IGF-1R/β-catenin signaling axis is implicated in streptozotocin exacerbating bone impairment in ovariectomized rats

Abstract

Objective

The aim of this study was to investigate the role of the insulin-like growth factor-1 receptor (IGF-1R)/β-catenin signaling axis in bone impairment induced by hyperglycemia in ovariectomized rats.

Methods

Rats were divided into four groups. The sham group received sham operation and a single intraperitoneal administration of vehicle. The ovariectomy (OVX) group was subjected to bilateral OVX and vehicle injection. The streptozotocin (STZ) group received sham operation and a single STZ injection to induce hyperglycemia. The OVX + STZ group received bilateral OVX and a single STZ injection. Dual-energy X-ray absorptiometry measurement, bone biomechanics test, micro-computed tomography scan, and hematoxylin–eosin staining were performed to evaluate bone alteration in this model. The expression of relevant signals including IGF-1R, glycogen synthase kinase-3β (GSK-3β), and β-catenin were examined by quantitative real-time polymerase chain reaction and western blot.

Results

The OVX, STZ, and OVX + STZ groups induced bone loss, attenuated bone strength, and impaired microarchitecture compared with the sham group, respectively. Compared with OVX, more serious bone damage was found in the OVX + STZ group, which showed enhanced phosphorylation of IGF-1R, GSK-3β, and β-catenin.

Conclusion

OVX plus STZ induced more serious bone impairment than OVX alone, which involves the IGF-1R/β-catenin signaling axis in the pathogenesis. This may provide a potential target for treatment of postmenopausal diabetic osteoporosis.

摘要

目的:研究胰岛素样生长因子-1受体(IGF-1R)/β-连环蛋白信号轴在去除卵巢大鼠高血糖所致骨损伤中的作用。

方法:大鼠分为四组。假手术组接受假手术和单次腹腔注射赋形剂。卵巢切除组(OVX)接受双侧OVX和载体注射。链脲佐菌素(STZ)组接受假手术和单次STZ注射诱导高血糖。OVX+STZ组接受了双侧OVX和单次STZ注射。进行双能X光吸收法测量、骨生物力学测试、显微计算机断层扫描和苏木精-伊红染色来评估该模型中的骨改变。通过定量实时聚合酶链反应和蛋白质印迹检测相关信号的表达, 包括IGF-1R、糖原合酶激酶-3β (GSK-3β)和β-连环蛋白。

结果:与假手术组相比, OVX组、STZ+STZ组分别导致骨丢失、骨强度减弱和微结构受损。与OVX相比, STZ组的骨损伤更严重, IGF-1R、GSK-3β和β-连环蛋白的磷酸化增强。

结论:OVX+STZ比单独OVX诱导更严重的骨损伤, 其发病机制涉及IGF-1R/β-连环蛋白信号轴。这可能为绝经后糖尿病性骨质疏松症的治疗提供一个潜在的靶点。

Keywords:

• Postmenopausal diabetic osteoporosis
• hyperglycemia
• bone metabolism
• bone impairment
• IGF-1R/β-catenin signaling axis

Potential conflict of interest

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by National Natural Science Foundation of China [Grant 81674000], [Grant 81774338]; Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2018); Youth Scientific Research Training Project of GZUCM [Grant 2019QNPY04]; Key Project of Basic Research and Applied Basic Research of Department of Education of Guangdong Province [Grant 2018KZDXM021].