ANGPTL8 accelerates bone loss in diabetic mice by promoting osteoclastic differentiation and inhibiting osteoblastic differentiation through AMPK pathway-mediated metabolic reprogramming

Disruptions in energy metabolism within skeletal cells play a critical role in the pathogenesis of diabetic osteoporosis (DOP), primarily by affecting bone’s metabolic balance. The exact causes and regulatory mechanisms of these energy metabolism disorders in DOP remain unclear. Angiopoietin-like protein 8 (ANGPTL8), a protein involved in energy metabolism, is elevated in diabetics. This study aimed to investigate the role of ANGPTL8 in DOP development. In this study, a murine model of diabetic osteoporosis was developed, and an increase in plasma levels of ANGPTL8 was observed. The knockout of ANGPTL8 in diabetic mice mitigated osteoporosis, as demonstrated by micro-computed tomography (Micro-CT) analysis. Immunohistochemical analysis revealed that ANGPTL8 knockout increased the number of osteoblasts and decreased the number of osteoclasts in the femur. Moreover, in vitro cellular experiments demonstrated that ANGPTL8 inhibited the phosphorylation of AMPK through binding to PirB, resulting in decreased activity of the PFK1 enzyme and increased activity of the PDH enzyme. This metabolic modulation reduced glycolysis and increased oxidative phosphorylation within the cells. The alteration in metabolic pathways induced by ANGPTL8 suppressed the differentiation of osteoblastic precursor cells while facilitating the differentiation of osteoclastic precursor cells. In conclusion, ANGPTL8 alters energy metabolism to inhibit osteoblastic differentiation and promote osteoclastic differentiation by inhibiting the AMPK signaling pathway. This change in energy metabolism subsequently resulting in an imbalance between osteoblasts and osteoclasts, ultimately exacerbating diabetic osteoporosis. These findings provide new insights into DOP’s pathogenesis and suggest ANGPTL8 as a potential therapeutic target for its treatment.