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

• Published in: Biomedicine & pharmacotherapy 2020-05, Vol.125, p.109979, Article 109979
• Main Authors: Jiang, Yu, Lu, Yajun, Jiang, Xu, Hu, Jiawei, Li, Rong, Liu, Yun, Zhu, Guoxing, Rong, Xiaoxu
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified; Bone; Disease Susceptibility; Gene Expression; Gene Knockdown Techniques; Glucocorticoid; Glucocorticoid receptor; Glucocorticoid-induced osteoporosis; Glucocorticoids - adverse effects; Hyaline Cartilage - growth & development; Hyaline Cartilage - metabolism; Immunohistochemistry; Mutation; Osteoblast; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteoporosis - etiology; Osteoporosis - metabolism; Osteoporosis - pathology; Phenotype; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Signal Transduction - drug effects; Zebrafish
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2020.109979

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.