Brown Adipose Tissue Secreted Nrg4 Prevents Bone Loss by Orchestrates Bone Resorption and Angiogenesis

ABSTRACT Beyond established roles in metabolic regulation, adipose tissue‐derived factors are increasingly recognized as critical modulators of bone mass. Nevertheless, the underlying mechanisms that coordinate the osteoclastogenesis–angiogenesis–osteogenesis axis to maintain skeletal homeostasis remain poorly defined. Mouse models including brown adipose tissue (BAT) removal, Neuregulin 4 (Nrg4) knockout ( Nrg4 −/− ), and BAT transplantation were used to evaluate the role of BAT‐secreted Nrg4 in bone homeostasis. In vitro experiments were performed to explore the effects of Nrg4 on osteoclastogenesis and the angiogenesis–osteogenesis coupling. Additionally, exogenous Nrg4 treatment was applied to ovariectomy (OVX)‐induced osteoporotic mice to assess its therapeutic potential. BAT removal or Nrg4 knockout resulted in increased bone resorption and decreased bone formation, thereby accelerating bone loss in mice; conversely, BAT transplantation rescued the skeletal phenotype of Nrg4 −/− mice. In vitro, Nrg4 significantly inhibited osteoclastogenesis, at least partially through the NF‐κB inflammatory signaling pathway, while simultaneously activating the angiogenesis–osteogenesis coupling via PDGF‐BB derived from preosteoclasts. Furthermore, exogenous Nrg4 treatment effectively attenuated bone loss in OVX‐induced osteoporotic mice. These findings demonstrate that BAT‐derived Nrg4 acts as a key regulator of bone homeostasis and represents a promising therapeutic target for bone loss disorders by orchestrating crosstalk between osteoclasts and endothelial cells.