Glucocorticoids induce osteoporosis mediated by glucocorticoid receptor-dependent and -independent pathways

Biomedicine & Pharmacotherapy

Xiaoxu Rong¹  Yun Liu²  Jiawei Hu³  Yu Jiang³  Guoxing Zhu³  Xu Jiang³  Yajun Lu⁴  Rong Li⁵ 

[1] Corresponding authors.;Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, 300350 China;Department of Orthopedics, The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214000, China;Department of Orthopedics, Yixin Shanjuan Orthopaedic Hospital, YiXing, Jiangsu, 214000, China;Department of Pharmacy, The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214000, China;

关键词: Glucocorticoid;    Glucocorticoid-induced osteoporosis;    Glucocorticoid receptor;    Osteoblast;    Bone;   

DOI  :  

来源: DOAJ

【 摘 要 】

Clinically, glucocorticoids (GCs) are widely used to treat inflammation-related diseases; however, their long-term use causes side effects, such as osteoporosis and predisposition to bone fractures, known as glucocorticoid-induced osteoporosis (GIOP). Nr3c1 is the major glucocorticoid receptor, and its downstream signaling pathway is involved in regulating various intracellular physiological processes, including those related to bone cells; however, its mechanism in glucocorticoid-induced osteoporosis (GIOP) remains unclear. In this study, a zebrafish nr3c1-mutant was successfully generated using CRISPR/Cas9 technology to investigate the role of nr3c1 in GIOP. Mutations in nr3c1 altered cartilage development and significantly decreased bone mineralization area. Additionally, qRT-PCR results showed that the expression of extracellular matrix-, osteoblast-, and osteoclast-related genes was altered in the nr3c1-mutant. The GC–Nr3c1 pathway regulates the expression of extracellular matrix-, osteoblast-, and osteoclast-related genes via Nr3c1-dependent and Nr3c1-independent pathways. A dual-luciferase reporter assay further revealed that GCs and Nr3c1 transcriptionally regulate matrix metalloproteinase 9 (mmp9), alkaline phosphatase (alp), and acid phosphatase 5a (acp5a). This study reveals that GCs/Nr3c1 affect the expression of genes involved in bone metabolism and provides a basis to determine the role of GIOP and Nr3c1 in bone metabolism and development. We also identified a new effector target for the clinical treatment of GIOP.

【 授权许可】

Unknown