C-type lectin domain family 11 member A protects osteogenic differentiation of mouse embryonic osteoblast precursor cells against lipotoxicity by inhibiting oxidative stress

Bone marrow contains abundant free fatty acids (FFA). Abnormal accumulation of FFAs can be triggered by pathological or physiologic conditions such as hyperlipidemia, diabetes mellitus, and menopause, leading to osteoporosis. Excess FFAs impair bone homeostasis by promoting osteoclast-mediated bone resorption and inhibiting the proliferation and differentiation of osteoblasts. C-type lectin domain family 11 member A (Clec11a) is an osteogenic growth factor that can protect islet proliferation and function against lipotoxicity. However, there is a lack of research on the function of Clec11a under bone marrow lipotoxic conditions. Here, we demonstrate that Clec11a counteracts the lipotoxicity-induced osteogenic inhibition and facilitates the proliferation and differentiation of osteoblasts. Clec11a effectively reverses palmitic acid(PA)-induced suppression of osteoblast proliferation and osteogenic differentiation, alleviates oxidative stress, and maintains mitochondrial homeostasis. Mechanistically, these protective effects of Clec11a depend on the SIRT3-SOD2 signaling axis, as the SIRT3 inhibitor 3-TYP abolishes its effects in both MC3T3-E1 cells and mouse bone marrow mesenchymal stem cells. Collectively, our findings reveal that Clec11a protects osteoblasts from PA-induced damage through regulation of the SIRT3-SOD2 signaling axis, providing mechanistic insights into bone impairment under lipotoxic conditions.