Salicin alleviates osteoporosis by reducing oxidative stress and promoting MSC osteogenesis through AMPK-ULK1 signaling

Osteoporosis is a common metabolic bone disorder in which progressive bone loss results from dysregulated bone remodeling, in which bone resorption by osteoclasts surpasses bone formation by osteoblasts. Current pharmacological treatments for osteoporosis are associated with various adverse effects, highlighting the need for safer therapeutic strategies. Salicin is a small-molecule drug with anti-inflammatory, antioxidant, and other properties. Osteoporosis usually manifests as an increased inflammatory microenvironment and elevated levels of cellular oxidative stress. Here, we investigated the therapeutic potential and underlying mechanisms of salicin in osteoporosis. In vitro, 10 mg/L salicin optimally enhanced hMSC proliferation, migration, and osteogenic differentiation while attenuating intracellular oxidative stress. Salicin at 10 mg/L promoted heterotopic osteogenesis of hBMSCs and preserved bone mass in both OVX and TS models. Mechanistically, activation of the adenosine 5′-monophosphate-activated protein kinase (AMPK)-unc-51 like autophagy activating kinase 1 (ULK1) signaling axis contributed to the antioxidant and pro-osteogenic effects of salicin. These findings provide novel perspectives into the physiological effects of salicin, and expand its potential therapeutic uses for osteoporosis. Scheme 1. Salicin promoted the proliferation of human mesenchymal stem cells (hMSCs) and reduces intracellular oxidative stress, thereby enhancing osteogenic differentiation of hMSCs. Additionally, salicin alleviates bone loss in ovariectomy (OVX) and tail suspension (TS) osteoporosis models. These effects may be mediated through the AMPK signaling pathway, which potentially facilitates the commitment of hMSCs to osteogenic lineages