依伏卡塞衍生物对糖尿病性骨质疏松的改善和促成骨作用OA

AIM:To evaluate the ameliorative ef-fect of calcium-sensing receptor(CaSR)agonist evo-calcet derivative on osteoporosis in diabetic mice and its stimulative effect on osteogenesis.METH-ODS:The C57BL/6 mice were randomly divided in-to a normal control group,a model group,and an evocalcet derivative group.A type 2 diabetes melli-tus(T2DM)mouse model was established by a high-fat diet combined with intraperitoneal injection of low-dose streptozotocin(30 mg/kg).The mice in the treatment group were daily administered with an evocalcet derivative(0.6 mg/kg,i.g.)in 0.5%CMC-Na solution,while the mice in other groups were administered with an equal volume of 0.5%CMC-Na solution for 6 weeks.During the adminis-tration period,the body weight and the fasting blood glucose levels of the mice were dynamically monitored at 2-week intervals.Serum calcium(Ca)and phosphorus(Pi)levels were measured in each group.Micro-CT was used to detect bone mineral density and bone microstructure,and a three-point bending biomechanics test was performed to de-tect the mechanical parameters at the mid-shaft of the mice femur.HE staining and ALP staining were respectively used to detect bone histomorphology and osteoblasts,and Western blot was carried out to measure the protein expression of CaSR down-stream molecules and osteogenic-related molecules.RESULTS:After intervention with an evocalcet derivative,serum Ca and Pi levels in mice were significantly reduced(P<0.05).Micro-CT showed a significant increase in bone mineral densi-ty(P<0.05)and in trabecular thickness(P<0.05),and a significant decrease in trabecular bone separation(P<0.001);moreover,the area percentage of tra-becular bone was dramatically enhanced(P<0.05)at the proximal end of the mice tibia.Biomechani-cal tests showed a significant elevation in maxi-mum load,maximum deformation,and elastic de-formation(P<0.05)at the diaphysis of the mice fe-mur.As compared to the model group,the drug treatment induced a significant increase(P<0.01)in the number of osteoblasts.The Western blot re-sults showed that the evocalcet derivative elevated the expression ratio of p-ERK/ERK(P<0.001)and up-regulated protein expression(P<0.05)of Runx2 and COL-Ⅰ in the bone tissue of T2DM mice.CONCLU-SION:The new generation calcimimetic agent evo-calcet derivative could directly act on CaSR in bone,followed by stimulating its downstream ERK/Runx2/COL-Ⅰ signaling pathway,thereby improving dia-betic osteoporosis by exerting its osteogenic effect.