Matrix Stiffness Aggravates Osteoarthritis Progression Through H3K27me3 Demethylation Induced by Mitochondrial Damage

Overview

Journal iScience

Publisher Cell Press

Date 2024 Aug 19

PMID 39156637

Authors

Tianyou Kan

Hanjun Li

Lingli Hou

Junqi Cui

Yao Wang

Lin Sun

Liao Wang

Mengning Yan

Zhifeng Yu

Affiliations

Soon will be listed here.

Abstract

Abnormal epigenetics is the initial factor of the occurrence and development of osteoarthritis (OA), and abnormal mechanical load is a key pathogenic factor of OA. However, how abnormal mechanical load affects chondrocyte epigenetics is unclear. Chondrocytes reportedly respond to mechanics through the extracellular matrix (ECM), which has a role in regulating epigenetics in various diseases, and mitochondria are potential mediators of communication between mechanics and epigenetics. Therefore, it is hypothesized that the matrix mechanics of cartilage regulates their epigenetics through mitochondria and leads to OA. The matrix stiffness of OA cartilage on the stress-concentrated side increases, mitochondrial damage of chondrocyte is severe, and the chondrocyte H3K27me3 is demethylated. Moreover, mitochondrial permeability transition pore (mPTP) opens to increase the translocation of plant homeodomain finger protein 8 (Phf8) into the nucleus to catalyze H3K27me3 demethylation. This provides a new perspective for us to understand the mechanism of OA based on mechanobiology.

Citing Articles

Progress in multi-omics studies of osteoarthritis.

Wei Y, Qian H, Zhang X, Wang J, Yan H, Xiao N Biomark Res. 2025; 13(1):26.

PMID: 39934890 PMC: 11817798. DOI: 10.1186/s40364-025-00732-y.

Protocol for microindentation analysis of human cartilage and methacrylated gelatin hydrogels with varying stiffness in ATDC5 cell cultures.

Wang H, Kan T, Sun L, Li H, Wang L, Yan M STAR Protoc. 2024; 6(1):103511.

PMID: 39675009 PMC: 11699419. DOI: 10.1016/j.xpro.2024.103511.

References

Stolz M, Gottardi R, Raiteri R, Miot S, Martin I, Imer R . Early detection of aging cartilage and osteoarthritis in mice and patient samples using atomic force microscopy. Nat Nanotechnol. 2009; 4(3):186-92. DOI: 10.1038/nnano.2008.410. View

Meekel J, Mattei G, Costache V, Balm R, Blankensteijn J, Yeung K . A multilayer micromechanical elastic modulus measuring method in ex vivo human aneurysmal abdominal aortas. Acta Biomater. 2019; 96:345-353. DOI: 10.1016/j.actbio.2019.07.019. View

Lian W, Ko J, Wu R, Sun Y, Chen Y, Wu S . MicroRNA-128a represses chondrocyte autophagy and exacerbates knee osteoarthritis by disrupting Atg12. Cell Death Dis. 2018; 9(9):919. PMC: 6134128. DOI: 10.1038/s41419-018-0994-y. View

Yang F, Zhou S, Wang C, Huang Y, Li H, Wang Y . Epigenetic modifications of interleukin-6 in synovial fibroblasts from osteoarthritis patients. Sci Rep. 2017; 7:43592. PMC: 5337936. DOI: 10.1038/srep43592. View

Pena-Oyarzun D, Rodriguez-Pena M, Burgos-Bravo F, Vergara A, Kretschmar C, Sotomayor-Flores C . PKD2/polycystin-2 induces autophagy by forming a complex with BECN1. Autophagy. 2020; 17(7):1714-1728. PMC: 8354594. DOI: 10.1080/15548627.2020.1782035. View

Chang S, Mori D, Kobayashi H, Mori Y, Nakamoto H, Okada K . Excessive mechanical loading promotes osteoarthritis through the gremlin-1-NF-κB pathway. Nat Commun. 2019; 10(1):1442. PMC: 6441020. DOI: 10.1038/s41467-019-09491-5. View

Peng Z, Sun H, Bunpetch V, Koh Y, Wen Y, Wu D . The regulation of cartilage extracellular matrix homeostasis in joint cartilage degeneration and regeneration. Biomaterials. 2020; 268:120555. DOI: 10.1016/j.biomaterials.2020.120555. View

Mow V, Ratcliffe A, Poole A . Cartilage and diarthrodial joints as paradigms for hierarchical materials and structures. Biomaterials. 1992; 13(2):67-97. DOI: 10.1016/0142-9612(92)90001-5. View

Rice S, Beier F, Young D, Loughlin J . Interplay between genetics and epigenetics in osteoarthritis. Nat Rev Rheumatol. 2020; 16(5):268-281. DOI: 10.1038/s41584-020-0407-3. View

10.

Wang X, Wu Q, Zhang R, Fan Z, Li W, Mao R . Stage-specific and location-specific cartilage calcification in osteoarthritis development. Ann Rheum Dis. 2022; 82(3):393-402. DOI: 10.1136/ard-2022-222944. View

11.

Dong X, Xu X, Yang C, Luo Y, Wu Y, Wang J . USP7 regulates the proliferation and differentiation of ATDC5 cells through the Sox9-PTHrP-PTH1R axis. Bone. 2020; 143:115714. DOI: 10.1016/j.bone.2020.115714. View

12.

Kim K, Park Y, Im G . Changes in the epigenetic status of the SOX-9 promoter in human osteoarthritic cartilage. J Bone Miner Res. 2012; 28(5):1050-60. DOI: 10.1002/jbmr.1843. View

13.

Katz J, Arant K, Loeser R . Diagnosis and Treatment of Hip and Knee Osteoarthritis: A Review. JAMA. 2021; 325(6):568-578. PMC: 8225295. DOI: 10.1001/jama.2020.22171. View

14.

Habiballa L, Salmonowicz H, Passos J . Mitochondria and cellular senescence: Implications for musculoskeletal ageing. Free Radic Biol Med. 2018; 132:3-10. DOI: 10.1016/j.freeradbiomed.2018.10.417. View

15.

Bolduc J, Collins J, Loeser R . Reactive oxygen species, aging and articular cartilage homeostasis. Free Radic Biol Med. 2018; 132:73-82. PMC: 6342625. DOI: 10.1016/j.freeradbiomed.2018.08.038. View

16.

Lui J, Garrison P, Nguyen Q, Ad M, Keembiyehetty C, Chen W . EZH1 and EZH2 promote skeletal growth by repressing inhibitors of chondrocyte proliferation and hypertrophy. Nat Commun. 2016; 7:13685. PMC: 5477487. DOI: 10.1038/ncomms13685. View

17.

Ying Z, Xiang G, Zheng L, Tang H, Duan L, Lin X . Short-Term Mitochondrial Permeability Transition Pore Opening Modulates Histone Lysine Methylation at the Early Phase of Somatic Cell Reprogramming. Cell Metab. 2019; 29(2):502. DOI: 10.1016/j.cmet.2018.12.017. View

18.

Darling E, Wilusz R, Bolognesi M, Zauscher S, Guilak F . Spatial mapping of the biomechanical properties of the pericellular matrix of articular cartilage measured in situ via atomic force microscopy. Biophys J. 2010; 98(12):2848-56. PMC: 2884253. DOI: 10.1016/j.bpj.2010.03.037. View

19.

Blanco F, June 2nd R . Cartilage Metabolism, Mitochondria, and Osteoarthritis. J Am Acad Orthop Surg. 2019; 28(6):e242-e244. PMC: 7060830. DOI: 10.5435/JAAOS-D-19-00442. View

20.

Li X, Kordsmeier J, Nookaew I, Kim H, Xiong J . Piezo1 stimulates mitochondrial function via cAMP signaling. FASEB J. 2022; 36(10):e22519. PMC: 10167693. DOI: 10.1096/fj.202200300R. View