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. 2025 Mar;24(1):259-274.
doi: 10.1007/s42000-024-00599-y. Epub 2024 Sep 17.

CUL1 exacerbates glucocorticoid-induced osteoporosis by enhancing ASAP1 ubiquitination

Jun Wu  1   2 , Weijian Ren  2 , Jun Liu  2 , Xizhuang Bai  3
Affiliations

CUL1 exacerbates glucocorticoid-induced osteoporosis by enhancing ASAP1 ubiquitination

Jun Wu et al. Hormones (Athens). 2025 Mar.

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.

Keywords: ASAP1; CUL1; FBXW7; Glucocorticoid-induced osteoporosis; Osteogenesis.

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Conflict of interest statement

Declarations. Ethical approval: All the procedures were conducted in line with the principles of the Medical Ethics Committee of Hunan Institute of Traditional Chinese Medicine, Grant No. IACUC2022-0037. Informed consent: Not applicable. Competing interests: The authors declare that they have no conflict of interest.

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