ICA treatment diabets induced bone loss via primary cilia/Gli2/Osteocalcin signaling pathway

Diabetes mellitus, as a metabolic system disorder disease, aggravates the disease burden of patients and affects the quality of human life. Diabetes-associated bone complications lead to decreased bone mechanical strength and osteoporosis. Evidences show that chronic hyperglycemia and metabolic intermediates, such as inflammatory factor, reactive oxygen species (ROS) and advanced glycation end products (AGEs), are regarded as dominant hazardous factors of primary cilia/Gli2 signal disorders. Case studies have demonstrated abnormal bone metabolism in diabetics, however, how diabetes damages primary cilia/Gli2 signal is largely unknown. Therefore, we studied the effects of diabetes on femoral primary cilia by establishing a Streptozocin (STZ)-induced diabetic (Sprague Dawley) SD rat model and diabetic bone loss cell model in vitro. Our results confirmed that diabetes impaired femur primary cilia, osteoblast differentiation and mineralization by inhibiting primary cilia/Gli2 signaling pathway, additionally, Icariin(ICA) treatment could rescue the impairment of osteoblast differentiation caused by high glucose medium in vitro. ICA activated primary cilia/Gli2/osteocalcin signaling pathway of osteoblasts by protecting primary cilia from glucotoxicity imposed by diabetes, intact primary cilia could be as anchoring sites, in which Gli2 was processed and modified, and matured Gli2 entered the nucleus to initiate downstream osteocalcin gene transcription. Additionally, ICA inhibited ROS production of mitochondria, thus balanced mitochondrial energy metabolism and oxidative phosphorylation. All results suggest that ICA can protect the primary cilia and mitochondria of osteoblast by reducing intracellular ROS, thereby recover primary cilia/Gli2 signaling pathway to facilitate osteoblast differentiation and mineralization, suggesting that ICA has potential as a novel type of drug treating bone loss induced by diabetes.