PUBLICATION
Glucocorticoids induce osteoporosis mediated by glucocorticoid receptor-dependent and -independent pathways
- Authors
- Jiang, Y., Lu, Y., Jiang, X., Hu, J., Li, R., Liu, Y., Zhu, G., Rong, X.
- ID
- ZDB-PUB-200212-17
- Date
- 2020
- Source
- Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 125: 109979 (Journal)
- Registered Authors
- Keywords
- Bone, Glucocorticoid, Glucocorticoid receptor, Glucocorticoid-induced osteoporosis, Osteoblast
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Disease Susceptibility
- Gene Expression
- Gene Knockdown Techniques
- Glucocorticoids/adverse effects*
- Hyaline Cartilage/growth & development
- Hyaline Cartilage/metabolism
- Immunohistochemistry
- Mutation
- Osteoblasts/drug effects
- Osteoblasts/metabolism
- Osteoporosis/etiology*
- Osteoporosis/metabolism*
- Osteoporosis/pathology
- Phenotype
- Receptors, Glucocorticoid/genetics
- Receptors, Glucocorticoid/metabolism*
- Signal Transduction/drug effects*
- Zebrafish
- PubMed
- 32044718 Full text @ Biomed. Pharmacother.
Citation
Jiang, Y., Lu, Y., Jiang, X., Hu, J., Li, R., Liu, Y., Zhu, G., Rong, X. (2020) Glucocorticoids induce osteoporosis mediated by glucocorticoid receptor-dependent and -independent pathways. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 125:109979.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping