cGAS-STING/HMGB1-mediated senescence induced by LRRK2 accelerates cartilage degeneration in osteoarthritis.

Abstract

Mitochondrial dysfunction-driven senescence is a central mechanism in the development of osteoarthritis (OA). Leucine-rich repeat kinase 2 (LRRK2), a multifunctional kinase implicated in maintaining mitochondrial homeostasis, has been examined in several inflammatory conditions. However, its role in regulating cellular senescence and its pathogenic contribution to OA remain insufficiently understood. To clarify the mechanism by which LRRK2 contributes to OA, RNA-seq and bioinformatics analysis were performed, followed by in vivo validation using a destabilization of medial meniscus (DMM) rat model in which LRRK2 was overexpressed via recombinant adeno-associated virus (rAAV). Complementary in vitro experiments were carried out to assess the impact of LRRK2 on mitochondrial dysfunction and senescence in chondrocytes. Our posttranscriptional analyses identified regulated factor influencing OA-related gene expression and revealed a strong association between LRRK2 and senescence-related regulatory genes in OA. rAAV-mediated LRRK2 overexpression accelerated chondrocyte senescence and worsened cartilage degeneration in DMM-induced OA. LRRK2 promoted HMGB1 upregulation by modulating GTPase activity, aggravating chondrocyte senescence. LRRK2 activated the cGAS-STING signaling pathway, increasing HMGB1 expression, exacerbating cellular senescence, and intensifying mitochondrial dysfunction. Treatment with the STING inhibitor H-151 partially mitigated the LRRK2-induced enhancement of chondrocyte senescence and mitochondrial impairment. This study demonstrates that LRRK2 drives chondrocyte senescence in OA by activating the cGAS-STING-HMGB1 axis, highlighting LRRK2 as a potential therapeutic target for OA.