Wu Jun, Ren Weijian, Liu Jun, Bai Xizhuang
Dalian Medical University, No. 9, West Section of Lushun South Road, Dalian, 116041, Liaoning, P.R. China.
Department of Orthopaedics, The People's Hospital of Liaoning Province, 33 Wenyi Road, Shenyang, 110016, Liaoning, People's Republic of China.
Hormones (Athens). 2025 Mar;24(1):259-274. doi: 10.1007/s42000-024-00599-y. Epub 2024 Sep 17.
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.
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.
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.
CUL1 suppressed osteoblast proliferation and osteogenesis by promoting ASAP1 ubiquitination via the SCF-FBXW7 complex in glucocorticoid-induced osteoporosis.
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病因。骨质疏松症患者中Cullin-1（CUL1）水平异常升高，但其潜在机制仍不清楚。本研究的目的是阐明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。
将C57BL/6J小鼠腹腔注射Dex以建立骨质疏松症模型。使用苏木精-伊红或Masson染色检测小鼠股骨骨损伤和骨形成。通过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染色监测ALP活性和钙化结节。通过免疫共沉淀（Co-IP）和泛素化测定验证分子机制。
在Dex诱导的骨质疏松症小鼠模型中CUL1表达增强。CUL1沉默减轻了Dex诱导的细胞增殖和骨生成抑制。此外，CUL1通过SKP1-CUL1-F-box（SCF）-FBXW7复合物促进ASAP1的泛素化和降解。CUL1通过ASAP1诱导细胞凋亡并抑制骨生成。CUL1沉默减轻了Dex诱导的小鼠骨质疏松症。
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骨生成。
