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

• DOI: 10.7554/elife.93087.2
• Publication Date: 2024-05-16T13:25:11Z
• Authors: Jiali Chen; Zeng Qinghe; Xu Wang; Rui Xu; Weidong Wang; Yuliang Huang; Qi Sun; Wenhua Yuan; Pinger Wang; Di Chen; Peijian Tong; Hongting Jin
• Keywords: Cartilage, Articular; DNA methylation; QH301-705.5; Science; Q; R; tenascin XB; Apoptosis; Tenascin; Cell Biology; cartilage degeneration; DNA Methylation; Hemophilia A; chondrocyte apoptosis; Extracellular Matrix; hemophilic arthropathy; Mice; Chondrocytes; Osteoarthritis; Medicine; Animals; Humans; Biology (General); Proto-Oncogene Proteins c-akt; Signal Transduction

Recurrent joint bleeding in patients with hemophilia frequently results hemophilic arthropathy (HA). Drastic degradation of articular cartilage is a major characteristic HA, but its pathological mechanisms has not yet been clarified. Here, we conducted genome-wide DNA methylation study the goal identifying critical genes for HA degeneration.DNA was isolated from human osteoarthritis (N = 5) and cartilages analyzed using Infinium Human Methylation 850 BeadChip array. Adeno-associated virus-mediated shRNA siRNA were used to knock down Tenascin XB (TNXB) chondrocytes F8 -/- male mice, respectively. Then histopathological analysis, qPCR, Western blotting immunofluorescence assays detected chondrocyte homeostasis progression.We found that Dnmt1 Dnmt3a protein levels increased compared OA patients. Genome-wide analysis identified 1228 differentially methylated regions (DMRs) associated HA. Functional enrichment analyses then revealed DMR (DMGs) related extracellular matrix organization. Among these DMGs, TNXB expression down-regulated mouse cartilages. Further, loss Tnxb provides disease-promoting role by augmenting degeneration subchondral bone loss. knockdown also promoted apoptosis inhibited phosphorylation AKT. Importantly, AKT agonist showed chondroprotective effect following knockdown.Our demonstrated central mediator bleeding, which functions regulating activation These mechanistic insights allow targeted development potentially new strategies protection