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

doi:10.12092/j.issn.1009-2501.2026.09.005

中国临床药理学与治疗学 ›› 2026, Vol. 31 ›› Issue (9): 1193-1199.doi: 10.12092/j.issn.1009-2501.2026.09.005

• 基础研究 • 上一篇

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

陈美轩¹(), 刘凯², 徐源¹, 华圆², 郭怡洵¹, 张恺³^,*(), 张岩¹^,*()

1. 上海中医药大学附属龙华医院脊柱病研究所，上海 200032
2. 仁合益康集团有限公司，石家庄 050035，河北
3. 河北医科大学药学院，石家庄 050017，河北

收稿日期:2026-03-20 修回日期:2026-05-12 出版日期:2026-09-26 发布日期:2026-10-08
通讯作者: 张恺,张岩 E-mail:15103225033@163.com;18100956@hebmu.edu.cn;medicineyan@aliyun.com
作者简介:陈美轩，女，硕士，研究方向：药理学。E-mail：15103225033@163.com
基金资助:
河北省创新能力提升计划项目——高水平人才团队建设专项（244A7615D）；河北省慢性肾病治疗药物开发重点实验室（SZQ202506）；河北省高等学校科学研究产学研合作项目（CXZX2025017）；上海中医药大学附属龙华医院“龙医学者”临床科技创新计划（KC2026009）；科技创新基础研究项目（CX202512）

Evocalcet derivative attenuates diabetic osteoporosis and promotes osteogenesis

Meixuan CHEN¹(), Kai LIU², Yuan XU¹, Yuan HUA², Yixun GUO¹, Kai ZHANG³^,*(), Yan ZHANG¹^,*()

1. Spinal Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
2. Renheyikang Group Co., Ltd, Shijiazhuang 050035, Hebei, China
3. College of Pharmacy, Hebei Medical University, Shijiazhuang 050017, Hebei, China

Received:2026-03-20 Revised:2026-05-12 Online:2026-09-26 Published:2026-10-08
Contact: Kai ZHANG,Yan ZHANG E-mail:15103225033@163.com;18100956@hebmu.edu.cn;medicineyan@aliyun.com

摘要/Abstract

摘要：

目的: 评估钙敏感受体（CaSR）激动剂依伏卡塞衍生物对糖尿病小鼠骨质疏松的改善作用及其促成骨作用。方法: C57BL/6小鼠随机分为正常对照组、模型组、依伏卡塞衍生物组。采用高脂饮食结合腹腔低剂量注射链脲佐菌素（30 mg/kg）的方法，建立2型糖尿病（T2DM）小鼠模型。治疗组每天灌胃给予以0.5%CMC-Na为溶剂的依伏卡塞衍生物（0.6 mg/kg），其余组给予等量0.5%CMC-Na溶液，连续6周，给药期间以2周为间隔动态监测小鼠体质量和空腹血糖。检测各组小鼠血清钙（Ca）、磷（Pi）含量，采用微焦点定量CT（Micro-CT）检测小鼠骨密度和骨微结构，通过三点弯曲生物力学检测小鼠股骨中段力学参数，使用HE染色、ALP染色检测骨组织形态学与成骨细胞，并通过Western blot检测CaSR下游分子及成骨相关分子的蛋白表达。结果: 依伏卡塞衍生物干预后，小鼠血清中Ca、Pi含量明显降低（P<0.05）；Micro-CT检测分析显示，小鼠胫骨近端骨密度明显增加（P<0.05），骨小梁间隙明显减小（P<0.001），骨小梁厚度明显增加（P<0.05），并且，骨小梁面积百分比明显增加（P<0.05）；生物力学测试表明，小鼠股骨中段的最大载荷、最大变形和弹性变形都显著增加（P<0.05）；相对于模型组，给药组的成骨细胞数量显著增加（P<0.01）；Western blot结果显示，依伏卡塞衍生物显著升高T2DM小鼠骨组织p-ERK/ERK表达比值（P<0.001），上调Runx2和COL-Ⅰ的蛋白表达（P<0.05）。结论: 新一代拟钙剂依伏卡塞衍生物通过直接作用于骨骼CaSR，进而激活其下游ERK/Runx2/COL-Ⅰ信号通路，发挥促成骨作用，改善糖尿病性骨质疏松。

关键词: 糖尿病性骨质疏松, 依伏卡塞衍生物, 骨骼, 成骨分化

Abstract:

AIM: To evaluate the ameliorative effect of calcium-sensing receptor (CaSR) agonist evocalcet derivative on osteoporosis in diabetic mice and its stimulative effect on osteogenesis. METHODS: The C57BL/6 mice were randomly divided into a normal control group, a model group, and an evocalcet derivative group. A type 2 diabetes mellitus (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 administration 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 detect 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 downstream 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 density (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 trabecular bone was dramatically enhanced (P<0.05) at the proximal end of the mice tibia. Biomechanical tests showed a significant elevation in maximum load, maximum deformation, and elastic deformation (P<0.05) at the diaphysis of the mice femur. As compared to the model group, the drug treatment induced a significant increase (P<0.01) in the number of osteoblasts. The Western blot results 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. CONCLUSION: The new generation calcimimetic agent evocalcet derivative could directly act on CaSR in bone, followed by stimulating its downstream ERK/Runx2/COL-Ⅰ signaling pathway, thereby improving diabetic osteoporosis by exerting its osteogenic effect.

Key words: diabetic osteoporosis, evocalcet derivative, bone, osteoblastic differentiation

中图分类号:

R965.2

陈美轩, 刘凯, 徐源, 华圆, 郭怡洵, 张恺, 张岩. 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[J]. 中国临床药理学与治疗学, 2026, 31(9): 1193-1199.

Meixuan CHEN, Kai LIU, Yuan XU, Yuan HUA, Yixun GUO, Kai ZHANG, Yan ZHANG. Evocalcet derivative attenuates diabetic osteoporosis and promotes osteogenesis[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(9): 1193-1199.

图/表 9

图 1

Fig.1 Chemical structures of evocalcet and its derivative

图 2

Fig.2 Experimental timeline

图 3

Fig.3 Changes in body weight and fasting blood glucose of mice A: body weight; B: fasting blood glucose; #P<0.05, ##P<0.01, ###P<0.001, compared with control group.

图 4

Fig.4 Ca and Pi levels in serum of mice A: serum calcium level; B: serum phosphorus level; ##P<0.01, ###P<0.001, compared with control group; &P<0.05, compared with model group.

图 5

Fig.5 Bone mineral density, structural parameters, and three-dimensional architecture of trabecular bone at the proximal tibia A: 3D structure of trabecular bone; B: biological parameters of trabecular bone #P<0.05,##P<0.01, compared with control group; &P<0.05,&&&P<0.001, compared with model group.

图 6 #P<0.05, ##P<0.01, ###P<0.001, compared with control group; &P<0.05, compared with model group.

Fig.6 Mechanical parameters of the mid-shaft femur #P<0.05, ##P<0.01, ###P<0.001, compared with control group; &P<0.05, compared with model group.

图 7

Fig.7 HE staining of the proximal tibia A: HE staining; B: area percentage of trabecular bone; ###P<0.001, compared with control group; &P<0.05, compared with model group.

图 8

Fig.8 ALP staining of the proximal tibia A: ALP staining; B: ALP staining-positive intensity; ###P<0.001, compared with control group; &&P<0.01, compared with model group.

图 9

Fig.9 Protein expression of osteogenic factors in femur A-C: immunoblotting detection; D: quantitative expression of proteins; ##P<0.01, ###P<0.001, compared with control group; &P<0.05,&&&P<0.001, compared with model group.

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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

Evocalcet derivative attenuates diabetic osteoporosis and promotes osteogenesis

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