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Drastic degradation of cartilage is a major characteristic of HA, but its pathological mechanisms has not yet been clarified. In HA cartilages, we found server matrix degradation and increased expression of DNA methyltransferase proteins. We thus performed genome-wide DNA methylation analysis on human HA (N=5) and osteoarthritis (OA) (N=5) articular cartilages, and identified 1228 differentially methylated regions (DMRs) associated with HA. Functional enrichment analyses revealed the association between DMR genes (DMGs) and extracellular matrix (ECM) organization. Among these DMGs, Tenascin XB (TNXB) expression was down-regulated in human and mouse HA cartilages. The loss of\n                    <jats:italic>Tnxb<\/jats:italic>\n                    in\n                    <jats:italic>\n                      F8\n                      <jats:sup>-\/-<\/jats:sup>\n                    <\/jats:italic>\n                    mouse cartilage provided a disease-promoting role in HA by augmenting cartilage degeneration and subchondral bone loss.\n                    <jats:italic>Tnxb<\/jats:italic>\n                    knockdown also promoted chondrocyte apoptosis and inhibited phosphorylation of AKT. Importantly, AKT agonist showed chondroprotective effects following\n                    <jats:italic>Tnxb<\/jats:italic>\n                    knockdown. Together, our findings indicate that exposure of cartilage to blood leads to alterations in DNA methylation, which is functionally related to ECM homeostasis, and further demonstrate a critical role of TNXB in HA cartilage degeneration by activating AKT signaling. These mechanistic insights allow development of potentially new strategies for HA cartilage protection.\n                  <\/jats:p>","DOI":"10.7554\/elife.93087","type":"journal-article","created":{"date-parts":[[2024,2,19]],"date-time":"2024-02-19T08:25:14Z","timestamp":1708331114000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.93087","source":"Crossref","is-referenced-by-count":7,"title":["Aberrant methylation and expression of TNXB promote chondrocyte apoptosis and extracullar matrix degradation in hemophilic arthropathy via AKT signaling"],"prefix":"10.7554","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9876-6103","authenticated-orcid":true,"given":"Jiali","family":"Chen","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04epb4p87","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Orthopaedics and Traumatology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Chinese 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