Aberrant methylation and expression of TNXB promote chondrocyte apoptosis and extracullar matrix degradation in hemophilic arthropathy via AKT signaling

• DOI: 10.7554/elife.93087.3
• Publication Date: 2024-05-31T14:26:38Z
• Authors: Jiali Chen; Qinghe Zeng; Xu Wang; Rui Xu; Weidong Wang; Yuliang Huang; Qi Sun; Wenhua Yuan; Pinger Wang; Di Chen; Peijian Tong; Hongting Jin
• Keywords: Male; Cartilage, Articular; QH301-705.5; Science; tenascin XB; Apoptosis; Hemophilia A; chondrocyte apoptosis; Mice; Chondrocytes; Osteoarthritis; Animals; Humans; Biology (General); DNA methylation; Q; R; Tenascin; Cell Biology; cartilage degeneration; DNA Methylation; Extracellular Matrix; hemophilic arthropathy; Medicine; Proto-Oncogene Proteins c-akt; Signal Transduction

Recurrent joint bleeding in hemophilia patients frequently causes hemophilic arthropathy (HA). Drastic degradation of cartilage is a major characteristic HA, but its pathological mechanisms has not yet been clarified. In HA cartilages, we found server matrix and increased expression DNA methyltransferase proteins. We thus performed genome-wide methylation analysis on human (N=5) osteoarthritis (OA) articular identified 1228 differentially methylated regions (DMRs) associated with HA. Functional enrichment analyses revealed the association between DMR genes (DMGs) extracellular (ECM) organization. Among these DMGs, Tenascin XB (TNXB) was down-regulated mouse cartilages. The loss Tnxb F8 -/- provided disease-promoting role by augmenting degeneration subchondral bone loss. knockdown also promoted chondrocyte apoptosis inhibited phosphorylation AKT. Importantly, AKT agonist showed chondroprotective effects following knockdown. Together, our findings indicate that exposure to blood leads alterations methylation, which functionally related ECM homeostasis, further demonstrate critical TNXB activating signaling. These mechanistic insights allow development potentially new strategies for protection.