Fexofenadine promotes bone formation and inhibits bone resorption via dual targeting of cPLA2 and Smad2.

Primary osteoporosis is a degenerative disease primarily caused by an imbalance between osteoblastogenesis and osteoclastogenesis, predominantly affecting postmenopausal women and the elderly. Current therapeutic strategies mainly focus on promoting bone formation and/or inhibiting bone resorption; however, ideal therapeutic options with low side effects and high cost-effectiveness are still lacking. This study aimed to explore the dual regulatory effect of Fexofenadine (FFD) on osteoblast-osteoclast equilibrium and elucidate its underlying molecular mechanisms. In vivo, FFD alleviated osteoporosis-related bone loss in both ovariectomized and naturally aged mouse models. In vitro, FFD inhibited RANKL-induced osteoclastogenesis in bone marrow-derived macrophages and directly promoted osteogenic differentiation in primary bone marrow mesenchymal stem cells. Mechanistically, cytosolic phospholipase A2 (cPLA2) and mothers against decapentaplegic homolog 2 (Smad2) were identified as the direct molecular targets of FFD via limited proteolysis-mass spectrometry: cPLA2 mediated the inhibitory effect of FFD on osteoclast differentiation, while Smad2 contributed to the pro-osteogenic action of FFD. These findings position FFD as a promising therapeutic candidate for maintaining bone homeostasis via dual targeting of cPLA2 and Smad2 to restore osteoblast-osteoclast balance, and also provide novel insights into the treatment of other bone metabolic disorders.