CUL1 exacerbates glucocorticoid-induced osteoporosis by enhancing ASAP1 ubiquitination

Hormones Pub Date : 2024-09-17 DOI:10.1007/s42000-024-00599-y

Jun Wu, Weijian Ren, Jun Liu, Xizhuang Bai

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Abstract

Background

Glucocorticoid-induced osteoporosis is a leading secondary cause of osteoporosis. Cullin-1 (CUL1) levels are abnormally elevated in patients with osteoporosis, but the underlying mechanism remains unclear. The purpose of this study was to elucidate the mechanism of action of CUL1 in a glucocorticoid (dexamethasone, Dex)-induced osteoporosis model.

Methods

C57BL/6J mice were intraperitoneally injected with Dex to establish an osteoporosis model. Mouse femur bone injury and bone formation were detected using hematoxylin-eosin or Masson staining. Apoptosis and cell cycle distribution were determined by flow cytometry. Alkaline phosphatase (ALP) activity and calcified nodules were monitored using ALP and Alizarin Red S staining. The molecular mechanism was validated by co-immunoprecipitation (Co-IP) and ubiquitination assays.

Results

CUL1 expression was enhanced in the Dex-induced osteoporosis mouse model. CUL1 silencing moderated the Dex-induced cell proliferation and osteogenesis inhibition. Moreover, CUL1 promoted the ubiquitination and degradation of ASAP1 via the SKP1-CUL1-F-box (SCF)-FBXW7 complex. CUL1 induced apoptosis and repressed osteogenesis by ASAP1. CUL1 silencing alleviated the Dex-induced osteoporosis in mice.

Conclusion

CUL1 suppressed osteoblast proliferation and osteogenesis by promoting ASAP1 ubiquitination via the SCF-FBXW7 complex in glucocorticoid-induced osteoporosis.

Graphical Abstract

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CUL1 通过增强 ASAP1 泛素化加剧糖皮质激素诱导的骨质疏松症

背景糖皮质激素诱导的骨质疏松症是骨质疏松症的主要继发性原因。骨质疏松症患者体内的库林-1（CUL1）水平异常升高，但其潜在机制仍不清楚。本研究旨在阐明 CUL1 在糖皮质激素（地塞米松，Dex）诱导的骨质疏松症模型中的作用机制。用苏木精-伊红或马森染色法检测小鼠股骨骨损伤和骨形成。流式细胞术测定细胞凋亡和细胞周期分布。使用碱性磷酸酶（ALP）和茜素红 S 染色法监测碱性磷酸酶（ALP）活性和钙化结节。共免疫共沉淀（Co-IP）和泛素化试验验证了其分子机制。结果CUL1在Dex诱导的骨质疏松症小鼠模型中表达增强，沉默CUL1可减轻Dex诱导的细胞增殖和成骨抑制。此外，CUL1通过SKP1-CUL1-F-box (SCF)-FBXW7 复合物促进了ASAP1的泛素化和降解。CUL1通过ASAP1诱导细胞凋亡并抑制成骨。结论在糖皮质激素诱导的骨质疏松症中，CUL1通过SCF-FBXW7复合物促进ASAP1泛素化，从而抑制成骨细胞增殖和成骨。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Hormones

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