Abstract

Maintaining chondrocyte homeostasis is crucial for the effective treatment of osteoarthritis. Chondrocytes reside in a hypoxic environment under physiological conditions. This study, conducted exclusively in male mice, examines the association between epigenetics and chondrocyte homeostasis and observes significant alterations in histone acetylation in chondrocytes under hypoxic conditions. We identify a key enhancer element that regulates the long non-coding RNA CADM1-AS1, which is essential for cartilage homeostasis. This work elucidates a mechanism of epigenetic modulation that contributes to chondrocyte dysfunction in osteoarthritis. Further mechanistic investigations show that CADM1-AS1 recruits histone deacetylase complexes to suppress the transcriptional activation of NOS2, thereby affecting amino acid metabolism in chondrocytes. Conditional knockout of CADM1-AS1 in chondrocytes accelerates osteoarthritis development in mice. Using a hybrid exosome delivery system, we successfully modulate the expression of CADM1-AS1 and effectively reduce cartilage damage. Collectively, these findings reveal the importance of epigenetic regulation via CADM1-AS1-mediated histone deacetylation in the pathogenesis of osteoarthritis. Thus, CADM1-AS1 represents a potential therapeutic target for reducing cartilage damage in osteoarthritis and improving disease management. Modulating CADM1-AS1 expression can restore proper histone acetylation patterns and mitigate the damaging effects observed in OA joints.