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-associatedbone complications lead to decreased bone mechanical strength and osteoporosis.Evidencesshow that chronic hyperglycemia and metabolic intermediates , such as inflammatory factor, reactive oxygen species(ROS) and advanced glycation end products(AGEs), are regarded as dominanthazardous factors of primary cilia/Gli2 signal disorders.Case studies have demonstrated abnormal bone metabolism in diabetics, however, how diabetes damages primarycilia/Gli2 signal is largely unknown. Therefore, we studied the effects of diabetes on femoral primary cilia by establishing aStreptozocin (STZ)-induced diabetic (SpragueDawley) SD rat model and diabetic bone loss cell modelin vitro. Our results confirmed that diabetes impaired femur primary cilia,osteoblast differentiation and mineralization by inhibiting primary cilia/Gli2signaling pathway, additionally,Icariin(ICA) treatment could rescue the impairment of osteoblast differentiation causedby high glucose mediumin vitro. ICA activated primary cilia/Gli2/osteocalcinsignaling pathway of osteoblasts by protecting primary cilia from glucotoxicityimposed by diabetes, intactprimary cilia couldbe as anchoring sites, in which Gli2 was processed and modified,and matured Gli2 entered the nucleus to initiate downstream osteocalcingene 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 osteoblastby reducingintracellular ROS, thereby recover primary cilia/Gli2signaling pathway to facilitateosteoblast differentiation and mineralization, suggesting that ICA has potential as a novel typeof drugtreatingbone loss induced bydiabetes.