Ezh2 Ameliorates Osteoarthritis by Activating TNFSF13B

Abstract

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.

Histone Demethylase UTX Compromises Articular Chondrocyte Anabolism and Aggravates Osteoarthritic Degeneration

“…Our data now reveal that upon UTX loss, EZH2 appears to curtail chondrocytic metabolism as EZH2 RNAi-mediated suppression maintained H3K27 hypomethylated and improves ECM synthesis, whereas downregulation of EED or SUZ12 appears to stimulate matrix anabolism, as restoring EED or SUZ12 results in H3K27 hypermethylation and compromised ECM synthesis. In agreement with our data, chondrocyte-speci c EZH2 or EED knockout mice show poor cartilage development and defective bone growth 13,15 . EED thus appears functionally indispensable for trimethylation of H3K27 by EZH2 56 .…”

“…Mice de cient in EZH1 and EZH2 in chondrocytes display poor chondrogenesis and skeletal tissue underdevelopment along with low H3K27me3 abundance 14 . Interestingly, EZH2 deletion accelerates the development of OA 15 , while chondrocyte-speci c EED knockout mice show a deformed skeleton and decreased chondrocyte survival 16 . Recently, JMJD3 is shown to regulate in vitro chondrogenic differentiation of human mesenchymal stem cells in monolayer culture 17 .…”

Histone Modifications and Chondrocyte Fate: Regulation and Therapeutic Implications

“…Induction of EZH2 activates β-catenin signaling by increasing H3K27me3 on the promoter of secreted frizzledrelated protein 1 (Sfrp1) gene, a modulator of Wnt. Conditional deletion of Ezh2 in chondrocytes deteriorates OA pathological changes in the medial meniscectomy induced mouse OA model, as indicated by inhibition of chondrocyte hypertrophy through activating tumor necrosis factor ligand superfamily member 13B (TNFSF13B) (Du et al, 2020). These studies indicate that EZH2 may serve as an effective target for OA therapy.…”

EZH2 inhibition reduces cartilage loss and functional impairment related to osteoarthritis

“…Recently, it has been reported that Enhancer of Zest Homolog 2 (EZH2), a histone methyltransferase which adds a methyl group (-CH 3 ) on the lysine 27 of the histone 3 (H3K27), is upregulated in cartilage from OA patients, and in chondrocytes treated with IL-1β 11,12 . Furthermore, we and others have demonstrated that EZH2 inhibition reduces the methylation of H3K27 and chondrocytes hypertrophy, a process responsible for osteophytes formation 11,13,14 .…”

“…Furthermore, we and others have demonstrated that EZH2 inhibition reduces the methylation of H3K27 and chondrocytes hypertrophy, a process responsible for osteophytes formation 11,13,14 . However, one study suggests on the contrary, that conditional knockout of EZH2 aggravates osteoarthritis development 12 .…”