Histone H3K27 demethylase UTX compromises articular chondrocyte anabolism and aggravates osteoarthritic degeneration

Abstract

Epigenome alteration in chondrocytes correlates with osteoarthritis (OA) development. H3K27me3 demethylase UTX regulates tissue homeostasis and deterioration, while its role was not yet studied in articulating joint tissue in situ. We now uncovered that increased UTX and H3K27me3 expression in articular chondrocytes positively correlated with human knee OA. Forced UTX expression upregulated the H3K27me3 enrichment at transcription factor Sox9 promoter, inhibiting key extracellular matrix molecules collagen II, aggrecan, and glycosaminoglycan in articular chondrocytes. Utx overexpression in knee joints aggravated the signs of OA, including articular cartilage damage, synovitis, osteophyte formation, and subchondral bone loss in mice. Chondrocyte-specific Utx knockout mice developed thicker articular cartilage than wild-type mice and showed few gonarthrotic symptoms during destabilized medial meniscus- and collagenase-induced joint injury. In vitro, Utx loss changed H3K27me3-binding epigenomic landscapes, which contributed to mitochondrial activity, cellular senescence, and cartilage development. Insulin-like growth factor 2 (Igf2) and polycomb repressive complex 2 (PRC2) core components Eed and Suz12 were, among others, functional target genes of Utx. Specifically, Utx deletion promoted Tfam transcription, mitochondrial respiration, ATP production and Igf2 transcription but inhibited Eed and Suz12 expression. Igf2 blockade or forced Eed or Suz12 expression increased H3K27 trimethylation and H3K27me3 enrichment at Sox9 promoter, compromising Utx loss-induced extracellular matrix overproduction. Taken together, UTX repressed articular chondrocytic activity, accelerating cartilage loss during OA. Utx loss promoted cartilage integrity through epigenetic stimulation of mitochondrial biogenesis and Igf2 transcription. This study highlighted a novel noncanonical role of Utx, in concert with PRC2 core components, in controlling H3K27 trimethylation and articular chondrocyte anabolism and OA development.

Kdm6a-CNN1 axis orchestrates epigenetic control of trauma-induced spinal cord microvascular endothelial cell senescence to balance neuroinflammation for improved neurological repair

“…Deletion of UTX inhibits the cellular senescence pathway and plays a crucial role in chondrocyte homeostasis. 45 Stem cell culture medium induced the production of fibroblast senescent markers such as SA-β-gal and senescence-associated heterochromatic foci (SAHF), while UTX knockout significantly reduced the expression of SA-β-gal and SASP factors IL-8 and IL-3. 46 In hematopoietic stem cells, UTX was closely related to the expression of senescent markers, reactive oxygen accumulation, and DNA damage repair.…”

Epigenetic regulation of embryonic ectoderm development in stem cell differentiation and transformation during ontogenesis

“…In this study, we comprehensively and systematically reviewed the research advances on EED/PRC2 function regulating ontogenesis (Table 1). PRC2 complex is the master epigenetic regulator of devel- Regulates vertebra development Cooney et al 151 Causes severely deformed thoracic spine, and shortening the long bones Kim et al 153 Mirzamohammadi et al 35 Shows few gonarthrotic symptoms in collagen-induced arthritis Lian et al 154 concise understanding of the role of EED-mediated epigenetic regula-…”

“…Moreover, H3K27me3 and H3K27me3 demethylase UTX enrichment in cartilage correlates are linked to osteoarthritis. The latest study shows that EED‐blocked expression is associated with UTX loss‐induced H3K27 hypomethylation, which showed few gonarthrotic symptoms in collagen‐induced arthritis 154 . Collectively, EED regulates early mesenchymal lineage to differentiate towards the osteogenic lineages, thereby having a great influence on bone formation, but further investigation is need to elucidate the specific mechanism.…”

Epigenetics in Knee Osteoarthritis: A 2020–2023 Update Systematic Review

“…UTX is a histone demethylase that targets di-and tri-methylated histone H3 lysine 27. Lian WS et al [61] studied how UTX altered the articular cartilage phenotype or KOA development and how it affected H3K27 tri-methylation and epigenomic landscapes, which impacted chondrocyte activity. The interaction between UTX and PRC2 core complex components was shown.…”