Inhibition of Histone Lysine Demethylase 6 A Promotes Chondrocytic Activity and Attenuates Osteoarthritis Development through Repressing H3K27me3 Enhancement of Wnt10a

Articular cartilage microstructure destruction causes joint integrity loss, enhancing the development of osteoarthritis (OA) (Sharma, 2021). Extracellular matrix (ECM) degradation in articular chondrocytes is a notable feature of osteoarthritic degeneration (Hunter and Bierma-Zeinstra, 2019) under chronic inflammatory stress, biomechanical impact, or hyperglycemic conditions (Sanchez-Lopez et al., 2022). Promotion of cartilage tissue homeostasis alleviates this arthritic disorder (Latourte et al., 2020). However, the chondroprotective mechanism preserving chondrocytic activity and articular cartilage integrity during OA development has not been fully studied.

The methylation of ε-amino group of lysine in histones (crucial structural proteins of chromatin) changes a loose chromatin structure into a tightly packed heterochromatin form (Allshire and Madhani, 2018), reducing histone enrichment at promoters to repress gene transcription (Bates, 2020). Increasing evidence reveals that histone methylation correlates with chondrocyte function or cartilage development. For example, mice carrying H3.3K36M mutants (i.e., the mutation of lysine 36 to methionine in histone 3.3) in chondrocytes have low H3K36me2 levels and develop dwarfism (Abe et al., 2021). Hypermethylation of H3K4 and H3K36 is present in chondrogenic differentiation of human mesenchymal stem cells (Cheung et al., 2020). H3K9 hypomethylation by deleting histone methyltransferases in chondrocytes induces cartilage hypoplasia in jaw joints (Shull et al., 2020). Hypoxia enhances H3K79 methylation and ECM expression in articular chondrocytes. Promotion of H3K79me2 attenuates osteoarthritis development in mice with destabilized medial meniscus-mediated knee injury (De Roover et al., 2021).

H3K27 trimethylation is catalyzed by histone methyltransferases, including enhancer of zeste homolog 2 (EZH2), embryonic ectoderm development (EED), and polycomb repressive complex 2 subunit (SUZ12). Histone demethylases KDM6A or JMJD3 removes the methyl group of H3K27me3 (Laugesen et al., 2019). Expanding evidence has revealed that H3K27me3 levels correlate with the development of arthritic diseases. Inhibition of H3K27 trimethylation attenuates IL-6 secretion in macrophages, reversing collagen-induced inflammatory arthritis in mice (Zhao et al., 2022). It also represses profibrogenic activity in skin fibroblasts of human systemic sclerosis via blocking Notch signaling (Wasson et al., 2020). Jmjd3 interference by RNAi mitigates apoptosis of chondrocytes upon incubating in excess nitric oxide donor and delays knee OA in mice with anterior cruciate ligament transection-mediated joint injury (Jin et al., 2022). Mice deficient in Ezh2 have severe articular cartilage damage in knee injury induced by medial meniscectomy (Du et al., 2020). Furthermore, H3K27me3 demethylase Kdm6a plays an essential role in bone tissue integrity and chondrogenic differentiation. Osteocyte-specific Kdm6a knockout mice develop osteoporosis (Xia et al., 2022). Kdm6a inhibitor represses chondrogenic differentiation of human mesenchymal stem cells (Yapp et al., 2016). Targeting Kdm6a by microRNA-758-3p downregulates chondrogenesis of human adipose-derived mesenchymal stem cells (Liao et al., 2022). Expression of Kdm6a and extracellular matrices is enhanced in articular chondrocytes upon co-incubating with bone-marrow mesenchymal stem cells (Zhi et al., 2020). The function of Kdm6a to OA development has not yet been thoroughly studied.

This study aimed to utilize chondrocyte-specific Kdm6a knockout mice (Kdm6aKO) and inhibitor GSK-J4 to investigate whether Kdm6a loss affected the development of OA symptoms in destabilized medial meniscus-induced joint injury. We elucidated how this molecule changed epigenome, which may regulate articular chondrocyte function.

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