human umbilical cords. The scaffold was manufactured using procedures involving decellularization and lyophilization. The resulting scaffold demonstrated superior characteristics, including high porosity, hydrophilic properties, and excellent biocompatibility. To enhance its function, SS31 peptides, known for their mitochondrial-protective properties, were chemically bonded to the scaffold surface, creating an SS31@DUCWJ system. This system aims to protect chondrocytes and regulate the mitochondrial respiratory chain (MRC), thereby improving cartilage repair mediated by allogeneic chondrocyte implantation. Results In vitro studies have shown that SS31 effectively attenuates metabolic dysfunction, extracellular matrix degradation, oxidative stress, inflammation, and mitochondrial damage induced by serial cell passages. Complementary in vivo experiments showed that the SS31@DUCWJ scaffold promoted regeneration of healthy articular cartilage in femoral condylar defects in rabbits. Conclusions This SS31-modified porous decellularized scaffold represents an innovative biomaterial with anti-inflammatory properties and targeted mitochondrial regulation. It offers a promising new approach for treating articular cartilage injuries. The translational potential of this article Our study was the first to successfully load the mitochondrial protectant SS31 onto a DUCWJ hydrogel scaffold for localized drug delivery. This method is highly efficacious in repairing cartilage defects and offers a promising new avenue for the treatment of such conditions.
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Affiliation(s)
- Chao Wang
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Hao Li
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Fakai Li
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Yongkang Yang
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Ziheng Xu
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Tianze Gao
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Runmeng Li
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Ruiyang Zhang
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Yuhao Mu
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Zheng Guo
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Quanyi Guo
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Shuyun Liu
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
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Wang Y, Zeng T, Tang D, Cui H, Wan Y, Tang H. Integrated Multi-Omics Analyses Reveal Lipid Metabolic Signature in Osteoarthritis. J Mol Biol 2025; 437:168888. [PMID: 39643156 DOI: 10.1016/j.jmb.2024.168888] [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: 08/14/2024] [Revised: 11/05/2024] [Accepted: 11/29/2024] [Indexed: 12/09/2024]
Abstract
Osteoarthritis (OA) is the most common degenerative joint disease and the second leading cause of disability worldwide. Single-omics analyses are far from elucidating the complex mechanisms of lipid metabolic dysfunction in OA. This study identified a shared lipid metabolic signature of OA by integrating metabolomics, single-cell and bulk RNA-seq, as well as metagenomics. Compared to the normal counterparts, cartilagesin OA patients exhibited significant depletion of homeostatic chondrocytes (HomCs) (P = 0.03) and showed lipid metabolic disorders in linoleic acid metabolism and glycerophospholipid metabolism which was consistent with our findings obtained from plasma metabolomics. Through high-dimensional weighted gene co-expression network analysis (hdWGCNA), weidentified PLA2G2A as a hub gene associated with lipid metabolic disorders in HomCs. And an OA-associated subtype of HomCs, namely HomC1 (marked by PLA2G2A, MT-CO1, MT-CO2, and MT-CO3) was identified, which also exhibited abnormal activation of lipid metabolic pathways. This suggests the involvement of HomC1 in OA progression through the shared lipid metabolism aberrancies, which were further validated via bulk RNA-Seq analysis. Metagenomic profiling identified specific gut microbial species significantly associated with the key lipid metabolism disorders, including Bacteroides uniformis (P < 0.001, R = -0.52), Klebsiella pneumonia (P = 0.003, R = 0.42), Intestinibacter_bartlettii (P = 0.009, R = 0.38), and Streptococcus anginosus (P = 0.009, R = 0.38). By integrating the multi-omics features, a random forest diagnostic model with outstanding performance was developed (AUC = 0.97). In summary, this study deciphered the crucial role of a integrated lipid metabolic signature in OA pathogenesis, and established a regulatory axis of gut microbiota-metabolites-cell-gene, providing new insights into the gut-joint axis and precision therapy for OA.
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Affiliation(s)
- Yang Wang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China
| | - Tianyu Zeng
- School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China
| | - Deqin Tang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China
| | - Haipeng Cui
- School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China
| | - Ying Wan
- School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China
| | - Hua Tang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China; Central Nervous System Drug Key Laboratory of Sichuan Province, Luzhou 646000, China; Medical Engineering & Medical Informatics Integration and Transformational Medicine Key Laboratory of Luzhou City, Luzhou 646000, China.
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Bergstrom AR, Glimm MG, Houske EA, Cooper G, Viles E, Chapman M, Bourekis K, Welhaven HD, Brahmachary PP, Hahn AK, June RK. Metabolic Profiles of Encapsulated Chondrocytes Exposed to Short-Term Simulated Microgravity. Ann Biomed Eng 2025; 53:785-797. [PMID: 39695002 PMCID: PMC11836148 DOI: 10.1007/s10439-024-03667-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 12/02/2024] [Indexed: 12/20/2024]
Abstract
The mechanism by which chondrocytes respond to reduced mechanical loading environments and the subsequent risk of developing osteoarthritis remains unclear. This is of particular concern for astronauts. In space the reduced joint loading forces during prolonged microgravity (10-6 g) exposure could lead to osteoarthritis (OA), compromising quality of life post-spaceflight. In this study, we encapsulated human chondrocytes in an agarose gel of similar stiffness to the pericellular matrix to mimic the cartilage microenvironment. We then exposed agarose-chondrocyte constructs to simulated microgravity (SM) for four days using a rotating wall vessel (RWV) bioreactor to better assess the cartilage health risks associated with spaceflight. Metabolites extracted from media and agarose gel constructs were analyzed on liquid chromatography-mass spectrometry. Global metabolomic profiling detected a total of 1205 metabolite features, with 497 significant metabolite features identified by ANOVA (FDR-corrected p-value < 0.05). Specific metabolic shifts detected in response to SM exposure resulted in clusters of co-regulated metabolites, with glutathione, nitrogen, histidine, vitamin B3, and aminosugars metabolism identified by variable importance in projection scores. Microgravity-induced metabolic shifts in gel constructs and media were indicative of protein synthesis, energy and nucleotide metabolism, and oxidative catabolism. Microgravity associated-metabolic shifts were consistent with our previously published early osteoarthritic metabolomic profiles in human synovial fluid, suggesting that even short-term exposure to microgravity (or other reduced mechanical loading environments) may lead to the development of OA. This work further suggests the potential to detect these metabolic perturbations in synovial fluid in vivo to ascertain osteoarthritis risk in astronauts.
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Affiliation(s)
- Annika R Bergstrom
- Department of Biological and Environmental Science, Carroll College, 1601 N Benton Ave, Helena, MT, 59625, USA
- Department of Chemical and Biological Engineering, Villanova University, Villanova, PA, 19085, USA
| | - Matthew G Glimm
- Department of Biological and Environmental Science, Carroll College, 1601 N Benton Ave, Helena, MT, 59625, USA
| | - Eden A Houske
- Department of Biological and Environmental Science, Carroll College, 1601 N Benton Ave, Helena, MT, 59625, USA
| | - Gwendolyn Cooper
- Molecular Biosciences Program, Montana State University, Bozeman, MT, 59717, USA
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, 59717, USA
| | - Ethan Viles
- Molecular Biosciences Program, Montana State University, Bozeman, MT, 59717, USA
- Department of Mechanical and Industrial Engineering, Montana State University, PO Box 173800, Bozeman, MT, 59717-3800, USA
| | - Marrin Chapman
- Department of Biological and Environmental Science, Carroll College, 1601 N Benton Ave, Helena, MT, 59625, USA
| | - Katherine Bourekis
- Department of Biological and Environmental Science, Carroll College, 1601 N Benton Ave, Helena, MT, 59625, USA
| | - Hope D Welhaven
- Molecular Biosciences Program, Montana State University, Bozeman, MT, 59717, USA
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, 59717, USA
| | - Priyanka P Brahmachary
- Department of Mechanical and Industrial Engineering, Montana State University, PO Box 173800, Bozeman, MT, 59717-3800, USA
| | - Alyssa K Hahn
- Department of Biological and Environmental Science, Carroll College, 1601 N Benton Ave, Helena, MT, 59625, USA.
| | - Ronald K June
- Department of Mechanical and Industrial Engineering, Montana State University, PO Box 173800, Bozeman, MT, 59717-3800, USA.
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Han J, Kim YH, Han S. Increased oxidative phosphorylation through pyruvate dehydrogenase kinase 2 deficiency ameliorates cartilage degradation in mice with surgically induced osteoarthritis. Exp Mol Med 2025; 57:390-401. [PMID: 39894827 PMCID: PMC11873213 DOI: 10.1038/s12276-025-01400-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 11/12/2024] [Accepted: 11/17/2024] [Indexed: 02/04/2025] Open
Abstract
Chondrocytes can shift their metabolism to oxidative phosphorylation (OxPhos) in the early stages of osteoarthritis (OA), but as the disease progresses, this metabolic adaptation becomes limited and eventually fails, leading to mitochondrial dysfunction and oxidative stress. Here we investigated whether enhancing OxPhos through the inhibition of pyruvate dehydrogenase kinase (PDK) 2 affects the metabolic flexibility of chondrocytes and cartilage degeneration in a surgical model of OA. Among the PDK isoforms, PDK2 expression was increased by IL-1β in vitro and in the articular cartilage of the DMM model in vivo, accompanied by an increase in phosphorylated PDH. Mice lacking PDK2 showed significant resistance to cartilage damage and reduced pain behaviors in the DMM model. PDK2 deficiency partially restored OxPhos in IL-1β-treated chondrocytes, leading to increases in APT and the NAD+/NADH ratio. These metabolic changes were accompanied by a decrease in reactive oxygen species and senescence in chondrocytes, as well as an increase in the expression of antioxidant proteins such as NRF2 and HO-1 after IL-1β treatment. At the signaling level, PDK2 deficiency reduced p38 signaling and maintained AMPK activation without affecting the JNK, mTOR, AKT and NF-κB pathways. p38 MAPK signaling was critically involved in reactive oxygen species production under glycolysis-dominant conditions in chondrocytes. Our study provides a proof of concept for PDK2-mediated metabolic reprogramming toward OxPhos as a new therapeutic strategy for OA.
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Affiliation(s)
- Jin Han
- Laboratory for Arthritis and Cartilage Biology, Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea
- Cell & Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Yoon Hee Kim
- Laboratory for Arthritis and Cartilage Biology, Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea
| | - Seungwoo Han
- Laboratory for Arthritis and Cartilage Biology, Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea.
- Cell & Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
- Division of Rheumatology, Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
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Zhong G, Liu W, Venkatesan JK, Wang D, Madry H, Cucchiarini M. Autologous transplantation of mitochondria/rAAV IGF-I platforms in human osteoarthritic articular chondrocytes to treat osteoarthritis. Mol Ther 2024:S1525-0016(24)00847-5. [PMID: 39741406 DOI: 10.1016/j.ymthe.2024.12.047] [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: 07/15/2024] [Revised: 10/24/2024] [Accepted: 12/27/2024] [Indexed: 01/03/2025] Open
Abstract
Despite various available treatments, highly prevalent osteoarthritis (OA) cannot be cured in patients. In light of evidence showing mitochondria dysfunction during the disease progression, our goal was to develop a novel therapeutic concept based on the transplantation of mitochondria as a platform to deliver recombinant adeno-associated virus (rAAV) gene vectors with potency for OA. For the first time, to our best knowledge, we report the successful creation of a safe mitochondria/rAAV system effectively promoting the overexpression of a candidate insulin-like growth factor I (IGF-I) by administration to autologous human osteoarthritic articular chondrocytes versus control conditions (reporter mitochondria/rAAV lacZ system, rAAV-free system, absence of mitochondria transplantation; up to 8.4-fold difference). The candidate mitochondria/rAAV IGF-I system significantly improved key activities in the transplanted cells (proliferation/survival, extracellular matrix production, mitochondria functions) relative to the control conditions (up to a 9.5-fold difference), including when provided in a pluronic F127 (PF127) hydrogel for reinforced delivery (up to a 5.9-fold difference). Such effects were accompanied by increased levels of cartilage-specific SOX9 and Mfn-1 (mitochondria fusion) and decreased levels of Drp-1 (mitochondria fission) and proinflammatory tumor necrosis factor alpha (TNF-α; up to 4.5-fold difference). This study shows the potential of combining the use of mitochondria with rAAV as a promising approach for human OA.
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Affiliation(s)
- Gang Zhong
- Center of Experimental Orthopaedics, Saarland University and Saarland University Medical Center, 66421 Homburg/Saar, Germany
| | - Wei Liu
- Center of Experimental Orthopaedics, Saarland University and Saarland University Medical Center, 66421 Homburg/Saar, Germany
| | - Jagadeesh K Venkatesan
- Center of Experimental Orthopaedics, Saarland University and Saarland University Medical Center, 66421 Homburg/Saar, Germany
| | - Dan Wang
- Center of Experimental Orthopaedics, Saarland University and Saarland University Medical Center, 66421 Homburg/Saar, Germany
| | - Henning Madry
- Center of Experimental Orthopaedics, Saarland University and Saarland University Medical Center, 66421 Homburg/Saar, Germany
| | - Magali Cucchiarini
- Center of Experimental Orthopaedics, Saarland University and Saarland University Medical Center, 66421 Homburg/Saar, Germany.
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Griffin TM, Lopes EBP, Cortassa D, Batushansky A, Jeffries MA, Makosa D, Jopkiewicz A, Mehta-D'souza P, Komaravolu RK, Kinter MT. Sexually dimorphic metabolic effects of a high fat diet on knee osteoarthritis in mice. Biol Sex Differ 2024; 15:103. [PMID: 39639386 PMCID: PMC11619521 DOI: 10.1186/s13293-024-00680-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND Women have a higher risk of developing osteoarthritis (OA) than men, including with obesity. To better understand this disparity, we investigated sex differences in metabolic and inflammatory factors associated with OA using a diet-induced mouse model of obesity. We hypothesized that 20 weeks of high-fat diet (HFD) would induce sexually dimorphic changes in both systemic and local risk factors of knee OA. METHODS Male and female C57BL/6J mice were fed Chow or HFD from 6 to 26 weeks of age (n = 12 per diet and sex). We performed broad metabolic phenotyping, 16 S gut microbiome analysis, targeted gene expression analysis of synovium-infrapatellar fat tissue, targeted gene expression and proteomic analysis of articular cartilage, chondrocyte metabolic profiling, and OA histopathology. Two-way ANOVA statistics were utilized to determine the contribution of sex and diet and their interaction on outcomes. RESULTS Mice fed HFD weighed 1.76-fold (p < 0.0001) and 1.60-fold (p < 0.0001) more than male and female Chow cohorts, respectively, with both sexes reaching similar body fat levels (male: 43.9 ± 2.2%; female: 44.1 ± 3.8%). HFD caused greater cartilage pathology (p < 0.024) and synovial hyperplasia (p < 0.038) versus Chow in both sexes. Cartilage pathology was greater in male versus female mice (p = 0.048), and only male mice developed osteophytes with HFD (p = 0.044). Both sexes exhibited metabolic inflexibility on HFD, but only male mice developed glucose intolerance (p < 0.0001), fatty liver (p < 0.0001), and elevated serum amylase (p < 0.0001) with HFD versus Chow. HFD treatment caused sex-dependent differences in gut microbiota beta diversity (p = 0.01) and alteration in specific microbiome clades, such as a HFD-dependent reduction in abundance of Bifidobacterium only in male mice. In knee synovium and infrapatellar fat tissue, HFD upregulated the expression of pro-inflammatory and pro-fibrotic genes predominantly in female mice. In cartilage, lipid metabolism proteins were more abundant with HFD in male mice, whereas proteins involved in glycolysis/gluconeogenesis and biosynthesis of amino acids were greater in cartilage of female mice. Sex-dependent metabolic differences were observed in cartilage from young, healthy mice prior to pubertal maturation, but not in primary juvenile chondrocytes studied in vitro. CONCLUSIONS HFD induced numerous sex differences in metabolic and inflammatory outcomes, especially in joint tissues, suggesting that sex-specific cellular processes are involved during development of early-stage OA with obesity.
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Affiliation(s)
- Timothy M Griffin
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA.
- Veterans Affairs Medical Center, Oklahoma City, OK, 73104, USA.
- University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
| | - Erika Barboza Prado Lopes
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
- Labcorp Drug Development, Indianapolis, IN, USA
| | - Dominic Cortassa
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
- VA Oklahoma City Health Care, Oklahoma City, OK, USA
| | - Albert Batushansky
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
- Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Be'er Sheva, 84105, Israel
| | - Matlock A Jeffries
- Veterans Affairs Medical Center, Oklahoma City, OK, 73104, USA
- University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Dawid Makosa
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
- University of Western Australia, Perth, Western Australia, Australia
| | - Anita Jopkiewicz
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
- Panier Group, Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9B, 50931, Cologne, Germany
| | - Padmaja Mehta-D'souza
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Ravi K Komaravolu
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
- Immunology Center of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Michael T Kinter
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
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Yang Y, Gao R, Zhu Z, Xiao W, Wang J, Zhao W, Li Y. Benzophenone-3 exposure induced apoptosis via impairing mitochondrial function in human chondrocytes. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 287:117286. [PMID: 39520751 DOI: 10.1016/j.ecoenv.2024.117286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 10/30/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024]
Abstract
Osteoarthritis (OA) is a chronic joint disease affecting millions of adults worldwide, characterized by degeneration of articular cartilage. Many environmental risk factors contribute to OA development. Benzophenone-3 (BP-3), a commonly used ultraviolet filter in personal care products, has been positively associated with OA risk. However, it remains unclear whether and how BP-3 induces toxic effects on articular chondrocytes and promote OA development. This study aims to investigate the damage of BP-3 at environmentally relevant concentrations to human chondrocytes, as well as potential mechanisms linking BP-3 with injury of chondrocytes. Notably, BP-3 significantly inhibited cell viability, induced apoptosis, and up-regulated matrix metalloproteinase (MMP) 1 and 13 which mediated cartilage degradation in C28/I2 human normal chondrocytes. Moreover, the function of mitochondria was impaired and oxidative stress occurred in BP-3 exposure groups, evidenced by elevation of reactive oxygen species (ROS) generation, reduction of mitochondrial membrane potential, decrease of ATP production and inhibition of mitochondrial respiratory chain complex I, II, III and IV. Meanwhile, BP-3 caused mitochondrial cristae vague and formation of autophagosomes. PTEN induced putative kinase 1/E3 ubiquitin protein ligase (PINK1/Parkin) pathway was also activated by BP-3. Addition of autophagy inhibitor, 3-Methyladenine (3-MA), suppressed PINK1/Parkin-mediated mitophagy, but increased BP-3-induced expression of MMP1 and 13, as well as exacerbated BP-3-induced apoptosis, suggesting mitophagy may exert a chondroprotective effect and partially alleviate apoptosis induced by this compound. In brief, BP-3 exposure may increase OA risk via inducing apoptosis and increasing breakdown of extracellular matrix in chondrocytes, and mitochondrial dysfunction and mitophagy may play a crucial role in the mechanisms of BP-3-induced toxicity to articular chondrocytes.
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Affiliation(s)
- Ye Yang
- School of Public Health, Hangzhou Medical College, Hangzhou 310013, China
| | - Rui Gao
- School of Public Health, Hangzhou Medical College, Hangzhou 310013, China
| | - Zhenyu Zhu
- School of Public Health, Hangzhou Medical College, Hangzhou 310013, China
| | - Wenfeng Xiao
- School of Public Health, Hangzhou Medical College, Hangzhou 310013, China
| | - Jing Wang
- School of Public Health, Hangzhou Medical College, Hangzhou 310013, China
| | - Wenxia Zhao
- School of Public Health, Hangzhou Medical College, Hangzhou 310013, China
| | - Yingjun Li
- School of Public Health, Hangzhou Medical College, Hangzhou 310013, China.
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9
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Cheng L, Zheng Q, Qiu K, Elmer Ker DF, Chen X, Yin Z. Mitochondrial destabilization in tendinopathy and potential therapeutic strategies. J Orthop Translat 2024; 49:49-61. [PMID: 39430132 PMCID: PMC11488423 DOI: 10.1016/j.jot.2024.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 08/21/2024] [Accepted: 09/01/2024] [Indexed: 10/22/2024] Open
Abstract
Tendinopathy is a prevalent aging-related disorder characterized by pain, swelling, and impaired function, often resulting from micro-scarring and degeneration caused by overuse or trauma. Current interventions for tendinopathy have limited efficacy, highlighting the need for innovative therapies. Mitochondria play an underappreciated and yet crucial role in tenocytes function, including energy production, redox homeostasis, autophagy, and calcium regulation. Abnormalities in mitochondrial function may lead to cellular senescence. Within this context, this review provides an overview of the physiological functions of mitochondria in tendons and presents current insights into mitochondrial dysfunction in tendinopathy. It also proposes potential therapeutic strategies that focus on targeting mitochondrial health in tenocytes. These strategies include: (1) utilizing reactive oxygen species (ROS) scavengers to mitigate the detrimental effects of aberrant mitochondria, (2) employing mitochondria-protecting agents to reduce the production of dysfunctional mitochondria, and (3) supplementing with exogenous normal mitochondria. In conclusion, mitochondria-targeted therapies hold great promise for restoring mitochondrial function and improving outcomes in patients with tendinopathy. The translational potential of this article: Tendinopathy is challenging to treat effectively due to its poorly understood pathogenesis. This review thoroughly analyzes the role of mitochondria in tenocytes and proposes potential strategies for the mitochondrial treatment of tendinopathy. These findings establish a theoretical basis for future research and the clinical translation of mitochondrial therapy for tendinopathy.
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Affiliation(s)
- Linxiang Cheng
- Department of Orthopedic Surgery of Sir Run Run Shaw Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, China
- State Key Laboratory of Transvascular Implantation Devices, Hangzhou, 310009, China
| | - Qiangqiang Zheng
- Department of Sports Medicine & Orthopedic Surgery, The Second Affiliated Hospital, And Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, China
- State Key Laboratory of Transvascular Implantation Devices, Hangzhou, 310009, China
| | - Kaijie Qiu
- Department of Sports Medicine & Orthopedic Surgery, The Second Affiliated Hospital, And Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
| | - Dai Fei Elmer Ker
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong
| | - Xiao Chen
- Department of Sports Medicine & Orthopedic Surgery, The Second Affiliated Hospital, And Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, China
- State Key Laboratory of Transvascular Implantation Devices, Hangzhou, 310009, China
| | - Zi Yin
- Department of Orthopedic Surgery of Sir Run Run Shaw Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, China
- State Key Laboratory of Transvascular Implantation Devices, Hangzhou, 310009, China
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10
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Lin J, Jia S, Cao F, Huang J, Chen J, Wang J, Liu P, Zeng H, Zhang X, Cui W. Research Progress on Injectable Microspheres as New Strategies for the Treatment of Osteoarthritis Through Promotion of Cartilage Repair. ADVANCED FUNCTIONAL MATERIALS 2024; 34. [DOI: 10.1002/adfm.202400585] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Indexed: 07/07/2024]
Abstract
AbstractOsteoarthritis (OA) is a degenerative disease caused by a variety of factors with joint pain as the main symptom, including fibrosis, chapping, ulcers, and loss of cartilage. Traditional treatment can only delay the progression of OA, and classical delivery system have many side effects. In recent years, microspheres have shown great application prospects in the field of OA treatment. Microspheres can support cells, reproduce the natural tissue microenvironment in vitro and in vivo, and are an efficient delivery system for the release of drugs or biological agents, which can promote cell proliferation, migration, and differentiation. Thus, they have been widely used in cartilage repair and regeneration. In this review, preparation processes, basic materials, and functional characteristics of various microspheres commonly used in OA treatment are systematically reviewed. Then it is introduced surface modification strategies that can improve the biological properties of microspheres and discussed a series of applications of microsphere functionalized scaffolds in OA treatment. Finally, based on bibliometrics research, the research development, future potential, and possible research hotspots of microspheres in the field of OA therapy is systematically and dynamically evaluated. The comprehensive and systematic review will bring new understanding to the field of microsphere treatment of OA.
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Affiliation(s)
- Jianjing Lin
- Department of Sports Medicine and Rehabilitation Peking University Shenzhen Hospital Shenzhen Guangdong 518036 P. R. China
| | - Shicheng Jia
- Department of Sports Medicine and Rehabilitation Peking University Shenzhen Hospital Shenzhen Guangdong 518036 P. R. China
- Shantou University Medical College Shantou Guangdong 515041 P. R. China
| | - Fuyang Cao
- Department of Orthopedics Second Hospital of Shanxi Medical University Taiyuan Shanxi 030001 P. R. China
| | - Jingtao Huang
- Shantou University Medical College Shantou Guangdong 515041 P. R. China
| | - Jiayou Chen
- Department of Sports Medicine and Rehabilitation Peking University Shenzhen Hospital Shenzhen Guangdong 518036 P. R. China
- Shantou University Medical College Shantou Guangdong 515041 P. R. China
| | - Juan Wang
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200025 P. R. China
| | - Peng Liu
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials Peking University Shenzhen Hospital Shenzhen Guangdong 518036 P. R. China
| | - Hui Zeng
- Shenzhen Second People's Hospital (First Affiliated Hospital of Shenzhen University) Shenzhen Guangdong 518035 China
| | - Xintao Zhang
- Department of Sports Medicine and Rehabilitation Peking University Shenzhen Hospital Shenzhen Guangdong 518036 P. R. China
| | - Wenguo Cui
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200025 P. R. China
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11
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Bergstrom AR, Glimm MG, Houske EA, Cooper G, Viles E, Chapman M, Bourekis K, Welhaven HD, Brahmachary PP, Hahn AK, June RK. Metabolic Profiles of Encapsulated Chondrocytes Exposed to Short-Term Simulated Microgravity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.01.601604. [PMID: 39005264 PMCID: PMC11245029 DOI: 10.1101/2024.07.01.601604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
The mechanism by which chondrocytes respond to reduced mechanical loading environments and the subsequent risk of developing osteoarthritis remains unclear. This is of particular concern for astronauts. In space the reduced joint loading forces during prolonged microgravity (10-6 g) exposure could lead to osteoarthritis (OA), compromising quality of life post-spaceflight. In this study, we encapsulated human chondrocytes in an agarose gel of similar stiffness to the pericellular matrix to mimic the cartilage microenvironment. We then exposed agarose-chondrocyte constructs to simulated microgravity (SM) using a rotating wall vessel (RWV) bioreactor to better assess the cartilage health risks associated with spaceflight. Global metabolomic profiling detected a total of 1205 metabolite features across all samples, with 497 significant metabolite features identified by ANOVA (FDR-corrected p-value < 0.05). Specific metabolic shifts detected in response to SM exposure resulted in clusters of co-regulated metabolites, as well as key metabolites identified by variable importance in projection scores. Microgravity-induced metabolic shifts in gel constructs and media were indicative of protein synthesis, energy metabolism, nucleotide metabolism, and oxidative catabolism. The microgravity associated-metabolic shifts were consistent with early osteoarthritic metabolomic profiles in human synovial fluid, which suggests that even short-term exposure to microgravity (or other reduced mechanical loading environments) may lead to the development of OA.
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Affiliation(s)
- Annika R. Bergstrom
- Department of Biological & Environmental Science, Carroll College, Helena, MT, USA, 59625
- Department of Chemical & Biological Engineering, Villanova University, Villanova, PA, USA, 19085
| | - Matthew G. Glimm
- Department of Biological & Environmental Science, Carroll College, Helena, MT, USA, 59625
| | - Eden A. Houske
- Department of Biological & Environmental Science, Carroll College, Helena, MT, USA, 59625
| | - Gwendolyn Cooper
- Molecular Biosciences Program, Montana State University, Bozeman, MT, USA, 59717
- Department of Chemistry & Biochemistry, Montana State University, Bozeman, MT, USA, 59717
| | - Ethan Viles
- Molecular Biosciences Program, Montana State University, Bozeman, MT, USA, 59717
- Department of Mechanical & Industrial Engineering, Montana State University, Bozeman, MT, USA, 59717
| | - Marrin Chapman
- Department of Biological & Environmental Science, Carroll College, Helena, MT, USA, 59625
| | - Katherine Bourekis
- Department of Biological & Environmental Science, Carroll College, Helena, MT, USA, 59625
| | - Hope D. Welhaven
- Molecular Biosciences Program, Montana State University, Bozeman, MT, USA, 59717
- Department of Chemistry & Biochemistry, Montana State University, Bozeman, MT, USA, 59717
| | - Priyanka P. Brahmachary
- Department of Mechanical & Industrial Engineering, Montana State University, Bozeman, MT, USA, 59717
| | - Alyssa K. Hahn
- Department of Biological & Environmental Science, Carroll College, Helena, MT, USA, 59625
| | - Ronald K. June
- Department of Mechanical & Industrial Engineering, Montana State University, Bozeman, MT, USA, 59717
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12
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Yue L, Lim R, Owens BD. Latest Advances in Chondrocyte-Based Cartilage Repair. Biomedicines 2024; 12:1367. [PMID: 38927573 PMCID: PMC11201646 DOI: 10.3390/biomedicines12061367] [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: 03/31/2024] [Revised: 06/08/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024] Open
Abstract
Chondrocyte-based cell therapy has been used for more than 30 years and is still considered to be a promising method of cartilage repair despite some limitations. This review introduces the latest developments of four generations of autologous chondrocyte implantation and current autologous chondrocyte products. The regeneration of cartilage from adult chondrocytes is limited by culture-induced dedifferentiation and patient age. Cartibeads is an innovative three-step method to produce high-quality hyaline cartilage microtissues, and it is developed from adult dedifferentiated chondrocytes with a high number of cell passages. In addition, allogeneic chondrocyte therapies using the Quantum hollow-fiber bioreactor and several signaling pathways involved in chondrocyte-based cartilage repair are mentioned, such as WNT signaling, the BMP-2/WISP1 pathway, and the FGF19 pathway.
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Affiliation(s)
- Li Yue
- Department of Orthopaedics, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI 02903, USA;
| | - Ryan Lim
- Department of Biology, Brown University, Providence, RI 02912, USA;
| | - Brett D. Owens
- Department of Orthopaedics, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI 02903, USA;
- University Orthopedics, East Providence, RI 02914, USA
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13
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Adam MS, Zhuang H, Ren X, Zhang Y, Zhou P. The metabolic characteristics and changes of chondrocytes in vivo and in vitro in osteoarthritis. Front Endocrinol (Lausanne) 2024; 15:1393550. [PMID: 38854686 PMCID: PMC11162117 DOI: 10.3389/fendo.2024.1393550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 05/07/2024] [Indexed: 06/11/2024] Open
Abstract
Osteoarthritis (OA) is an intricate pathological condition that primarily affects the entire synovial joint, especially the hip, hand, and knee joints. This results in inflammation in the synovium and osteochondral injuries, ultimately causing functional limitations and joint dysfunction. The key mechanism responsible for maintaining articular cartilage function is chondrocyte metabolism, which involves energy generation through glycolysis, oxidative phosphorylation, and other metabolic pathways. Some studies have shown that chondrocytes in OA exhibit increased glycolytic activity, leading to elevated lactate production and decreased cartilage matrix synthesis. In OA cartilage, chondrocytes display alterations in mitochondrial activity, such as decreased ATP generation and increased oxidative stress, which can contribute to cartilage deterioration. Chondrocyte metabolism also involves anabolic processes for extracellular matrix substrate production and energy generation. During OA, chondrocytes undergo considerable metabolic changes in different aspects, leading to articular cartilage homeostasis deterioration. Numerous studies have been carried out to provide tangible therapies for OA by using various models in vivo and in vitro targeting chondrocyte metabolism, although there are still certain limitations. With growing evidence indicating the essential role of chondrocyte metabolism in disease etiology, this literature review explores the metabolic characteristics and changes of chondrocytes in the presence of OA, both in vivo and in vitro. To provide insight into the complex metabolic reprogramming crucial in chondrocytes during OA progression, we investigate the dynamic interaction between metabolic pathways, such as glycolysis, lipid metabolism, and mitochondrial function. In addition, this review highlights prospective future research directions for novel approaches to diagnosis and treatment. Adopting a multifaceted strategy, our review aims to offer a comprehensive understanding of the metabolic intricacies within chondrocytes in OA, with the ultimate goal of identifying therapeutic targets capable of modulating chondrocyte metabolism for the treatment of OA.
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Affiliation(s)
| | | | | | | | - Panghu Zhou
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China
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14
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Jia S, Liang R, Chen J, Liao S, Lin J, Li W. Emerging technology has a brilliant future: the CRISPR-Cas system for senescence, inflammation, and cartilage repair in osteoarthritis. Cell Mol Biol Lett 2024; 29:64. [PMID: 38698311 PMCID: PMC11067114 DOI: 10.1186/s11658-024-00581-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 04/19/2024] [Indexed: 05/05/2024] Open
Abstract
Osteoarthritis (OA), known as one of the most common types of aseptic inflammation of the musculoskeletal system, is characterized by chronic pain and whole-joint lesions. With cellular and molecular changes including senescence, inflammatory alterations, and subsequent cartilage defects, OA eventually leads to a series of adverse outcomes such as pain and disability. CRISPR-Cas-related technology has been proposed and explored as a gene therapy, offering potential gene-editing tools that are in the spotlight. Considering the genetic and multigene regulatory mechanisms of OA, we systematically review current studies on CRISPR-Cas technology for improving OA in terms of senescence, inflammation, and cartilage damage and summarize various strategies for delivering CRISPR products, hoping to provide a new perspective for the treatment of OA by taking advantage of CRISPR technology.
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Affiliation(s)
- Shicheng Jia
- Department of Sports Medicine and Rehabilitation, Peking University Shenzhen Hospital, Shenzhen, 518036, China
- Shantou University Medical College, Shantou, 515041, China
| | - Rongji Liang
- Shantou University Medical College, Shantou, 515041, China
| | - Jiayou Chen
- Department of Sports Medicine and Rehabilitation, Peking University Shenzhen Hospital, Shenzhen, 518036, China
- Shantou University Medical College, Shantou, 515041, China
| | - Shuai Liao
- Department of Bone and Joint, Peking University Shenzhen Hospital, Shenzhen, 518036, China
- Shenzhen University School of Medicine, Shenzhen, 518060, China
| | - Jianjing Lin
- Department of Sports Medicine and Rehabilitation, Peking University Shenzhen Hospital, Shenzhen, 518036, China.
| | - Wei Li
- Department of Sports Medicine and Rehabilitation, Peking University Shenzhen Hospital, Shenzhen, 518036, China.
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15
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Deng W, He Q, Zhang W. Analysis of the mechanism of curcumin against osteoarthritis using metabolomics and transcriptomics. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:3313-3329. [PMID: 37938371 PMCID: PMC11074044 DOI: 10.1007/s00210-023-02785-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 10/12/2023] [Indexed: 11/09/2023]
Abstract
Curcumin, a polyphenolic compound derived from the turmeric plant (Curcuma longa), has been extensively studied for its anti-inflammatory and anti-proliferative properties. The safety and efficacy of curcumin have been thoroughly validated. Nevertheless, the underlying mechanism for treating osteoarthritis remains ambiguous. This study aims to reveal the potential mechanism of curcumin in treating osteoarthritis by using metabolomics and transcriptomics. Firstly, we validated the effect of curcumin on inflammatory factors in human articular chondrocytes. Secondly, we explored the cellular metabolism mechanism of curcumin against osteoarthritis using cell metabolomics. Thirdly, we assessed the differences in gene expression of human articular chondrocytes through transcriptomics. Lastly, to evaluate the essential targets and elucidate the potential mechanism underlying the therapeutic effects of curcumin in osteoarthritis, we conducted a screening of the proteins within the shared pathway of metabolomics and transcriptomics. Our results demonstrated that curcumin significantly decreased the levels of inflammatory markers, such as IL-β, IL-6, and TNF-α, in human articular chondrocytes. Cell metabolomics identified 106 differential metabolites, including beta-aminopropionitrile, 3-amino-2-piperidone, pyrrole-2-carboxaldehyde, and various other components. The transcriptomic analysis yielded 1050 differential mRNAs. Enrichment analysis showed that the differential metabolites and mRNAs were significantly enriched in seven pathways, including glycine, serine, and threonine metabolism; pentose and glucuronate interconversions; glycerolipid metabolism; histidine metabolism; mucin-type o-glycan biosynthesis; inositol phosphate metabolism; and cysteine and methionine metabolism. A total of 23 key targets were identified to be involved in these pathways. We speculate that curcumin may alleviate osteoarthritis by targeting key proteins involved in glycine, serine, and threonine metabolism; inhibiting pyruvate production; and modulating glycolysis.
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Affiliation(s)
- Wenxiang Deng
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, 410208, Hunan, China
| | - Qinghu He
- Department of Rehabilitation and Healthcare, Hunan University of Medicine, Huaihua, 418000, Hunan, China.
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, 410208, Hunan, China.
| | - Wenan Zhang
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, 410208, Hunan, China
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16
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Song Y, Wu S, Zhang R, Zhong Q, Zhang X, Sun X. Therapeutic potential of hydrogen sulfide in osteoarthritis development. Front Pharmacol 2024; 15:1336693. [PMID: 38370481 PMCID: PMC10869529 DOI: 10.3389/fphar.2024.1336693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 01/22/2024] [Indexed: 02/20/2024] Open
Abstract
The pathological mechanisms and treatments of osteoarthritis (OA) are critical topics in medical research. This paper reviews the regulatory mechanisms of hydrogen sulfide (H2S) in OA and the therapeutic potential of H2S donors. The review highlights the importance of changes in the endogenous H2S pathway in OA development and systematically elaborates on the role of H2S as a third gaseous transmitter that regulates inflammation, oxidative stress, and pain associated with OA. It also explains how H2S can lessen bone and joint inflammation by inhibiting leukocyte adhesion and migration, reducing pro-inflammatory mediators, and impeding the activation of key inflammatory pathways such as nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK). Additionally, H2S is shown to mitigate mitochondrial dysfunction and endoplasmic reticulum stress, and to modulate Nrf2, NF-κB, PI3K/Akt, and MAPK pathways, thereby decreasing oxidative stress-induced chondrocyte apoptosis. Moreover, H2S alleviates bone and joint pain through the activation of Kv7, K-ATP, and Nrf2/HO-1-NQO1 pathways. Recent developments have produced a variety of H2S donors, including sustained-release H2S donors, natural H2S donors, and synthetic H2S donors. Understanding the role of H2S in OA can lead to the discovery of new therapeutic targets, while innovative H2S donors offer promising new treatments for patients with OA.
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Affiliation(s)
- Yunjia Song
- Department of Pharmacology, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Siyu Wu
- Department of Pharmacology, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Rong Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Qing Zhong
- Department of Pharmacology, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Xuanming Zhang
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xutao Sun
- Department of Typhoid, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, China
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17
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Giordo R, Tulasigeri Totiger S, Caggiari G, Cossu A, Manunta AF, Posadino AM, Pintus G. Protective Effect of Knee Postoperative Fluid on Oxidative-Induced Damage in Human Knee Articular Chondrocytes. Antioxidants (Basel) 2024; 13:188. [PMID: 38397786 PMCID: PMC10886415 DOI: 10.3390/antiox13020188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/15/2024] [Accepted: 01/30/2024] [Indexed: 02/25/2024] Open
Abstract
The oxidative-stress-elicited deterioration of chondrocyte function is the initial stage of changes leading to the disruption of cartilage homeostasis. These changes entail a series of catabolic damages mediated by proinflammatory cytokines, MMPs, and aggrecanases, which increase ROS generation. Such uncontrolled ROS production, inadequately balanced by the cellular antioxidant capacity, eventually contributes to the development and progression of chondropathies. Several pieces of evidence show that different growth factors, single or combined, as well as anti-inflammatory cytokines and chemokines, can stimulate chondrogenesis and improve cartilage repair and regeneration. In this view, hypothesizing a potential growth-factor-associated action, we investigate the possible protective effect of post-operation knee fluid from patients undergoing prosthesis replacement surgery against ROS-induced damage on normal human knee articular chondrocytes (HKACs). To this end, HKACs were pre-treated with post-operation knee fluid and then exposed to H2O2 to mimic oxidative stress. Intracellular ROS levels were measured by using the molecular probe H2DCFDA; cytosolic and mitochondrial oxidative status were assessed by using HKACs infected with lentiviral particles harboring the redox-sensing green fluorescent protein (roGFP); and cell proliferation was determined by measuring the rate of DNA synthesis with BrdU incorporation. Moreover, superoxide dismutase (SOD), catalase, and glutathione levels from the cell lysates of treated cells were also measured. Postoperative peripheral blood sera from the same patients were used as controls. Our study shows that post-operation knee fluid can counteract H2O2-elicited oxidative stress by decreasing the intracellular ROS levels, preserving the cytosolic and mitochondrial redox status, maintaining the proliferation of oxidatively stressed HKACs, and upregulating chondrocyte antioxidant defense. Overall, our results support and propose an important effect of post-operation knee fluid substances in maintaining HKAC function by mediating cell antioxidative system upregulation and protecting cells from oxidative stress.
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Affiliation(s)
- Roberta Giordo
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (R.G.); (S.T.T.); (A.C.)
| | - Smitha Tulasigeri Totiger
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (R.G.); (S.T.T.); (A.C.)
| | - Gianfilippo Caggiari
- Orthopaedic and Traumatology Department, University Hospital, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (G.C.); (A.F.M.)
| | - Annalisa Cossu
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (R.G.); (S.T.T.); (A.C.)
| | - Andrea Fabio Manunta
- Orthopaedic and Traumatology Department, University Hospital, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (G.C.); (A.F.M.)
| | - Anna Maria Posadino
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (R.G.); (S.T.T.); (A.C.)
| | - Gianfranco Pintus
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (R.G.); (S.T.T.); (A.C.)
- Department of Medical Laboratory Sciences, College of Health Sciences, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
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18
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Fernández-Moreno M, Hermida-Gómez T, Larkins N, Reynolds A, Blanco FJ. Anti-Inflammatory Activity of APPA (Apocynin and Paeonol) in Human Articular Chondrocytes. Pharmaceuticals (Basel) 2024; 17:118. [PMID: 38256951 PMCID: PMC10818286 DOI: 10.3390/ph17010118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/10/2024] [Accepted: 01/12/2024] [Indexed: 01/24/2024] Open
Abstract
Osteoarthritis (OA) is a chronic joint disease leading to cartilage loss and reduction in the joint space which results in pain. The current pharmacological treatment of OA is inadequate and pharmacological interventions focus on symptom management. APPA, a combination of apocynin (AP) and paeonol (PA), is a potential drug for treating OA. The aim of this study was to analyze the effects of APPA on the modulation of the inflammatory response in chondrocytes. Samples were incubated with IL-1β and APPA, and their responses to proinflammatory cytokines, catabolic mediators and redox responses were then measured. The effect of APPA on mitogenesis was also evaluated. Results show that APPA attenuated the expression of IL-8, TNF-α, MMP-3, MMP-13, SOD-2 and iNOS, resulting in the protection of human articular cartilage. APPA decreased PGC-1α gene expression induced by IL-1β. APPA did not modulate the gene expression of Mfn2, Sirt-1 or Sirt-3. The overall findings indicate that APPA may be an effective treatment for OA by targeting several of the pathways involved in OA pathogenesis.
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Affiliation(s)
- Mercedes Fernández-Moreno
- Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade de A Coruña (UDC), 15071 A Coruña, Spain;
- Grupo de Investigación en Reumatología y Salud (GIR-S), Centro Interdisciplinar de Química y Biología (CICA), Universidade de A Coruña (UDC), Campus de Elviña, 15071 A Coruña, Spain
| | - Tamara Hermida-Gómez
- Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade de A Coruña (UDC), 15071 A Coruña, Spain;
- Grupo de Investigación en Reumatología y Salud (GIR-S), Centro Interdisciplinar de Química y Biología (CICA), Universidade de A Coruña (UDC), Campus de Elviña, 15071 A Coruña, Spain
- Centro de Investigación Biomédica en Red, Bioingenieria, Biomatereial y Nanomedicina (CIBER-BBN), 50018 Zaragoza, Spain
| | - Nicholas Larkins
- AKL Therapeutics Ltd., Stevenage Bioscience, Gunnels Wood Rd, Stevenage SG1 2FX, UK; (N.L.); (A.R.)
| | - Alan Reynolds
- AKL Therapeutics Ltd., Stevenage Bioscience, Gunnels Wood Rd, Stevenage SG1 2FX, UK; (N.L.); (A.R.)
| | - Francisco J. Blanco
- Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade de A Coruña (UDC), 15071 A Coruña, Spain;
- Grupo de Investigación en Reumatología y Salud (GIR-S), Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Fisioterapia, Centro Interdisciplinar de Química y Biología (CICA), INIBIC-Sergas, Universidade de A Coruña (UDC), Campus de Oza, 15008 A Coruña, Spain
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19
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Xu K, Li J, Wen R, Chang B, Cheng Y, Yi X. Role of SIRT3 in bone homeostasis and its application in preventing and treating bone diseases. Front Pharmacol 2023; 14:1248507. [PMID: 38192409 PMCID: PMC10773770 DOI: 10.3389/fphar.2023.1248507] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 12/11/2023] [Indexed: 01/10/2024] Open
Abstract
Bone homeostasis refers to the balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption and the maintenance of stable bone mass. SIRT3 is a class of mitochondrial protein deacetylase that influences various mitochondrial functions and is involved in the mechanisms underlying resistance to aging; regulation of bone marrow mesenchymal stem cells, osteoblasts, and osteoclasts; and development of osteoporosis, osteoarthritis, and other bone diseases. Moreover, exercise affects bones through SIRT3. Thus, studies on SIRT3 may provide insights for the treatment of bone diseases. Although SIRT3 can exert multiple effects on bone, the specific mechanism by which it regulates bone homeostasis remains unclear. By evaluating the relevant literature, this review discusses the structure and function of SIRT3, reveals the role and associated mechanisms of SIRT3 in regulating bone homeostasis and mediating bone health during exercise, and highlights the potential pharmacological value of SIRT3 in treating bone diseases.
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Affiliation(s)
- Ke Xu
- School of Sports Health, Shenyang Sport University, Shenyang, China
| | - Jing Li
- School of Physical Education, Liaoning Normal University, Dalian, China
| | - Ruiming Wen
- School of Sports Health, Shenyang Sport University, Shenyang, China
| | - Bo Chang
- School of Sports Health, Shenyang Sport University, Shenyang, China
| | - Yang Cheng
- School of Sports Health, Shenyang Sport University, Shenyang, China
| | - Xuejie Yi
- School of Sports Health, Shenyang Sport University, Shenyang, China
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20
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Horváth E, Sólyom Á, Székely J, Nagy EE, Popoviciu H. Inflammatory and Metabolic Signaling Interfaces of the Hypertrophic and Senescent Chondrocyte Phenotypes Associated with Osteoarthritis. Int J Mol Sci 2023; 24:16468. [PMID: 38003658 PMCID: PMC10671750 DOI: 10.3390/ijms242216468] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/12/2023] [Accepted: 11/15/2023] [Indexed: 11/26/2023] Open
Abstract
Osteoarthritis (OA) is a complex disease of whole joints with progressive cartilage matrix degradation and chondrocyte transformation. The inflammatory features of OA are reflected in increased synovial levels of IL-1β, IL-6 and VEGF, higher levels of TLR-4 binding plasma proteins and increased expression of IL-15, IL-18, IL-10 and Cox2, in cartilage. Chondrocytes in OA undergo hypertrophic and senescent transition; in these states, the expression of Sox-9, Acan and Col2a1 is suppressed, whereas the expression of RunX2, HIF-2α and MMP-13 is significantly increased. NF-kB, which triggers many pro-inflammatory cytokines, works with BMP, Wnt and HIF-2α to link hypertrophy and inflammation. Altered carbohydrate metabolism and the upregulation of GLUT-1 contribute to the formation of end-glycation products that trigger inflammation via the RAGE pathway. In addition, a glycolytic shift, increased rates of oxidative phosphorylation and mitochondrial dysfunction generate reactive oxygen species with deleterious effects. An important surveyor mechanism, the YAP/TAZ signaling system, controls chondrocyte differentiation, inhibits ageing by protecting the nuclear envelope and suppressing NF-kB, MMP-13 and aggrecanases. The inflammatory microenvironment and synthesis of key matrix components are also controlled by SIRT1 and mTORc. Senescent chondrocytes represent the functional end stage of hypertrophic differentiation and characteristically upregulate p16 and p21, but also a variety of inflammatory cytokines, chemokines and metalloproteinases, developing the senescence-associated secretory phenotype. Senolysis with dendrobin, miR29b-5p and other agents has been shown to be efficient under experimental conditions, and appears to be a promising tool for the treatment of OA, as it restores COL2A1 and aggrecan synthesis, suppressing NF-kB and destructive metalloproteinases.
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Affiliation(s)
- Emőke Horváth
- Department of Pathology, Faculty of Medicine, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 38 Gheorghe Marinescu Street, 540142 Targu Mures, Romania;
- Pathology Service, County Emergency Clinical Hospital of Targu Mures, 50 Gheorghe Marinescu Street, 540136 Targu Mures, Romania
| | - Árpád Sólyom
- Department of Orthopedics-Traumatology, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 38 Gh. Marinescu Street, 540142 Targu Mures, Romania;
- Clinic of Orthopaedics and Traumatology, County Emergency Clinical Hospital of Targu Mures, 50 Gheorghe Marinescu Street, 540136 Targu Mures, Romania;
| | - János Székely
- Clinic of Orthopaedics and Traumatology, County Emergency Clinical Hospital of Targu Mures, 50 Gheorghe Marinescu Street, 540136 Targu Mures, Romania;
| | - Előd Ernő Nagy
- Department of Biochemistry and Environmental Chemistry, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology of Targu Mures, 38 Gheorghe Marinescu Street, 540142 Targu Mures, Romania
- Laboratory of Medical Analysis, Clinical County Hospital Mures, 6 Bernády György Square, 540394 Targu Mures, Romania
| | - Horațiu Popoviciu
- Department of Rheumatology, Physical and Medical Rehabilitation, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 38 Gheorghe Marinescu Street, 540139 Targu Mures, Romania;
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21
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Main EN, Cruz TM, Bowlin GL. Mitochondria as a therapeutic: a potential new frontier in driving the shift from tissue repair to regeneration. Regen Biomater 2023; 10:rbad070. [PMID: 37663015 PMCID: PMC10468651 DOI: 10.1093/rb/rbad070] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 07/12/2023] [Accepted: 08/08/2023] [Indexed: 09/05/2023] Open
Abstract
Fibrosis, or scar tissue development, is associated with numerous pathologies and is often considered a worst-case scenario in terms of wound healing or the implantation of a biomaterial. All that remains is a disorganized, densely packed and poorly vascularized bundle of connective tissue, which was once functional tissue. This creates a significant obstacle to the restoration of tissue function or integration with any biomaterial. Therefore, it is of paramount importance in tissue engineering and regenerative medicine to emphasize regeneration, the successful recovery of native tissue function, as opposed to repair, the replacement of the native tissue (often with scar tissue). A technique dubbed 'mitochondrial transplantation' is a burgeoning field of research that shows promise in in vitro, in vivo and various clinical applications in preventing cell death, reducing inflammation, restoring cell metabolism and proper oxidative balance, among other reported benefits. However, there is currently a lack of research regarding the potential for mitochondrial therapies within tissue engineering and regenerative biomaterials. Thus, this review explores these promising findings and outlines the potential for mitochondrial transplantation-based therapies as a new frontier of scientific research with respect to driving regeneration in wound healing and host-biomaterial interactions, the current successes of mitochondrial transplantation that warrant this potential and the critical questions and remaining obstacles that remain in the field.
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Affiliation(s)
- Evan N Main
- Department of Biomedical Engineering, University of Memphis, 330 Engineering Technology Building, Memphis, TN 38152, USA
| | - Thaiz M Cruz
- Department of Biomedical Engineering, University of Memphis, 330 Engineering Technology Building, Memphis, TN 38152, USA
| | - Gary L Bowlin
- Department of Biomedical Engineering, University of Memphis, 330 Engineering Technology Building, Memphis, TN 38152, USA
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22
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Defois A, Bon N, Charpentier A, Georget M, Gaigeard N, Blanchard F, Hamel A, Waast D, Armengaud J, Renoult O, Pecqueur C, Maugars Y, Boutet MA, Guicheux J, Vinatier C. Osteoarthritic chondrocytes undergo a glycolysis-related metabolic switch upon exposure to IL-1b or TNF. Cell Commun Signal 2023; 21:137. [PMID: 37316888 DOI: 10.1186/s12964-023-01150-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 04/28/2023] [Indexed: 06/16/2023] Open
Abstract
BACKGROUND Osteoarthritis is an age-related disease that currently faces a lack of symptomatic treatment. Inflammation, which is mainly sustained by pro-inflammatory cytokines such as IL-1b, TNF, and IL-6, plays an important role in osteoarthritis progression. In this context, pro-inflammatory cytokines are widely used to mimic the inflammatory component of osteoarthritis in vitro. However, the therapeutic failures of clinical trials evaluating anti-cytokines drugs highlight the lack of overall understanding of the effects of these cytokines on chondrocytes. METHODS Here, we generated a comprehensive transcriptomic and proteomic dataset of osteoarthritic chondrocytes treated with these cytokines to describe their pro-inflammatory signature and compare it to the transcriptome of non-osteoarthritic chondrocytes. Then, the dysregulations highlighted at the molecular level were functionally confirmed by real-time cellular metabolic assays. RESULTS We identified dysregulation of metabolic-related genes in osteoarthritic chondrocytes but not in non-osteoarthritic chondrocytes. A metabolic shift, toward increased glycolysis at the expense of mitochondrial respiration, was specifically confirmed in osteoarthritic chondrocytes treated with IL-1b or TNF. CONCLUSION These data show a strong and specific association between inflammation and metabolism in osteoarthritic chondrocytes, which was not found in non-osteoarthritic chondrocytes. This indicates that the link between inflammation and metabolic dysregulation may be exacerbated during chondrocyte damage in osteoarthritis. Video Abstract.
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Affiliation(s)
- Anais Defois
- Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, 44000, Nantes, France
| | - Nina Bon
- Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, 44000, Nantes, France
| | - Alexandre Charpentier
- Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, 44000, Nantes, France
| | - Melina Georget
- Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, 44000, Nantes, France
| | - Nicolas Gaigeard
- Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, 44000, Nantes, France
| | - Frederic Blanchard
- Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, 44000, Nantes, France
| | - Antoine Hamel
- Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, 44000, Nantes, France
| | - Denis Waast
- Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, 44000, Nantes, France
| | - Jean Armengaud
- Département Médicaments Et Technologies Pour La Santé (DMTS), Université Paris-Saclay, CEA, INRAE, SPI, Bagnols-Sur-Cèze, 30200, France
| | - Ophelie Renoult
- Nantes Université, INSERM, CNRS, CRCI2NA, F-44000, Nantes, France
| | - Claire Pecqueur
- Nantes Université, INSERM, CNRS, CRCI2NA, F-44000, Nantes, France
| | - Yves Maugars
- Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, 44000, Nantes, France
| | - Marie-Astrid Boutet
- Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, 44000, Nantes, France
- Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute and Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Jerome Guicheux
- Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, 44000, Nantes, France.
| | - Claire Vinatier
- Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, 44000, Nantes, France.
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23
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Wakale S, Wu X, Sonar Y, Sun A, Fan X, Crawford R, Prasadam I. How are Aging and Osteoarthritis Related? Aging Dis 2023; 14:592-604. [PMID: 37191424 PMCID: PMC10187698 DOI: 10.14336/ad.2022.0831] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 08/31/2022] [Indexed: 05/17/2023] Open
Abstract
Osteoarthritis is the most prevalent degenerative joint disease and one of the leading causes of physical impairment in the world's aging population. The human lifespan has significantly increased as a result of scientific and technological advancements. According to estimates, the world's elderly population will increase by 20% by 2050. Aging and age-related changes are discussed in this review in relation to the development of OA. We specifically discussed the cellular and molecular changes that occur in the chondrocytes during aging and how these changes may make synovial joints more susceptible to OA development. These changes include chondrocyte senescence, mitochondrial dysfunction, epigenetic modifications, and decreased growth factor response. The age-associated changes occur not only in the chondrocytes but also in the matrix, subchondral bone, and synovium. This review aims to provide an overview of the interplay between chondrocytes and matrix and how age-related changes affect the normal function of cartilage and contribute to OA development. Understanding the alterations that affect the function of chondrocytes will emerge new possibilities for prospective therapeutic options for the treatment of OA.
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Affiliation(s)
- Shital Wakale
- Centre for Biomedical Technologies, Faculty of Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
| | - Xiaoxin Wu
- Centre for Biomedical Technologies, Faculty of Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
| | - Yogita Sonar
- Centre for Biomedical Technologies, Faculty of Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
| | - Antonia Sun
- Centre for Biomedical Technologies, Faculty of Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
| | - Xiwei Fan
- Centre for Biomedical Technologies, Faculty of Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
| | - Ross Crawford
- Centre for Biomedical Technologies, Faculty of Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
- Orthopaedic Department, The Prince Charles Hospital, Brisbane, Queensland, Australia.
| | - Indira Prasadam
- Centre for Biomedical Technologies, Faculty of Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
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24
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Noriega-González D, Caballero-García A, Roche E, Álvarez-Mon M, Córdova A. Inflammatory Process on Knee Osteoarthritis in Cyclists. J Clin Med 2023; 12:jcm12113703. [PMID: 37297897 DOI: 10.3390/jcm12113703] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 05/17/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
Osteoarthritis is a disorder affecting the joints and is characterized by cellular stress and degradation of the extracellular matrix cartilage. It begins with the presence of micro- and macro-lesions that fail to repair properly, which can be initiated by multiple factors: genetic, developmental, metabolic, and traumatic. In the case of the knee, osteoarthritis affects the tissues of the diarthrodial joint, manifested by morphological, biochemical, and biomechanical modifications of the cells and the extracellular matrix. All this leads to remodeling, fissuring, ulceration, and loss of articular cartilage, as well as sclerosis of the subchondral bone with the production of osteophytes and subchondral cysts. The symptomatology appears at different time points and is accompanied by pain, deformation, disability, and varying degrees of local inflammation. Repetitive concentric movements, such as while cycling, can produce the microtrauma that leads to osteoarthritis. Aggravation of the gradual lesion in the cartilage matrix can evolve to an irreversible injury. The objective of the present review is to explain the evolution of knee osteoarthritis in cyclists, to show the scarce research performed in this particular field and extract recommendations to propose future therapeutic strategies.
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Affiliation(s)
- David Noriega-González
- Department of Surgery, Ophthalmology, Otorhinolaryngology and Physiotherapy, Faculty of Medicine, HVUV, 47003 Valladolid, Spain
| | - Alberto Caballero-García
- Department of Anatomy and Radiology, Faculty of Health Sciences, GIR Physical Exercise and Aging, University of Valladolid, Campus Los Pajaritos, 42004 Soria, Spain
| | - Enrique Roche
- Department of Applied Biology-Nutrition and Institute of Bioengineering, Miguel Hernández University (UMH), 03202 Elche, Spain
- Institute for Health and Biomedical Research (ISABIAL), 03010 Alicante, Spain
- CIBER Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Melchor Álvarez-Mon
- Department of Internal Medicine, University of Alcalá de Henares, 28801 Alcalá de Henares, Spain
| | - Alfredo Córdova
- Department of Biochemistry, Molecular Biology and Physiology, Faculty of Health Sciences, GIR Physical Exercise and Aging, University of Valladolid, Campus Duques de Soria, 42004 Soria, Spain
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25
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Wang H, Su J, Yu M, Xia Y, Wei Y. PGC-1α in osteoarthritic chondrocytes: From mechanism to target of action. Front Pharmacol 2023; 14:1169019. [PMID: 37089944 PMCID: PMC10117990 DOI: 10.3389/fphar.2023.1169019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 03/30/2023] [Indexed: 04/08/2023] Open
Abstract
Osteoarthritis (OA) is one of the most common degenerative joint diseases, often involving the entire joint. The degeneration of articular cartilage is an important feature of OA, and there is growing evidence that the mitochondrial biogenesis master regulator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) exert a chondroprotective effect. PGC-1α delays the development and progression of OA by affecting mitochondrial biogenesis, oxidative stress, mitophagy and mitochondrial DNA (mtDNA) replication in chondrocytes. In addition, PGC-1α can regulate the metabolic abnormalities of OA chondrocytes and inhibit chondrocyte apoptosis. In this paper, we review the regulatory mechanisms of PGC-1α and its effects on OA chondrocytes, and introduce potential drugs and novel nanohybrid for the treatment of OA which act by affecting the activity of PGC-1α. This information will help to further elucidate the pathogenesis of OA and provide new ideas for the development of therapeutic strategies for OA.
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Affiliation(s)
- Haochen Wang
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jianbang Su
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Minghao Yu
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yang Xia
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Yang Xia, ; Yingliang Wei,
| | - Yingliang Wei
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Yang Xia, ; Yingliang Wei,
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26
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Zhang Y, Liu Y, Hou M, Xia X, Liu J, Xu Y, Shi Q, Zhang Z, Wang L, Shen Y, Yang H, He F, Zhu X. Reprogramming of Mitochondrial Respiratory Chain Complex by Targeting SIRT3-COX4I2 Axis Attenuates Osteoarthritis Progression. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2206144. [PMID: 36683245 PMCID: PMC10074136 DOI: 10.1002/advs.202206144] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/09/2022] [Indexed: 06/17/2023]
Abstract
Mitochondrial homeostasis is of great importance for cartilage integrity and associated with the progression of osteoarthritis (OA); however, the underlying mechanisms are unknown. This study aims to investigate the role of mitochondrial deacetylation reaction and investigate the mechanistic relationship OA development. Silent mating type information regulation 2 homolog 3 (SIRT3) expression has a negative correlation with the severity of OA in both human arthritic cartilage and mice inflammatory chondrocytes. Global SIRT3 deletion accelerates pathological phenotype in post-traumatic OA mice, as evidenced by cartilage extracellular matrix collapse, osteophyte formation, and synovial macrophage M1 polarization. Mechanistically, SIRT3 prevents OA progression by targeting and deacetylating cytochrome c oxidase subunit 4 isoform 2 (COX4I2) to maintain mitochondrial homeostasis at the post-translational level. The activation of SIRT3 by honokiol restores cartilage metabolic equilibrium and protects mice from the development of post-traumatic OA. Collectively, the loss of mitochondrial SIRT3 is essential for the development of OA, whereas SIRT3-mediated proteins deacetylation of COX4I2 rescues OA-impaired mitochondrial respiratory chain functions to improve the OA phenotype. Herein, the induction of SIRT3 provides a novel therapeutic candidate for OA treatment.
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Affiliation(s)
- Yijian Zhang
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhou215006China
- Orthopaedic InstituteMedical CollegeSoochow UniversitySuzhou215007China
| | - Yang Liu
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhou215006China
- Orthopaedic InstituteMedical CollegeSoochow UniversitySuzhou215007China
| | - Mingzhuang Hou
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhou215006China
- Orthopaedic InstituteMedical CollegeSoochow UniversitySuzhou215007China
| | - Xiaowei Xia
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhou215006China
- Orthopaedic InstituteMedical CollegeSoochow UniversitySuzhou215007China
| | - Junlin Liu
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhou215006China
- Orthopaedic InstituteMedical CollegeSoochow UniversitySuzhou215007China
| | - Yong Xu
- Orthopaedic InstituteMedical CollegeSoochow UniversitySuzhou215007China
| | - Qin Shi
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhou215006China
- Orthopaedic InstituteMedical CollegeSoochow UniversitySuzhou215007China
| | - Zhongmin Zhang
- Department of OrthopedicsNanfang HospitalSouthern Medical UniversityGuangzhou510515China
| | - Liang Wang
- Department of OrthopedicsThe Third Affiliated HospitalSouthern Medical UniversityGuangzhou510630China
| | - Yifan Shen
- Department of Orthopedic SurgeryZhejiang University School of MedicineHangzhou310003China
| | - Huilin Yang
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhou215006China
- Orthopaedic InstituteMedical CollegeSoochow UniversitySuzhou215007China
| | - Fan He
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhou215006China
- Orthopaedic InstituteMedical CollegeSoochow UniversitySuzhou215007China
| | - Xuesong Zhu
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhou215006China
- Orthopaedic InstituteMedical CollegeSoochow UniversitySuzhou215007China
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27
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Kan S, Pi C, Zhang L, Guo D, Niu Z, Liu Y, Duan M, Pu X, Bai M, Zhou C, Zhang D, Xie J. FGF19 increases mitochondrial biogenesis and fusion in chondrocytes via the AMPKα-p38/MAPK pathway. Cell Commun Signal 2023; 21:55. [PMID: 36915160 PMCID: PMC10009974 DOI: 10.1186/s12964-023-01069-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Accepted: 02/05/2023] [Indexed: 03/16/2023] Open
Abstract
Fibroblast growth factor 19 (FGF19) is recognized to play an essential role in cartilage development and physiology, and has emerged as a potential therapeutic target for skeletal metabolic diseases. However, FGF19-mediated cellular behavior in chondrocytes remains a big challenge. In the current study, we aimed to investigate the role of FGF19 on chondrocytes by characterizing mitochondrial biogenesis and fission-fusion dynamic equilibrium and exploring the underlying mechanism. We first found that FGF19 enhanced mitochondrial biogenesis in chondrocytes with the help of β Klotho (KLB), a vital accessory protein for assisting the binding of FGF19 to its receptor, and the enhanced biogenesis accompanied with a fusion of mitochondria, reflecting in the elongation of individual mitochondria and the up-regulation of mitochondrial fusion proteins. We then revealed that FGF19-mediated mitochondrial biogenesis and fusion required the binding of FGF19 to the membrane receptor, FGFR4, and the activation of AMP-activated protein kinase alpha (AMPKα)/peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α)/sirtuin 1 (SIRT1) axis. Finally, we demonstrated that FGF19-mediated mitochondrial biogenesis and fusion was mainly dependent on the activation of p-p38 signaling. Inhibition of p38 signaling largely reduced the high expression of AMPKα/PGC-1α/SIRT1 axis, decreased the up-regulation of mitochondrial fusion proteins and impaired the enhancement of mitochondrial network morphology in chondrocytes induced by FGF19. Taking together, our results indicate that FGF19 could increase mitochondrial biogenesis and fusion via AMPKα-p38/MAPK signaling, which enlarge the understanding of FGF19 on chondrocyte metabolism. Video Abstract.
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Affiliation(s)
- Shiyi Kan
- Lab of Bone and Joint Disease, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610064, Sichuan, China
| | - Caixia Pi
- Lab of Bone and Joint Disease, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610064, Sichuan, China
| | - Li Zhang
- Lab of Bone and Joint Disease, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610064, Sichuan, China
| | - Daimo Guo
- Lab of Bone and Joint Disease, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610064, Sichuan, China
| | - Zhixing Niu
- Lab of Bone and Joint Disease, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610064, Sichuan, China
| | - Yang Liu
- Lab of Bone and Joint Disease, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610064, Sichuan, China
| | - Mengmeng Duan
- Lab of Bone and Joint Disease, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610064, Sichuan, China
| | - Xiahua Pu
- Lab of Bone and Joint Disease, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610064, Sichuan, China
| | - Mingru Bai
- Lab of Bone and Joint Disease, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610064, Sichuan, China
| | - Chenchen Zhou
- Lab of Bone and Joint Disease, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610064, Sichuan, China
| | - Demao Zhang
- Lab of Bone and Joint Disease, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610064, Sichuan, China
| | - Jing Xie
- Lab of Bone and Joint Disease, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610064, Sichuan, China.
- National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610064, China.
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Wu Y, Shen S, Chen J, Ni W, Wang Q, Zhou H, Chen J, Zhang H, Mei Z, Sun X, Shen P, Jie Z, Xu W, Hong Z, Ma Y, Wang K, Wan S, Wu H, Xie Z, Qin A, Fan S. Metabolite asymmetric dimethylarginine (ADMA) functions as a destabilization enhancer of SOX9 mediated by DDAH1 in osteoarthritis. SCIENCE ADVANCES 2023; 9:eade5584. [PMID: 36753544 PMCID: PMC9908022 DOI: 10.1126/sciadv.ade5584] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 01/06/2023] [Indexed: 06/18/2023]
Abstract
Osteoarthritis (OA) is a degenerative disease with a series of metabolic changes accompanied by many altered enzymes. Here, we report that the down-regulated dimethylarginine dimethylaminohydrolase-1 (DDAH1) is accompanied by increased asymmetric dimethylarginine (ADMA) in degenerated chondrocytes and in OA samples. Global or chondrocyte-conditional knockout of ADMA hydrolase DDAH1 accelerated OA development in mice. ADMA induces the degeneration and senescence of chondrocytes and reduces the extracellular matrix deposition, thereby accelerating OA progression. ADMA simultaneously binds to SOX9 and its deubiquitinating enzyme USP7, blocking the deubiquitination effects of USP7 on SOX9 and therefore leads to SOX9 degradation. The ADMA level in synovial fluids of patients with OA is increased and has predictive value for OA diagnosis with good sensitivity and specificity. Therefore, activating DDAH1 to reduce ADMA level might be a potential therapeutic strategy for OA treatment.
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Affiliation(s)
- Yizheng Wu
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Shuying Shen
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Jiaxin Chen
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Weiyu Ni
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Qinxin Wang
- Department of Orthopaedic Surgery, China Coast Guard Hospital of the People’s Armed Police Force, Jiaxing, China
| | - Hongyi Zhou
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Junxin Chen
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Haitao Zhang
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Zixuan Mei
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Xuewu Sun
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Panyang Shen
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Zhiwei Jie
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Wenbin Xu
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Zhenghua Hong
- Department of Orthopaedic Surgery, Taizhou Hospital of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Yan Ma
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Kefan Wang
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Shuanglin Wan
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Hongfei Wu
- Department of Orthopaedic Surgery, China Coast Guard Hospital of the People’s Armed Police Force, Jiaxing, China
| | - Ziang Xie
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - An Qin
- Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Shunwu Fan
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
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Zhang RD, Chen C, Wang P, Fang Y, Jiang LQ, Fang X, Zhao Y, Ni J, Wang DG, Pan HF. Air pollution exposure and auto-inflammatory and autoimmune diseases of the musculoskeletal system: a review of epidemiologic and mechanistic evidence. ENVIRONMENTAL GEOCHEMISTRY AND HEALTH 2023:10.1007/s10653-023-01495-x. [PMID: 36735155 DOI: 10.1007/s10653-023-01495-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 01/24/2023] [Indexed: 06/18/2023]
Abstract
Auto-inflammatory and autoimmune diseases of the musculoskeletal system can be perceived as a spectrum of rheumatic diseases, with the joints and connective tissues are eroded severely that progressively develop chronic inflammation and lesion. A wide range of risk factors represented by genetic and environmental factors have been uncovered by population-based surveys and experimental studies. Lately, the exposure to air pollution has been found to be potentially involved in the mechanisms of occurrence or development of such diseases, principally manifest in oxidative stress, local and systemic inflammation, and epigenetic modifications, as well as the mitochondrial dysfunction, which has been reported to participate in the intermediate links. The lungs might serve as a starting area of air pollutants, which would cause oxidative stress-induced bronchial-associated lymphoid tissue (iBALT) to further to influence T, B cells, and the secretion of pro-inflammatory cytokines. The binding of aromatic hydrocarbon receptor (AhR) to the corresponding contaminant ligands tends to regulate the reaction of Th17 and Tregs. Furthermore, air pollution components might spur on immune and inflammatory responses by damaging mitochondria that could interact with and exacerbate oxidative stress and pro-inflammatory cytokines. In this review, we focused on the association between air pollution and typical auto-inflammatory and autoimmune diseases of the musculoskeletal system, mainly including osteoarthritis (OA), rheumatoid arthritis (RA), spondyloarthritis (SpA) and juvenile idiopathic arthritis (JIA), and aim to collate the mechanisms involved and the potential channels. A complete summary and in-depth understanding of the autoimmune and inflammatory effects of air pollution exposure should hopefully contribute new perspectives on how to formulate better public health policies to alleviate the adverse health effects of air pollutants.
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Affiliation(s)
- Ruo-Di Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
- Institute of Kidney Disease, Inflammation and Immunity Mediated Diseases, The Second Hospital of Anhui Medical University, Hefei, 230032, Anhui, People's Republic of China
| | - Cong Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
- Institute of Kidney Disease, Inflammation and Immunity Mediated Diseases, The Second Hospital of Anhui Medical University, Hefei, 230032, Anhui, People's Republic of China
| | - Peng Wang
- Institute of Kidney Disease, Inflammation and Immunity Mediated Diseases, The Second Hospital of Anhui Medical University, Hefei, 230032, Anhui, People's Republic of China
- Teaching Center for Preventive Medicine, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
| | - Yang Fang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
- Institute of Kidney Disease, Inflammation and Immunity Mediated Diseases, The Second Hospital of Anhui Medical University, Hefei, 230032, Anhui, People's Republic of China
| | - Ling-Qiong Jiang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
- Institute of Kidney Disease, Inflammation and Immunity Mediated Diseases, The Second Hospital of Anhui Medical University, Hefei, 230032, Anhui, People's Republic of China
| | - Xi Fang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
- Institute of Kidney Disease, Inflammation and Immunity Mediated Diseases, The Second Hospital of Anhui Medical University, Hefei, 230032, Anhui, People's Republic of China
| | - Yan Zhao
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
- Institute of Kidney Disease, Inflammation and Immunity Mediated Diseases, The Second Hospital of Anhui Medical University, Hefei, 230032, Anhui, People's Republic of China
| | - Jing Ni
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China
- Institute of Kidney Disease, Inflammation and Immunity Mediated Diseases, The Second Hospital of Anhui Medical University, Hefei, 230032, Anhui, People's Republic of China
| | - De-Guang Wang
- Institute of Kidney Disease, Inflammation and Immunity Mediated Diseases, The Second Hospital of Anhui Medical University, Hefei, 230032, Anhui, People's Republic of China
- Department of Nephrology, The Second Hospital of Anhui Medical University, Hefei, 230032, Anhui, People's Republic of China
| | - Hai-Feng Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People's Republic of China.
- Institute of Kidney Disease, Inflammation and Immunity Mediated Diseases, The Second Hospital of Anhui Medical University, Hefei, 230032, Anhui, People's Republic of China.
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Zhang W, Xia CL, Ma JN, Li JX, Chen Q, Ou SJ, Yang Y, Qi Y, Xu CP. Effects of mitochondrial dysfunction on bone metabolism and related diseases: a scientometric study from 2003 to 2022. BMC Musculoskelet Disord 2022; 23:1016. [DOI: 10.1186/s12891-022-05911-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 10/25/2022] [Indexed: 11/28/2022] Open
Abstract
Abstract
Background
In recent years, mitochondrial dysfunction has been extensively studied and published, but research on the effects of mitochondrial dysfunction on bone metabolism and related diseases is only just beginning. Furthermore, no studies have been carried out to systematically illustrate this area from a scientometric point of view. The goal of this research is to review existing knowledge and identify new trends and possible hotspots in this area.
Methods
All publications related to the relationship between mitochondrial dysfunction and bone metabolism and related diseases from 2003 to 2022 were searched at the Web of Science Core Collection (WoSCC) on May 7, 2022. Four different analytical tools: VOSviewer 1.6.18, CiteSpace V 6.1, HistorCite (12.03.07), and Excel 2021 were used for the scientometric research.
Results
The final analysis included 555 valid records in total. Journal of Biological Chemistry (Co-citations = 916) is the most famous journal in this field. China (Percentage = 37%), the United States (Percentage = 24%), and Korea (Percentage = 12%) are the most productive countries. Blanco FJ and Choi EM are the main researchers with significant academic influence. Current research hotspots are basic research on mitochondrial dysfunction and the prevention or treatment of bone metabolism-related diseases.
Conclusion
The study of the consequences of mitochondrial dysfunction on bone metabolism and associated diseases is advancing rapidly. Several prominent researchers have published extensive literature and are widely cited. Future research in this area will focus on oxidative stress, aging, gene expression, and the pathogenesis of bone metabolism-related diseases.
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Wu X, Liyanage C, Plan M, Stark T, McCubbin T, Barrero RA, Batra J, Crawford R, Xiao Y, Prasadam I. Dysregulated energy metabolism impairs chondrocyte function in osteoarthritis. Osteoarthritis Cartilage 2022; 31:613-626. [PMID: 36410637 DOI: 10.1016/j.joca.2022.11.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 11/07/2022] [Accepted: 11/12/2022] [Indexed: 11/21/2022]
Abstract
OBJECTIVES Metabolic pathways are a series of chemical reactions by which cells take in nutrient substrates for energy and building blocks needed to maintain critical cellular processes. Details of chondrocyte metabolism and how it rewires during the progression of osteoarthritis (OA) are unknown. This research aims to identify what changes in the energy metabolic state occur in OA cartilage. METHODS Patient matched OA and non-OA cartilage specimens were harvested from total knee replacement patients. Cartilage was first collected for metabolomics, proteomics, and transcriptomics analyses to study global alterations in OA metabolism. We then determined the metabolic routes by tracking [U-13C] isotope with liquid chromatography-mass spectrometry (LC-MS). We further evaluated cellular bioenergetic profiles by measuring oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) and investigated the effects of low-dose and short-term effects of 2-deoxyglucose (2DG) on chondrocytes. RESULTS OA chondrocytes showed increased basal ECAR and more lactate production compared to non-OA chondrocytes. [U-13C] glucose labelling revealed that less glucose-derived carbon entered the tricarboxylic acid (TCA) cycle. On the other hand, mitochondrial respiratory rates were markedly decreased in the OA chondrocytes compared to non-OA chondrocytes. These changes were accompanied by decreased cellular ATP production, mitochondrial membrane potential and disrupted mitochondrial morphology. We further demonstrated in vitro that short-term inhibition of glycolysis suppressed matrix degeneration gene expression in chondrocytes and bovine cartilage explants cultured under inflammatory conditions. CONCLUSION This study represents the first comprehensive comparative analysis of metabolism in OA chondrocytes and lays the groundwork for therapeutic targeting of metabolism in OA.
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Affiliation(s)
- X Wu
- Centre for Biomedical Technologies, Queensland University of Technology, Brisbane, QLD 4059, Australia; Department of Orthopaedic Surgery, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - C Liyanage
- Centre for Biomedical Technologies, Queensland University of Technology, Brisbane, QLD 4059, Australia; Australian Prostate Cancer Research Centre-Queensland, Translational Research Institute, Queensland University of Technology, Brisbane, QLD 4102, Australia
| | - M Plan
- Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD 4072, Australia; Metabolomics Australia (Queensland Node), AIBN, The University of Queensland, Brisbane, QLD 4072, Australia
| | - T Stark
- Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD 4072, Australia; Metabolomics Australia (Queensland Node), AIBN, The University of Queensland, Brisbane, QLD 4072, Australia
| | - T McCubbin
- Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD 4072, Australia; Metabolomics Australia (Queensland Node), AIBN, The University of Queensland, Brisbane, QLD 4072, Australia
| | - R A Barrero
- eResearch Office, Queensland University of Technology, Brisbane, QLD 4000, Australia
| | - J Batra
- Centre for Biomedical Technologies, Queensland University of Technology, Brisbane, QLD 4059, Australia; Australian Prostate Cancer Research Centre-Queensland, Translational Research Institute, Queensland University of Technology, Brisbane, QLD 4102, Australia
| | - R Crawford
- The Prince Charles Hospital, Chermside, Brisbane, QLD 4032, Australia
| | - Y Xiao
- Centre for Biomedical Technologies, Queensland University of Technology, Brisbane, QLD 4059, Australia; Australia-China Centre for Tissue Engineering and Regenerative Medicine, Queensland University of Technology, Brisbane, QLD 4059, Australia
| | - I Prasadam
- Centre for Biomedical Technologies, Queensland University of Technology, Brisbane, QLD 4059, Australia.
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Vaamonde-García C, Capelo-Mera E, Flórez-Fernández N, Torres MD, Rivas-Murias B, Mejide-Faílde R, Blanco FJ, Domínguez H. In Vitro Study of the Therapeutic Potential of Brown Crude Fucoidans in Osteoarthritis Treatment. Int J Mol Sci 2022; 23:14236. [PMID: 36430716 PMCID: PMC9698873 DOI: 10.3390/ijms232214236] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 11/11/2022] [Accepted: 11/14/2022] [Indexed: 11/19/2022] Open
Abstract
Osteoarthritis, one of the most common joint degenerative pathologies, still has no cure, and current treatments, such as nonsteroidal anti-inflammatory drugs, can cause serious adverse effects when taken for a long time. Brown seaweed crude fucoidans are used for the clinical treatment of several pathologies. In this study, the therapeutical potential of these biocompounds was analyzed in primary chondrocytes and the 260TT human chondrocyte cell line. Crude fucoidan from Undaria pinnatifida (Up) and Sargassum muticum (Sm) was obtained by different extraction techniques (microwave-assisted extraction, pressurized hot-water extraction, ultrasound-assisted extraction) and chemically and structurally characterized by Fourier transform infrared spectroscopy, high-performance size-exclusion chromatography, proton nuclear magnetic resonance, and scanning electron microscopy. Once cell viability was confirmed in chondrocytes treated with crude fucoidans, we evaluated their anti-inflammatory effects, observing a significant reduction in IL-6 production stimulated by IL-1β. Findings were confirmed by analysis of IL-6 and IL-8 gene expression, although only fucoidans from Up achieved a statistically significant reduction. Besides this, the antioxidant capacity of crude fucoidans was observed through the upregulation of Nrf-2 levels and the expression of its transcriptional target genes HO-1 and SOD-2, with compounds from Up again showing a more consistent effect. However, no evidence was found that crude fucoidans modulate senescence, as they failed to reduced β-galactosidase activity, cell proliferation, or IL-6 production in chondrocytes stimulated with etoposide. Thus, the findings of this research seem to indicate that the tested crude fucoidans are capable of partially alleviating OA-associated inflammation and oxidative stress, but fail to attenuate chondrocyte senescence.
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Affiliation(s)
- Carlos Vaamonde-García
- Grupo de Investigación de Reumatología y Salud (GIR-S), Departamento de Biología, Facultad de Ciencias, CICA-Centro Interdisciplinar de Química y Biología, INIBIC-Sergas, Universidade da Coruña, Campus da Zapateira, 15011 A Coruña, Spain
| | - Emma Capelo-Mera
- Grupo de Investigación de Reumatología y Salud (GIR-S), Departamento de Biología, Facultad de Ciencias, CICA-Centro Interdisciplinar de Química y Biología, INIBIC-Sergas, Universidade da Coruña, Campus da Zapateira, 15011 A Coruña, Spain
| | - Noelia Flórez-Fernández
- Grupo de Biomasa y Desarrollo Sostenible (EQ2), Departamento de Ingeniería Química, Facultad de Ciencias, CINBIO, Universidade de Vigo, 32004 Ourense, Spain
| | - María Dolores Torres
- Grupo de Biomasa y Desarrollo Sostenible (EQ2), Departamento de Ingeniería Química, Facultad de Ciencias, CINBIO, Universidade de Vigo, 32004 Ourense, Spain
| | | | - Rosa Mejide-Faílde
- Grupo de Terapia Celular y Medicina Regenerativa, Universidade da Coruña, CICA-Centro Interdisciplinar de Química y Biología, Complexo Hospitalario Universitario A Coruña, Campus Oza, 15006 A Coruña, Spain
| | - Francisco J. Blanco
- Grupo de Investigación de Reumatología y Salud (GIR-S), Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Fisioterapia, CICA-Centro Interdisciplinar de Química y Biología, INIBIC-Sergas, Universidade da Coruña, Campus de Oza, 15006 A Coruña, Spain
| | - Herminia Domínguez
- Grupo de Biomasa y Desarrollo Sostenible (EQ2), Departamento de Ingeniería Química, Facultad de Ciencias, CINBIO, Universidade de Vigo, 32004 Ourense, Spain
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Tan C, Li L, Han J, Xu K, Liu X. A new strategy for osteoarthritis therapy: Inhibition of glycolysis. Front Pharmacol 2022; 13:1057229. [PMID: 36438808 PMCID: PMC9685317 DOI: 10.3389/fphar.2022.1057229] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 10/27/2022] [Indexed: 11/12/2022] Open
Abstract
Osteoarthritis (OA) is a common degenerative disease of the joints. It is primarily caused by age, obesity, mechanical damage, genetics, and other factors, leading to cartilage degradation, synovial inflammation, and subchondral sclerosis with osteophyte formation. Many recent studies have reported that glycolysis disorders are related lead to OA. There is a close relationship between glycolysis and OA. Because of their hypoxic environment, chondrocytes are highly dependent on glycolysis, their primary energy source for chondrocytes. Glycolysis plays a vital role in OA development. In this paper, we comprehensively summarized the abnormal expression of related glycolytic enzymes in OA, including Hexokinase 2 (HK2), Pyruvate kinase 2 (PKM2), Phosphofructokinase-2/fructose-2, 6-Bisphosphatase 3 (PFKFB3), lactate dehydrogenase A (LDHA), and discussed the potential application of glycolysis in treating OA. Finally, the natural products that can regulate the glycolytic pathway were summarized. Targeting glucose transporters and rate-limiting enzymes to glycolysis may play an essential role in treating OA.
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Affiliation(s)
| | | | | | - Kang Xu
- *Correspondence: Kang Xu, ; Xianqiong Liu,
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Involvement of Mitochondrial Dysfunction in the Inflammatory Response in Human Mesothelial Cells from Peritoneal Dialysis Effluent. Antioxidants (Basel) 2022; 11:antiox11112184. [DOI: 10.3390/antiox11112184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/25/2022] [Accepted: 11/01/2022] [Indexed: 11/09/2022] Open
Abstract
Recent studies have related mitochondrial impairment with peritoneal membrane damage during peritoneal dialysis (PD) therapy. Here, we assessed the involvement of mitochondrial dysfunction in the inflammatory response in human mesothelial cells, a hallmark in the pathogenesis of PD-related peritoneal membrane damage. Our ex vivo studies showed that IL-1β causes a drop in the mitochondrial membrane potential in cells from peritoneal effluent. Moreover, when mitochondrial damage was induced by inhibitors of mitochondrial function, a low-grade inflammatory response was generated. Interestingly, mitochondrial damage sensitized mesothelial cells, causing a significant increase in the inflammatory response induced by cytokines, in which ROS generation and NF-κB activation appear to be involved, since inflammation was counteracted by both mitoTEMPO (mitochondrial ROS scavenger) and BAY-117085 (NF-κB inhibitor). Furthermore, the natural anti-inflammatory antioxidant resveratrol significantly attenuated the inflammatory response, by reversing the decline in mitochondrial membrane potential and decreasing the expression of IL-8, COX-2 and PGE2 caused by IL-1β. These findings suggest that IL-1β regulates mitochondrial function in mesothelial cells and that mitochondrial dysfunction could induce an inflammatory scenario that sensitizes these cells, causing significant amplification of the inflammatory response induced by cytokines. Resveratrol may represent a promising strategy in controlling the mesothelial inflammatory response to PD.
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Breakthrough of extracellular vesicles in pathogenesis, diagnosis and treatment of osteoarthritis. Bioact Mater 2022; 22:423-452. [PMID: 36311050 PMCID: PMC9588998 DOI: 10.1016/j.bioactmat.2022.10.012] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/06/2022] [Accepted: 10/10/2022] [Indexed: 11/16/2022] Open
Abstract
Osteoarthritis (OA) is a highly prevalent whole-joint disease that causes disability and pain and affects a patient's quality of life. However, currently, there is a lack of effective early diagnosis and treatment. Although stem cells can promote cartilage repair and treat OA, problems such as immune rejection and tumorigenicity persist. Extracellular vesicles (EVs) can transmit genetic information from donor cells and mediate intercellular communication, which is considered a functional paracrine factor of stem cells. Increasing evidences suggest that EVs may play an essential and complex role in the pathogenesis, diagnosis, and treatment of OA. Here, we introduced the role of EVs in OA progression by influencing inflammation, metabolism, and aging. Next, we discussed EVs from the blood, synovial fluid, and joint-related cells for diagnosis. Moreover, we outlined the potential of modified and unmodified EVs and their combination with biomaterials for OA therapy. Finally, we discuss the deficiencies and put forward the prospects and challenges related to the application of EVs in the field of OA.
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Silva Santos Ribeiro P, Willemen HLDM, Eijkelkamp N. Mitochondria and sensory processing in inflammatory and neuropathic pain. FRONTIERS IN PAIN RESEARCH 2022; 3:1013577. [PMID: 36324872 PMCID: PMC9619239 DOI: 10.3389/fpain.2022.1013577] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 09/26/2022] [Indexed: 01/24/2023] Open
Abstract
Rheumatic diseases, such as osteoarthritis and rheumatoid arthritis, affect over 750 million people worldwide and contribute to approximately 40% of chronic pain cases. Inflammation and tissue damage contribute to pain in rheumatic diseases, but pain often persists even when inflammation/damage is resolved. Mechanisms that cause this persistent pain are still unclear. Mitochondria are essential for a myriad of cellular processes and regulate neuronal functions. Mitochondrial dysfunction has been implicated in multiple neurological disorders, but its role in sensory processing and pain in rheumatic diseases is relatively unexplored. This review provides a comprehensive understanding of how mitochondrial dysfunction connects inflammation and damage-associated pathways to neuronal sensitization and persistent pain. To provide an overall framework on how mitochondria control pain, we explored recent evidence in inflammatory and neuropathic pain conditions. Mitochondria have intrinsic quality control mechanisms to prevent functional deficits and cellular damage. We will discuss the link between neuronal activity, mitochondrial dysfunction and chronic pain. Lastly, pharmacological strategies aimed at reestablishing mitochondrial functions or boosting mitochondrial dynamics as therapeutic interventions for chronic pain are discussed. The evidence presented in this review shows that mitochondria dysfunction may play a role in rheumatic pain. The dysfunction is not restricted to neuronal cells in the peripheral and central nervous system, but also includes blood cells and cells at the joint level that may affect pain pathways indirectly. Pre-clinical and clinical data suggest that modulation of mitochondrial functions can be used to attenuate or eliminate pain, which could be beneficial for multiple rheumatic diseases.
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Affiliation(s)
| | | | - Niels Eijkelkamp
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
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Jávor P, Mácsai A, Butt E, Baráth B, Jász DK, Horváth T, Baráth B, Csonka Á, Török L, Varga E, Hartmann P. Mitochondrial Dysfunction Affects the Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis Differently. Int J Mol Sci 2022; 23:ijms23147553. [PMID: 35886901 PMCID: PMC9319158 DOI: 10.3390/ijms23147553] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/03/2022] [Accepted: 07/06/2022] [Indexed: 02/06/2023] Open
Abstract
There is growing evidence regarding the role of mitochondrial dysfunction in osteoarthritis (OA) and rheumatoid arthritis (RA). However, quantitative comparison of synovial mitochondrial derangements in these main arthritis forms is missing. A prospective clinical study was conducted on adult patients undergoing knee surgery. Patients were allocated into RA and OA groups based on disease-specific clinical scores, while patients without arthritis served as controls. Synovial samples were subjected to high-resolution respirometry to analyze mitochondrial functions. From the total of 814 patients, 109 cases were enrolled into the study (24 RA, 47 OA, and 38 control patients) between 1 September 2019 and 31 December 2021. The decrease in complex I-linked respiration and dyscoupling of mitochondria were characteristics of RA patients, while both arthritis groups displayed reduced OxPhos activity compared to the control group. However, no significant difference was found in complex II-related activity between the OA and RA groups. The cytochrome C release and H2O2 formation were increased in both arthritis groups. Mitochondrial dysfunction was present in both arthritis groups; however, to a different extent. Consequently, mitochondrial protective agents may have major benefits for arthritis patients. Based on our current study, we recommend focusing on respiratory complex I in rheumatoid arthritis research.
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Affiliation(s)
- Péter Jávor
- Department of Traumatology, University of Szeged, 6720 Szeged, Hungary; (P.J.); (A.M.); (E.B.); (B.B.); (Á.C.); (L.T.); (E.V.)
| | - Attila Mácsai
- Department of Traumatology, University of Szeged, 6720 Szeged, Hungary; (P.J.); (A.M.); (E.B.); (B.B.); (Á.C.); (L.T.); (E.V.)
| | - Edina Butt
- Department of Traumatology, University of Szeged, 6720 Szeged, Hungary; (P.J.); (A.M.); (E.B.); (B.B.); (Á.C.); (L.T.); (E.V.)
| | - Bálint Baráth
- Department of Traumatology, University of Szeged, 6720 Szeged, Hungary; (P.J.); (A.M.); (E.B.); (B.B.); (Á.C.); (L.T.); (E.V.)
- Institute of Surgical Research, University of Szeged, 6720 Szeged, Hungary; (D.K.J.); (T.H.)
| | - Dávid Kurszán Jász
- Institute of Surgical Research, University of Szeged, 6720 Szeged, Hungary; (D.K.J.); (T.H.)
| | - Tamara Horváth
- Institute of Surgical Research, University of Szeged, 6720 Szeged, Hungary; (D.K.J.); (T.H.)
| | - Bence Baráth
- Department of Pathology, University of Szeged, 6720 Szeged, Hungary;
| | - Ákos Csonka
- Department of Traumatology, University of Szeged, 6720 Szeged, Hungary; (P.J.); (A.M.); (E.B.); (B.B.); (Á.C.); (L.T.); (E.V.)
| | - László Török
- Department of Traumatology, University of Szeged, 6720 Szeged, Hungary; (P.J.); (A.M.); (E.B.); (B.B.); (Á.C.); (L.T.); (E.V.)
- Department of Sports Medicine, University of Szeged, 6720 Szeged, Hungary
| | - Endre Varga
- Department of Traumatology, University of Szeged, 6720 Szeged, Hungary; (P.J.); (A.M.); (E.B.); (B.B.); (Á.C.); (L.T.); (E.V.)
| | - Petra Hartmann
- Department of Traumatology, University of Szeged, 6720 Szeged, Hungary; (P.J.); (A.M.); (E.B.); (B.B.); (Á.C.); (L.T.); (E.V.)
- Correspondence:
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D'Amico D, Olmer M, Fouassier AM, Valdés P, Andreux PA, Rinsch C, Lotz M. Urolithin A improves mitochondrial health, reduces cartilage degeneration, and alleviates pain in osteoarthritis. Aging Cell 2022; 21:e13662. [PMID: 35778837 PMCID: PMC9381911 DOI: 10.1111/acel.13662] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 05/11/2022] [Accepted: 06/07/2022] [Indexed: 01/22/2023] Open
Abstract
Osteoarthritis (OA) is the most common age‐related joint disorder with no effective therapy. According to the World Health Organization, OA affects over 500 million people and is characterized by degradation of cartilage and other joint tissues, severe pain, and impaired mobility. Mitochondrial dysfunction contributes to OA pathology. However, interventions to rescue mitochondrial defects in human OA are not available. Urolithin A (Mitopure) is a natural postbiotic compound that promotes mitophagy and mitochondrial function and beneficially impacts muscle health in preclinical models of aging and in elderly and middle‐aged humans. Here, we showed that Urolithin A improved mitophagy and mitochondrial respiration in primary chondrocytes from joints of both healthy donors and OA patients. Furthermore, Urolithin A reduced disease progression in a mouse model of OA, decreasing cartilage degeneration, synovial inflammation, and pain. These improvements were associated with increased mitophagy and mitochondrial content, in joints of OA mice. These findings indicate that UA promotes joint mitochondrial health, alleviates OA pathology, and supports Urolithin A's potential to improve mobility with beneficial effects on structural damage in joints.
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Affiliation(s)
- Davide D'Amico
- Amazentis SA, EPFL Innovation Park, Lausanne, Switzerland
| | - Merissa Olmer
- Department of Molecular Medicine, Scripps Research, La Jolla, CA, USA
| | | | - Pamela Valdés
- Amazentis SA, EPFL Innovation Park, Lausanne, Switzerland
| | | | - Chris Rinsch
- Amazentis SA, EPFL Innovation Park, Lausanne, Switzerland
| | - Martin Lotz
- Department of Molecular Medicine, Scripps Research, La Jolla, CA, USA
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The Role of Mitochondrial Metabolism, AMPK-SIRT Mediated Pathway, LncRNA and MicroRNA in Osteoarthritis. Biomedicines 2022; 10:biomedicines10071477. [PMID: 35884782 PMCID: PMC9312479 DOI: 10.3390/biomedicines10071477] [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: 04/04/2022] [Revised: 06/16/2022] [Accepted: 06/17/2022] [Indexed: 11/20/2022] Open
Abstract
Osteoarthritis (OA) is the most common joint disease characterized by degeneration of articular cartilage and causes severe joint pain, physical disability, and impaired quality of life. Recently, it was found that mitochondria not only act as a powerhouse of cells that provide energy for cellular metabolism, but are also involved in crucial pathways responsible for maintaining chondrocyte physiology. Therefore, a growing amount of evidence emphasizes that impairment of mitochondrial function is associated with OA pathogenesis; however, the exact mechanism is not well known. Moreover, the AMP-activated protein kinase (AMPK)–Sirtuin (SIRT) signaling pathway, long non-coding RNA (lncRNA), and microRNA (miRNA) are important for regulating the physiological and pathological processes of chondrocytes, indicating that these may be targets for OA treatment. In this review, we first focus on the importance of mitochondria metabolic dysregulation related to OA. Then, we show recent evidence on the AMPK-SIRT mediated pathway associated with OA pathogenesis and potential treatment options. Finally, we discuss current research into the effects of lncRNA and miRNA on OA progression or inhibition.
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Jiang N, Xing B, Peng R, Shang J, Wu B, Xiao P, Lin S, Xu X, Lu H. Inhibition of Cpt1a alleviates oxidative stress-induced chondrocyte senescence via regulating mitochondrial dysfunction and activating mitophagy. Mech Ageing Dev 2022; 205:111688. [PMID: 35728631 DOI: 10.1016/j.mad.2022.111688] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 06/08/2022] [Accepted: 06/15/2022] [Indexed: 11/24/2022]
Abstract
Osteoarthritis (OA) is an age-related chronic degenerative disease, and chondrocyte senescence has been established to play an important role in the pathological process. There is ample evidence to suggest that lipid metabolism plays an important role in the aging process. However, the effect of lipid metabolism on chondrocyte senescence and OA remains unclear. Accordingly, we constructed a TBHP-induced senescent chondrocytes model and a destabilization of the medial meniscus (DMM) mouse model. We found that lipid accumulation and fatty acid oxidation were enhanced in senescent chondrocytes. Interestingly, carnitine palmitoyltransferase 1A (Cpt1a), the rate-limiting enzyme for fatty acid oxidation, was highly expressed in senescent chondrocytes and murine knee cartilage tissue. Suppressing Cpt1a expression using siRNA or Etomoxir, an inhibitor of Cpt1a, could attenuate oxidative stress-induced premature senescence and OA phenotype of primary murine chondrocytes, decrease cellular ROS levels, restore mitochondrial function, and maintain mitochondrial homeostasis via activating mitophagy. In vivo, pharmacological inhibition of Cpt1a by Etomoxir attenuated cartilage destruction, relieved joint space narrowing and osteophyte formation in the DMM mouse model. Overall, these findings suggested that knockdown of Cpt1a alleviated chondrocyte senescence by regulating mitochondrial dysfunction and promoting mitophagy, providing a new therapeutic strategy and target for OA treatment.
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Affiliation(s)
- Ning Jiang
- Department of Orthopedics, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Department of Orthopedics, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong, China
| | - Baizhou Xing
- Department of Orthopedics, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China
| | - Rong Peng
- Department of Orthopedics, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China
| | - Jie Shang
- Department of Orthopedics, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China
| | - Biao Wu
- Department of Orthopedics, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China
| | - Peilun Xiao
- Department of Orthopedics, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China
| | - Shiyuan Lin
- Department of Orthopedics, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China
| | - Xianghe Xu
- Department of Orthopedics, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China.
| | - Huading Lu
- Department of Orthopedics, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong, China.
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López-Armada MJ, Fernández-Rodríguez JA, Blanco FJ. Mitochondrial Dysfunction and Oxidative Stress in Rheumatoid Arthritis. Antioxidants (Basel) 2022; 11:antiox11061151. [PMID: 35740048 PMCID: PMC9220001 DOI: 10.3390/antiox11061151] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/08/2022] [Accepted: 06/09/2022] [Indexed: 02/04/2023] Open
Abstract
Control of excessive mitochondrial oxidative stress could provide new targets for both preventive and therapeutic interventions in the treatment of chronic inflammation or any pathology that develops under an inflammatory scenario, such as rheumatoid arthritis (RA). Increasing evidence has demonstrated the role of mitochondrial alterations in autoimmune diseases mainly due to the interplay between metabolism and innate immunity, but also in the modulation of inflammatory response of resident cells, such as synoviocytes. Thus, mitochondrial dysfunction derived from several danger signals could activate tricarboxylic acid (TCA) disruption, thereby favoring a vicious cycle of oxidative/mitochondrial stress. Mitochondrial dysfunction can act through modulating innate immunity via redox-sensitive inflammatory pathways or direct activation of the inflammasome. Besides, mitochondria also have a central role in regulating cell death, which is deeply altered in RA. Additionally, multiple evidence suggests that pathological processes in RA can be shaped by epigenetic mechanisms and that in turn, mitochondria are involved in epigenetic regulation. Finally, we will discuss about the involvement of some dietary components in the onset and progression of RA.
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Affiliation(s)
- María José López-Armada
- Grupo de Investigación en Envejecimiento e Inflamación (ENVEINF), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, 15006 A Coruña, Spain;
- Correspondence: (M.J.L.-A.); (F.J.B.); Tel./Fax: +34-981-178272-73 (M.J.L.-A.)
| | - Jennifer Adriana Fernández-Rodríguez
- Grupo de Investigación en Envejecimiento e Inflamación (ENVEINF), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, 15006 A Coruña, Spain;
| | - Francisco Javier Blanco
- Grupo de Investigación de Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, 15006 A Coruña, Spain
- Grupo de Investigación de Reumatología y Salud (GIR-S), Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Fisioterapia, Campus de Oza, Universidade da Coruña, 15001 A Coruña, Spain
- Correspondence: (M.J.L.-A.); (F.J.B.); Tel./Fax: +34-981-178272-73 (M.J.L.-A.)
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Osteoarthritis-Induced Metabolic Alterations of Human Hip Chondrocytes. Biomedicines 2022; 10:biomedicines10061349. [PMID: 35740371 PMCID: PMC9220245 DOI: 10.3390/biomedicines10061349] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/19/2022] [Accepted: 06/02/2022] [Indexed: 11/24/2022] Open
Abstract
Osteoarthritis (OA) alters chondrocyte metabolism and mitochondrial biology. We explored whether OA and non-OA chondrocytes show persistent differences in metabolism and mitochondrial function and different responsiveness to cytokines and cAMP modulators. Hip chondrocytes from patients with OA or femoral neck fracture (non-OA) were stimulated with IL-1β, TNF, forskolin and opioid peptides. Mediators released from chondrocytes were measured, and mitochondrial functions and glycolysis were determined (Seahorse Analyzer). Unstimulated OA chondrocytes exhibited significantly higher release of IL-6, PGE2 and MMP1 and lower production of glycosaminoglycan than non-OA chondrocytes. Oxygen consumption rates (OCR) and mitochondrial ATP production were comparable in unstimulated non-OA and OA chondrocytes, although the non-mitochondrial OCR was higher in OA chondrocytes. Compared to OA chondrocytes, non-OA chondrocytes showed stronger responses to IL-1β/TNF stimulation, consisting of a larger decrease in mitochondrial ATP production and larger increases in non-mitochondrial OCR and NO production. Enhancement of cAMP by forskolin prevented IL-1β-induced mitochondrial dysfunction in OA chondrocytes but not in non-OA chondrocytes. Endogenous opioids, present in OA joints, influenced neither cytokine-induced mitochondrial dysfunction nor NO upregulation. Glycolysis was not different in non-OA and OA chondrocytes, independent of stimulation. OA induces persistent metabolic alterations, but the results suggest upregulation of cellular mechanisms protecting mitochondrial function in OA.
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Liu D, Cai ZJ, Yang YT, Lu WH, Pan LY, Xiao WF, Li YS. Mitochondrial quality control in cartilage damage and osteoarthritis: new insights and potential therapeutic targets. Osteoarthritis Cartilage 2022; 30:395-405. [PMID: 34715366 DOI: 10.1016/j.joca.2021.10.009] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 10/15/2021] [Accepted: 10/21/2021] [Indexed: 02/02/2023]
Abstract
Osteoarthritis (OA) is a multifactorial arthritic disease of weight-bearing joints concomitant with chronic and intolerable pain, loss of locomotion and impaired quality of life in the elderly population. Although the prevalence of OA increases with age, its specific mechanisms have not been elucidated and effective therapeutic disease-modifying drugs have not been developed. As essential organelles in chondrocytes, mitochondria supply energy and play vital roles in cellular metabolism, proliferation and apoptosis. Mitochondrial quality control (MQC) is the key mechanism to coordinate various mitochondrial biofunctions, primarily through mitochondrial biogenesis, dynamics, autophagy and the newly discovered mitocytosis. An increasing number of studies have revealed that a loss of MQC homeostasis contributes to the cartilage damage during the occurrence and development of OA. Several master MQC-associated signaling pathways and regulators exert chondroprotective roles in OA, while cartilage damage-related molecular mechanisms have been partially identified. In this review, we summarized known mechanisms mediated by dysregulated MQC in the pathogenesis of OA and latent bioactive ingredients and drugs for the prevention and treatment of OA through the maintenance of MQC.
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Affiliation(s)
- D Liu
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Z-J Cai
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Y-T Yang
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - W-H Lu
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - L-Y Pan
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - W-F Xiao
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
| | - Y-S Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
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Mitochondrial Genome Editing to Treat Human Osteoarthritis-A Narrative Review. Int J Mol Sci 2022; 23:ijms23031467. [PMID: 35163384 PMCID: PMC8835930 DOI: 10.3390/ijms23031467] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 01/24/2022] [Accepted: 01/26/2022] [Indexed: 12/27/2022] Open
Abstract
Osteoarthritis (OA) is a severe, common chronic orthopaedic disorder characterised by a degradation of the articular cartilage with an incidence that increases over years. Despite the availability of various clinical options, none can stop the irreversible progression of the disease to definitely cure OA. Various mutations have been evidenced in the mitochondrial DNA (mtDNA) of cartilage cells (chondrocytes) in OA, leading to a dysfunction of the mitochondrial oxidative phosphorylation processes that significantly contributes to OA cartilage degeneration. The mitochondrial genome, therefore, represents a central, attractive target for therapy in OA, especially using genome editing procedures. In this narrative review article, we present and discuss the current advances and breakthroughs in mitochondrial genome editing as a potential, novel treatment to overcome mtDNA-related disorders such as OA. While still in its infancy and despite a number of challenges that need to be addressed (barriers to effective and site-specific mtDNA editing and repair), such a strategy has strong value to treat human OA in the future, especially using the groundbreaking clustered regularly interspaced short palindromic repeats (CRIPSR)/CRISPR-associated 9 (CRISPR/Cas9) technology and mitochondrial transplantation approaches.
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Xia K, Yu LY, Huang XQ, Zhao ZH, Liu J. Epigenetic regulation by long noncoding RNAs in osteo-/adipogenic differentiation of mesenchymal stromal cells and degenerative bone diseases. World J Stem Cells 2022; 14:92-103. [PMID: 35126830 PMCID: PMC8788182 DOI: 10.4252/wjsc.v14.i1.92] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 07/07/2021] [Accepted: 01/05/2022] [Indexed: 02/06/2023] Open
Abstract
Bone is a complex tissue that undergoes constant remodeling to maintain homeostasis, which requires coordinated multilineage differentiation and proper proliferation of mesenchymal stromal cells (MSCs). Mounting evidence indicates that a disturbance of bone homeostasis can trigger degenerative bone diseases, including osteoporosis and osteoarthritis. In addition to conventional genetic modifications, epigenetic modifications (i.e., DNA methylation, histone modifications, and the expression of noncoding RNAs) are considered to be contributing factors that affect bone homeostasis. Long noncoding RNAs (lncRNAs) were previously regarded as 'transcriptional noise' with no biological functions. However, substantial evidence suggests that lncRNAs have roles in the epigenetic regulation of biological processes in MSCs and related diseases. In this review, we summarized the interactions between lncRNAs and epigenetic modifiers associated with osteo-/adipogenic differentiation of MSCs and the pathogenesis of degenerative bone diseases and highlighted promising lncRNA-based diagnostic and therapeutic targets for bone diseases.
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Affiliation(s)
- Kai Xia
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Li-Yuan Yu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin-Qi Huang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Zhi-He Zhao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jun Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China.
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Welhaven HD, McCutchen CN, June RK. Effects of mechanical stimulation on metabolomic profiles of SW1353 chondrocytes: shear and compression. Biol Open 2022; 11:274218. [PMID: 35113136 PMCID: PMC8822358 DOI: 10.1242/bio.058895] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 11/15/2021] [Indexed: 12/21/2022] Open
Abstract
Mechanotransduction is a biological phenomenon where mechanical stimuli are converted to biochemical responses. A model system for studying mechanotransduction are the chondrocytes of articular cartilage. Breakdown of this tissue results in decreased mobility, increased pain, and reduced quality of life. Either disuse or overloading can disrupt cartilage homeostasis, but physiological cyclical loading promotes cartilage homeostasis. To model this, we exposed SW1353 cells to cyclical mechanical stimuli, shear and compression, for different durations of time (15 and 30 min). By utilizing liquid chromatography-mass spectroscopy (LC-MS), metabolomic profiles were generated detailing metabolite features and biological pathways that are altered in response to mechanical stimulation. In total, 1457 metabolite features were detected. Statistical analyses identified several pathways of interest. Taken together, differences between experimental groups were associated with inflammatory pathways, lipid metabolism, beta-oxidation, central energy metabolism, and amino acid production. These findings expand our understanding of chondrocyte mechanotransduction under varying loading conditions and time periods. This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Hope D Welhaven
- Department of Chemistry & Biochemistry and Molecular Biosciences Program, Montana State University, Bozeman, MT 59717, USA
| | - Carley N McCutchen
- Department of Mechanical & Industrial Engineering, Montana State University, Bozeman, MT 59717, USA
| | - Ronald K June
- Department of Mechanical & Industrial Engineering, Montana State University, Bozeman, MT 59717, USA.,Department of Microbiology & Cell Biology, Montana State University, Bozeman MT 59717, USA.,Department of Orthopaedics & Sports Medicine, University of Washington, Seattle, WA 98195, USA
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PPARα-ACOT12 axis is responsible for maintaining cartilage homeostasis through modulating de novo lipogenesis. Nat Commun 2022; 13:3. [PMID: 34987154 PMCID: PMC8733009 DOI: 10.1038/s41467-021-27738-y] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 12/03/2021] [Indexed: 12/25/2022] Open
Abstract
Here, in Ppara−/− mice, we found that an increased DNL stimulated the cartilage degradation and identified ACOT12 as a key regulatory factor. Suppressed level of ACOT12 was observed in cartilages of OA patient and OA-induced animal. To determine the role and association of ACOT12 in the OA pathogenesis, we generated Acot12 knockout (KO) (Acot12−/−) mice using RNA-guided endonuclease. Acot12−/− mice displayed the severe cartilage degradation with the stimulation of matrix MMPs and chondrocyte apoptosis through the accumulation of acetyl CoA. Delivery of acetyl CoA-conjugated chitosan complex into cartilage stimulated DNL and cartilage degradation. Moreover, restoration of ACOT12 into human OA chondrocytes and OA-induced mouse cartilage effectively rescued the pathophysiological features of OA by regulating DNL. Taken together, our study suggested ACOT12 as a novel regulatory factor in maintaining cartilage homeostasis and targeting ACOT12 could contribute to developing a new therapeutic strategy for OA. Increasing evidence suggested that dysregulation in lipid metabolism is linked to OA pathogenesis, but the underlying regulatory mechanism is not well understood. Here, the authors show that PPARα-ACOT12 signalling regulates cartilage homeostasis by regulating de novo lipogenesis in mice.
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Abstract
PROPOSE OF REVIEW To summarize the evidence that suggests that osteoarthritis (OA) is a mitochondrial disease. RECENT FINDINGS Mitochondrial dysfunction together with mtDNA damage could contribute to cartilage degradation via several processes such as: (1) increased apoptosis; (2) decreased autophagy; (3) enhanced inflammatory response; (4) telomere shortening and increased senescence chondrocytes; (5) decreased mitochondrial biogenesis and mitophagy; (6) increased cartilage catabolism; (7) increased mitochondrial fusion leading to further reactive oxygen species production; and (8) impaired metabolic flexibility. SUMMARY Mitochondria play an important role in some events involved in the pathogenesis of OA, such as energy production, the generation of reactive oxygen and nitrogen species, apoptosis, authophagy, senescence and inflammation. The regulation of these processes in the cartilage is at least partially controlled by retrograde regulation from mitochondria and mitochondrial genetic variation. Retrograde regulation through mitochondrial haplogroups exerts a signaling control over the nuclear epigenome, which leads to the modulation of nuclear genes, cellular functions and development of OA. All these data suggest that OA could be considered a mitochondrial disease as well as other complex chronic disease as cancer, cardiovascular and neurologic diseases.
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Metabolic and Transcriptional Changes across Osteogenic Differentiation of Mesenchymal Stromal Cells. Bioengineering (Basel) 2021; 8:bioengineering8120208. [PMID: 34940360 PMCID: PMC8698318 DOI: 10.3390/bioengineering8120208] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 12/03/2021] [Accepted: 12/08/2021] [Indexed: 12/23/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are multipotent post-natal stem cells with applications in tissue engineering and regenerative medicine. MSCs can differentiate into osteoblasts, chondrocytes, or adipocytes, with functional differences in cells during osteogenesis accompanied by metabolic changes. The temporal dynamics of these metabolic shifts have not yet been fully characterized and are suspected to be important for therapeutic applications such as osteogenesis optimization. Here, our goal was to characterize the metabolic shifts that occur during osteogenesis. We profiled five key extracellular metabolites longitudinally (glucose, lactate, glutamine, glutamate, and ammonia) from MSCs from four donors to classify osteogenic differentiation into three metabolic stages, defined by changes in the uptake and secretion rates of the metabolites in cell culture media. We used a combination of untargeted metabolomic analysis, targeted analysis of 13C-glucose labelled intracellular data, and RNA-sequencing data to reconstruct a gene regulatory network and further characterize cellular metabolism. The metabolic stages identified in this proof-of-concept study provide a framework for more detailed investigations aimed at identifying biomarkers of osteogenic differentiation and small molecule interventions to optimize MSC differentiation for clinical applications.
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Kan S, Duan M, Liu Y, Wang C, Xie J. Role of Mitochondria in Physiology of Chondrocytes and Diseases of Osteoarthritis and Rheumatoid Arthritis. Cartilage 2021; 13:1102S-1121S. [PMID: 34894777 PMCID: PMC8804744 DOI: 10.1177/19476035211063858] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
PURPOSE OF REVIEW Mitochondria are recognized to be one of the most important organelles in chondrocytes for their role in triphosphate (ATP) generation through aerobic phosphorylation. Mitochondria also participate in many intracellular processes involving modulating reactive oxygen species (ROS), responding to instantaneous hypoxia stress, regulating cytoplasmic transport of calcium ion, and directing mitophagy to maintain the homeostasis of individual chondrocytes. DESIGNS To summarize the specific role of mitochondria in chondrocytes, we screened related papers in PubMed database and the search strategy is ((mitochondria) AND (chondrocyte)) AND (English [Language]). The articles published in the past 5 years were included and 130 papers were studied. RESULTS In recent years, the integrity of mitochondrial structure has been regarded as a prerequisite for normal chondrocyte survival and defect in mitochondrial function has been found in cartilage-related diseases, such as osteoarthritis (OA) and rheumatoid arthritis (RA). However, the understanding of mitochondria in cartilage is still largely limited. The mechanism on how the changes in mitochondrial structure and function directly lead to the occurrence and development of cartilage-related diseases remains to be elusive. CONCLUSION This review aims to summarize the role of mitochondria in chondrocytes under the physiological and pathological changes from ATP generation, calcium homeostasis, redox regulation, mitophagy modulation, mitochondria biogenesis to immune response activation. The enhanced understanding of molecular mechanisms in mitochondria might offer some new cues for cartilage remodeling and pathological intervention.
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Affiliation(s)
- Shiyi Kan
- State Key Laboratory of Oral Diseases,
West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Mengmeng Duan
- State Key Laboratory of Oral Diseases,
West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yang Liu
- State Key Laboratory of Oral Diseases,
West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chunli Wang
- “111” Project Laboratory of
Biomechanics and Tissue Repair, Bioengineering College, Chongqing University,
Chongqing, China
| | - Jing Xie
- State Key Laboratory of Oral Diseases,
West China Hospital of Stomatology, Sichuan University, Chengdu, China,“111” Project Laboratory of
Biomechanics and Tissue Repair, Bioengineering College, Chongqing University,
Chongqing, China,Lab of Bone & Joint Disease, State
Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan
University, Chengdu, China,Jing Xie, Lab of Bone & Joint Disease,
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology,
Sichuan University, Chengdu 610064, Sichuan, China.
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