Rapamycin regulates osteogenic differentiation through Parkin-mediated mitophagy in rheumatoid arthritis

Varying degrees of bone destruction and bone loss occur in the development of rheumatoid arthritis (RA). Nevertheless, the mechanism underlying osteoporosis in the development of RA is not completely elucidated. Recent evidence indicates that mitophagy may play a vital role in regulating the differentiation and function of preosteoblast. Parkin is associated with mitophagy and various inflammatory diseases, but the precise role of Parkin in the treatment of osteoporosis in RA is unclear. In the present study, we found that the abnormal bone metabolism of RA is related to the activation of the mechanistic targets of mTORC1 pathway, and chronic inflammation which regulates the differentiation of preosteoblast through mitophagy. In this study, we found that Parkin was upregulated, and the mitochondrion was damaged in tumor necrosis factor alpha (TNF-α) stimulated preosteoblasts. Rapamycin (RAPA, an mTORC1 pathway blocker) upregulation of Parkin-mediated mitophagy tends to attenuate mitochondrial impairment caused by TNF-α in preosteoblasts. The experiment in vivo demonstrated that the combination therapy with TNF-α neutralizing antibody and RAPA significantly reduced osteoporosis in AIA mice. Drug inhibition of this pathway can be a potential treatment for osteoporosis in patients with RA.