The inhibition of EZH2 ameliorates osteoarthritis development through the Wnt/β-catenin pathway

Chen, Linwei; Wu, Yaosen; Wu, Yan; Wang, Ye; Sun, Liaojun; Li, Fangcai

doi:10.1038/srep29176

Cited by 68 publications

(75 citation statements)

References 39 publications

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“…We found that EZH2 inhibition by EPZ-6438 opposites to the major effects of TGF-β1: it increases COL2A1, ACAN as well as SOX9 expression and decreases MMP13 and COL10A1 synthesis. These results are fully in agreement with published data from in vivo experiments showing that intra-articular injections of an inhibitor of histone methyltransferase enhancer of zeste homolog 2 (EZH2), a chromatin modifier that activates Wnt/β-catenin signaling, reduced cartilage hypertrophy and also decreased articular cartilage degradation in surgically induced osteoarthritis (21). We also validate our model using two others drugs, pterosin B (a Sik-3 inhibitor) and DMOG (a mimic of hypoxia), which are known to reduce hypertrophy cartilage in vivo (22,24).…”

Section: Discussionsupporting

confidence: 92%

“…Recently, it has been shown that the inhibition of Enhancer of zeste homolog 2 (EZH2), an histone methyltransferase, ameliorates osteoarthritis development in mouse OA model, through the reduction of cartilage hypertrophy (21). Consequently, an EZH2 inhibitor should be a good tool to test the ability of our in vitro model to predict ability of drugs to reduce cartilage hypertrophy in vivo.…”

Section: β1 and Reduced Hypertrophy In Vitromentioning

confidence: 99%

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Development of a simple osteoarthritis model useful to predict in vitro the anti-hypertrophic action of drugs

Allas¹,

Rochoux²,

Leclercq³

et al. 2020

Laboratory Investigation

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Development of a simple osteoarthritis model useful to predict in vitro the anti-hypertrophic action of drugs. AbstractOsteoarthritis (OA) is characterized by cartilage degradation, inflammation and hypertrophy.Therapies are mainly symptomatic and aim to manage pain. Consequently, medical community is waiting for new treatments able to reduce OA process. This study aims to develop an in vitro simple OA model useful to predict drug ability to reduce cartilage hypertrophy.Human primary OA chondrocytes were incubated with transforming growth factor beta 1 (TGF-β1). Hypertrophy was evaluated by Runx2, type X collagen, MMP13 and VEGF expression. Cartilage anabolism was investigated by Sox9, aggrecan, type II collagen and glycosaminoglycan expression.In chondrocytes, TGF-β1 increased expression of hypertrophic genes and activated canonical WNT pathway, while it decreased dramatically cartilage anabolism, suggesting that this treatment could mimic some OA features in vitro. Additionally, EZH2 inhibition, that has been previously reported to decrease cartilage hypertrophy and reduce OA development in vivo, attenuated COL10A1 and MMP13 upregulation and SOX9 downregulation induced by TGF-β1 treatment. Similarly, pterosin B (an inhibitor of Sik3), and DMOG (a hypoxiainducible factor prolyl hydroxylase which mimicks hypoxia), repressed the expression of hypertrophy markers in TGF-β stimulated chondrocytes.In conclusion, we established an innovative OA model in vitro. This cheap and simple model will be useful to quickly screen new drugs with potential anti-arthritic effects, in complementary to current inflammatory models, and should permit to accelerate development of efficient treatments against OA able to reduce cartilage hypertrophy.

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Section: Discussionsupporting

confidence: 92%

Section: β1 and Reduced Hypertrophy In Vitromentioning

confidence: 99%

Development of a simple osteoarthritis model useful to predict in vitro the anti-hypertrophic action of drugs

Allas¹,

Rochoux²,

Leclercq³

et al. 2020

Laboratory Investigation

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“…From a therapeutic perspective, EZH2 inhibition using pharmacological drugs (e.g., GSK126, UNC1999, and EPZ005687) has been considered for delaying progression of OA, or to promote bone anabolic effects . EZH2 inhibition mitigates bone loss in a mouse model for estrogen deficiency, but also inhibits osteoclastogenesis .…”

Section: The Basics Of Epigeneticsmentioning

confidence: 99%

Epigenetics as a New Frontier in Orthopedic Regenerative Medicine and Oncology

Wijnen

Westendorf

2019

Journal Orthopaedic Research

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Skeletal regenerative medicine aims to repair or regenerate skeletal tissues using pharmacotherapies, cell-based treatments, and/or surgical interventions. The field is guided by biological principles active during development, wound healing, aging, and carcinogenesis. Skeletal development and tissue maintenance in adults represent highly intricate biological processes that require continuous adjustments in the expression of cell type-specific genes that generate, remodel, and repair the skeletal extracellular matrix. Errors in these processes can facilitate musculoskeletal disease including cancers or injury. The fundamental molecular mechanisms by which cell type-specific patterns in gene expression are established and retained during successive mitotic divisions require epigenetic control, which we review here. We focus on epigenetic regulatory proteins that control the mammalian epigenome at the level of chromatin with emphasis on proteins that are amenable to drug intervention to mitigate skeletal tissue degeneration (e.g., osteoarthritis and osteoporosis). We highlight recent findings on a number of druggable epigenetic regulators, including DNA methyltransferases (e.g., DNMT1, DNMT3A, and DNMT3B) and hydroxylases (e.g., TET1, TET2, and TET3), histone methyltransferases (e.g., EZH1, EZH2, and DOT1L) as well as histone deacetylases (e.g., HDAC3, HDAC4, and HDAC7) and histone acetyl readers (e.g., BRD4) in relation to the development of bone or cartilage regenerative drug therapies. We also review how histone mutations lead to epigenomic catastrophe and cause musculoskeletal tumors. The combined body of molecular and genetic studies focusing on epigenetic regulators indicates that these proteins are critical for normal skeletogenesis and viable candidate drug targets for short-term local pharmacological strategies to mitigate musculoskeletal tissue degeneration.

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“…Our group recently found that the H3K27 (lysine 27 on histone H3) demethylase KDM6B regulated chondrocyte anabolic metabolism in vivo . Interestingly, the expression of Enhancer of Zeste Homolog 2 (EZH2), which catalyzes the trimethylation of H3K27, is elevated during the pathological process of OA in vitro . This prompted us to further explore the exact function of EZH2 in OA development.…”

Section: Introductionmentioning

confidence: 99%

Ezh2 Ameliorates Osteoarthritis by Activating TNFSF13B

Chen

Zhang

et al. 2020

Journal of Bone and Mineral Research

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Epigenetic regulation is highly correlated with osteoarthritis (OA) development, whereas its role and detailed mechanisms remain elusive. In this study, we explored the expression of EZH2, an H3K27me3 transferase, in human OA cartilages and its roles in regulating OA pathogenesis. Here, we found EZH2 was highly expressed in both mice and human OA cartilage samples by using histological analysis and RNA sequencing (RNA-Seq). The medial meniscectomy (MMx) OA model results indicated the conditional knockout of Ezh2 deteriorated OA pathological conditions. Furthermore, we showed the positive role of Ezh2 in cartilage wound healing and inhibition of hypertrophy through activating TNFSF13B, a member of the tumor necrosis factor superfamily. Further, we also indicated that the effect of TNFSF13B, increased by Ezh2, might boost the healing of chondrocytes through increasing the phosphorylation of Akt. Taken together, our results uncovered an EZH2-positive subpopulation existed in OA patients, and that EZH2-TNFSF13B signaling was responsible for regulating chondrocyte healing and hypertrophy. Thus, EZH2 might act as a new potential target for OA diagnosis and treatment. n 956 DU ET AL. 23. Ohata J, Zvaifler NJ, Nishio M, et al. Fibroblast-like synoviocytes of mesenchymal origin express functional B cell-activating factor of the TNF family in response to proinflammatory cytokines. J Immunol. 2005;174(2):864-70. 24. Bradley EW, Carpio LR, Westendorf JJ. Histone deacetylase 3 suppression increases PH domain and leucine-rich repeat phosphatase (Phlpp)1 expression in chondrocytes to suppress Akt signaling and matrix secretion. J Biol Chem. 2013;288:9572-82. 25. Zhang S, Chuah SJ, Lai RC, JHP H, Lim SK, Toh WS. MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials. 2018;156: 16-27. Journal of Bone and Mineral Research n 964 DU ET AL.

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The inhibition of EZH2 ameliorates osteoarthritis development through the Wnt/β-catenin pathway

Cited by 68 publications

References 39 publications

Development of a simple osteoarthritis model useful to predict in vitro the anti-hypertrophic action of drugs

Development of a simple osteoarthritis model useful to predict in vitro the anti-hypertrophic action of drugs

Epigenetics as a New Frontier in Orthopedic Regenerative Medicine and Oncology

Ezh2 Ameliorates Osteoarthritis by Activating TNFSF13B

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