Branched-chain amino acid metabolic disorder promotes osteoporosis by inhibiting HIF1-α-mediated glycolytic reprogramming in osteoblasts

Osteoporosis is the leading cause of fractures in the elderly, and metabolic changes, including elevated levels of branched-chain amino acids (BCAAs), have been implicated in its pathogenesis. This study explores the impact of high BCAAs levels on bone health. After feeding mice a diet containing twice the normal BCAAs levels for six months, serum BCAAs levels were elevated, and trabecular bone density decreased. In vivo experiments revealed that high concentrations of BCAAs adversely affected the microstructure of bone in mice, and further targeted metabolomics analysis suggested impaired energy metabolism, potentially associated with “carbohydrate digestion and absorption,” “starch and sucrose metabolism,” and “riboflavin metabolism.” In vitro experiments showed that BCAAs inhibited the proliferation, osteogenic differentiation, and glycolysis of MC3T3-E1 cells, possibly through the regulation of HIF-1α and GLUT1. Excessive BCAAs may reduce bone mass and increase the risk of osteoporosis. • Excessive accumulation of branched-chain amino acids in the body can lead to alterations in bone microstructure. • Valine, leucine, and isoleucine can all inhibit the proliferation and differentiation of osteoblasts. • Valine inhibits bone formation by downregulating HIF-1α and its downstream transcriptional target GLUT1.