Role of Wnt5a in modulation of osteoporotic adipose‐derived stem cells and osteogenesis

Abstract Osteoporosis, a condition marked by the deterioration of bone microarchitecture and increased facture risk, arises from a disruption in bone metabolism, with osteoclasts surpassing osteoblasts in bone resorption versus formation. The Wnt signalling pathway, a key regulator of bone maintenance, remains partially understood in osteoporosis. Our research delves into the role of Wnt‐related molecules in this disease. In osteoporotic adipose‐derived stem cells (OP‐ASCs), we detected a significant decrease in Ctnnb1 and Frizzled‐6 ( Fzd6 ), contrasted by an increase in Gsk‐3β and Wnt5a . Activation of the Wnt pathway by LiCl resulted in elevated Ctnnb1 and Fzd6 , but decreased Gsk‐3β and Wnt5a levels, promoting OP‐ASCs' bone‐formation capacity. In contrast, inhibition of this pathway by DKK‐1 led to diminished Ctnnb1 and Fzd6 , and increased Gsk‐3β and Wnt5a , adversely affecting osteogenesis. Furthermore, our findings show that overexpressing Wnt5a impedes, while silencing it enhances the bone‐forming capability of OP‐ASCs. In a cranial bone defect model, the implantation of Wnt5a ‐silenced OP‐ASCs with biphasic calcium phosphate scaffolds significantly promoted new bone formation. These observations indicated a repression of the canonical Wnt pathway and a stimulation of the non‐canonical pathway in OP‐ASCs. Silencing Wnt5a increased the osteogenic and regenerative abilities of OP‐ASCs. Our study suggests targeting Wnt5a could be a promising strategy for enhancing bone regeneration in post‐menopausal osteoporosis.