Combined effect of teriparatide and an anti-RANKL monoclonal antibody on bone defect regeneration in mice with glucocorticoid-induced osteoporosis
Combined effect of teriparatide and an anti-RANKL monoclonal antibody on bone defect regeneration in mice with glucocorticoid-induced osteoporosis
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DOI：
10.1016/j.bone.2020.115525
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发表时间：
2020-10-01
期刊：
影响因子：
4.1
通讯作者：
Yoshikawa, Hideki
中科院分区：
文献类型：
--
作者：
Etani, Yuki;Ebina, Kosuke;Yoshikawa, Hideki
目的：本研究的目的是检查特立哌齐（TPTD）和抗小鼠核因子受体激活剂B配体单克隆抗体单独或联合治疗的效果在糖皮质激素诱导的骨质疏松症（GIOP）小鼠模型中，观察抗RANKL抗体（antiRANKL Ab）对松质骨和皮质骨再生的影响。（24周龄）分为5组：（1）SHAM组：假手术+生理盐水;（2）泼尼松龙（PSL）组：PSL +生理盐水;（3）TPTD组：PSL + TPTD;（4）Ab组：PSL+抗RANKL Ab;（5）COMB组：PSL+ TPTD+抗RANKL Ab（每组n = 8）。除假手术组外，将7.5 mg PSL皮下插入小鼠体内，以产生GIOP的小鼠模型。插入后四周，创建直径为0.9 mm的骨缺损，以评估股骨干骺端（松质骨）和骨干（皮质骨）上的骨再生。手术后，治疗干预持续4周。每周5次皮下注射生理盐水（200 μ l）或TPTD（40 μ g/kg），而抗RANKL Ab（5 mg/kg）在手术后第二天皮下注射1次。随后，进行了以下分析：骨再生和骨矿物质密度（BMD）的测量，通过显微计算机断层扫描，组织学，组织形态计量学和生物力学分析与nanoindentation.Results：COMB组表现出最高的腰椎BMD增加（与PSL，TPTD，和抗体组）的微观结构评估。与PSL、TPTD和Ab组相比，COMB组骨缺损部位的再生松质骨体积更高。与PSL组相比，COMB组的再生皮质骨体积显著增加，其硬度显著增加。结论：在糖皮质激素诱导的骨质疏松症的小鼠模型中，TPTD联合抗-与每种药物单次给药相比，RANKL Ab增加了腰椎骨密度和再生松质骨体积，与单次给药TPTD相比，还增加了再生皮质骨强度。
Objective: The purpose of this study was to examine the effect of single or combination therapy of teriparatide (TPTD) and a monoclonal antibody against the murine receptor activator of nuclear factor.B ligand (antiRANKL Ab) on cancellous and cortical bone regeneration in a mouse model of glucocorticoid-induced osteoporosis (GIOP).Methods: C57BL/6 J mice (24 weeks of age) were divided into five groups: (1) the SHAM group: sham operation + saline; (2) the prednisolone (PSL) group: PSL + saline; (3) the TPTD group: PSL + TPTD; (4) the Ab group: PSL+ anti-RANKL Ab; and (5) the COMB group: PSL+ TPTD+ anti-RANKL Ab (n = 8 per group). With the exception of the SHAM group, 7.5 mg of PSL was inserted subcutaneously into mice, to generate a mouse model of GIOP. Four weeks after insertion, bone defects with a diameter of 0.9 mm were created to assess bone regeneration on both femoral metaphysis (cancellous bone) and diaphysis (cortical bone). After surgery, therapeutic intervention was continued for 4 weeks. Saline (200 mu l) or TPTD (40 mu g/kg) was injected subcutaneously five times per week, whereas the anti-RANKL Ab (5 mg/kg) was injected subcutaneously once on the day after surgery. Subsequently, the following analyses were performed: microstructural assessment of bone regeneration and bone mineral density (BMD) measurement via micro-computed tomography, and histological, histomorphometrical, and biomechanical analyses with nanoindentation.Results: The COMB group showed the highest lumbar spine BMD increase (vs. the PSL, TPTD, and Ab groups). The volume of regenerated cancellous bone at the bone defect site was higher in the COMB group compared with the PSL, TPTD, and Ab group. The volume of the regenerated cortical bone was significantly higher in the COMB group compared with the PSL group, and its hardness was significantly higher in the COMB group compared with the PSL and TPTD groups.Conclusion: In a mouse model of glucocorticoid-induced osteoporosis, the combination therapy of TPTD plus the anti-RANKL Ab increased bone mineral density in the lumbar spine and regenerated cancellous bone volume compared with single administration of each agent, and also increased regenerated cortical bone strength compared with single administration of TPTD.