Brown Adipose Tissue-Derived Nrg4 Prevents Bone Loss by Orchestrating Resorption and Angiogenesis

Osteoporosis and age-related bone loss are major public health concerns, characterized by an imbalance between bone formation and resorption. Current treatments often target osteoclasts or osteoblasts individually, but the complex interplay between bone resorption, angiogenesis, and new bone formation (the osteoclastogenesis-angiogenesis-osteogenesis axis) remains poorly understood. Adipose tissue, particularly brown adipose tissue (BAT), is increasingly recognized for secreting factors that modulate bone mass, offering a novel avenue to explore this intricate skeletal homeostasis. Identifying key regulators from BAT could lead to more comprehensive therapeutic strategies.

Researchers utilized multiple mouse models, including brown adipose tissue (BAT) removal, Neuregulin 4 (Nrg4) knockout (Nrg4-/-), and BAT transplantation, to investigate Nrg4's role in bone homeostasis. In vitro experiments explored Nrg4's effects on osteoclastogenesis and the angiogenesis-osteogenesis coupling. For therapeutic assessment, exogenous Nrg4 treatment was administered to ovariectomy (OVX)-induced osteoporotic mice. Primary endpoints included measures of bone resorption, bone formation, and cellular mechanisms underlying bone remodeling.

The study revealed that BAT removal or Nrg4 knockout in mice consistently led to increased bone resorption and decreased bone formation, consequently accelerating overall bone loss. Conversely, BAT transplantation successfully rescued the adverse skeletal phenotype observed in Nrg4-/- mice, directly implicating BAT-derived Nrg4 in maintaining bone health. > In vitro investigations demonstrated that Nrg4 significantly inhibited osteoclastogenesis, a process at least partially mediated through the NF-κB inflammatory signaling pathway. Simultaneously, Nrg4 was found to activate the crucial angiogenesis-osteogenesis coupling, a process facilitated by PDGF-BB derived from preosteoclasts. Most notably, exogenous Nrg4 treatment effectively attenuated the progressive bone loss in OVX-induced osteoporotic mice, highlighting its therapeutic potential. These findings collectively establish Nrg4 as a pivotal regulator orchestrating the crosstalk between osteoclasts and endothelial cells.