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

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.