Resveratrol Reverses Osteogenic Decline of Bone Marrow Mesenchymal Stem Cells Via Upregulation of Yes-Associated Protein Expression in Inflammatory Environment

Osteoporosis is an age-related bone disease, characterized by rapid boneloss, decreased bone mineral density (BMD), and consequent risk of fractures. The most prevalent form of clinically significant osteoporosis involves various inflammatory conditions, especially age-dependent osteoporosis and postmenopausal osteoporosis. Tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory cytokine, plays a critical role in the development of inflammatory, which also plays an important role in bone formation and bone loss during osteoporosis. In this report, we examined the effect of TNF-alpha on osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and its modulation by resveratrol (Res). We found that TNF-alpha can upregulate inflammatory cytokines, Il-6, Mmp-9, and Il-1 beta, and establish an inflammatory environment. High inflammatory cytokine expression significantly inhibited osteogenic differentiation of BMSCs by overactivating upstream Hippo kinases and decreasing the nuclear Yes-associated protein (YAP) signals. With Res treatment, decreasing inflammatory cytokine expression normalized Hippo/YAP signaling and effectively rescued YAP-mediated osteogenesis. Thus, through these studies, we present a mechanism by which TNF-alpha can affect BMSCs osteogenesis through modulation of Hippo/YAP signaling.