Abstract / Summary
Osteoarthritis (OA) is a prevalent degenerative disease in the elderly. KAT7 is a key regulator of aging and inflammatory diseases including OA, yet its direct downstream targets in OA remain unknown. CUT&TAG sequencing identified Nlrp3 as a target, and NLRP3, a core inflammasome component, is closely associated with OA progression. This study aims to elucidate KAT7’s epigenetic regulation on Nlrp3 and its role in osteoarthritis progression. The osteoarthritis (OA) mouse model was established through the destabilization of the medial meniscus (DMM). AAV-mediated gene regulation, involving the knockdown and overexpression of Kat7 as well as the knockdown of Nlrp3 , was integrated with an LPS-induced inflammatory model in chondrocytes. The expression correlation and regulatory mechanisms of KAT7 and NLRP3, along with their effects on the pathological progression of OA, were systematically analyzed using histological staining, immunohistochemistry, Western blotting, RT-qPCR, CUT&Tag sequencing, and ChIP-qPCR. Joint function was assessed through behavioral tests. KAT7 exhibited a time-dependent increase in expression within the cartilage tissue of osteoarthritis (OA) mice. The knockdown of Kat7 markedly mitigated cartilage damage, decreased OARSI scores, enhanced the synthesis of cartilage matrix components (aggrecan and type II collagen), and inhibited the expression of inflammatory mediators (IL-6, TNF-α, COX-2) as well as matrix-degrading enzymes (MMP13, ADAMTS5). Conversely, the overexpression of Kat7 exacerbated inflammation, matrix degradation, and chondrocyte apoptosis. CUT&Tag sequencing and ChIP-qPCR analyses demonstrated that KAT7 directly binds to the promoter region of Nlrp3 , thereby up-regulating its transcription through the catalysis of H3K14ac modification. Functional rescue experiments indicated that the knockdown of Nlrp3 significantly counteracted the OA progression induced by Kat7 overexpression, leading to reduced cartilage damage, diminished inflammatory responses, and improved motor function and pain sensitivity in mice. KAT7 epigenetically activates Nlrp3 transcription, thereby exacerbating cartilage inflammation and matrix destruction to drive the overall progression of osteoarthritis. Targeting this regulatory axis may provide a new strategy and experimental basis for epigenetic therapy of OA.