Senescence Induced by Nox4 Expressed Aberrantly in Osteoclast Precursors Accelerates Ostoeclastogenesis to Promote Osteoarthritis

Abstract Abnormal bone remodeling of subchondral bone is associated with osteoclast formation during early osteoarthritis (OA) while senescent phenotypes are detected during osteoclast differentiation. However, the associations between cellular senescence and osteoclastogenesis remain unclear in early OA. The present study found that Nox4 positively regulated the senescence of OCPs to promote multinucleated osteoclastogenesis. Overexpression of Nox4 induced overproduction of ROS, thereby promoting senescence of OCPs. Senescent OCPs secreted SASP factors to spread the senescence in OCPs clusters, over-activating the TRAF6/MAPK/c-Fos/NFATc1 axis to accelerate the fusion and osteoclast differentiation. Interestingly, the senescence of OCPs mediated by Nox4/ROS may be an essential step in initiating osteoclast differentiation. Compared to WT mice, subchondral bone loss was reduced in early OA and cartilage degeneration alleviated throughout the course of OA in Nox4-deficient mice. In addition, pharmacological inhibition of Nox4 significantly delayed OA development. In conclusion, we have identified Nox4-induced cellular senescence as an important regulator of osteoclast differentiation, suggesting that it might be a potential target to retard or prevent OA.