Glucocorticoids induce osteoporosis mediated by glucocorticoid receptor-dependent and -independent pathways
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...
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doaj-c939ab464fc743a6a41f4df0db7869032021-05-20T07:40:53ZengElsevierBiomedicine & Pharmacotherapy0753-33222020-05-01125109979Glucocorticoids induce osteoporosis mediated by glucocorticoid receptor-dependent and -independent pathwaysYu Jiang0Yajun Lu1Xu Jiang2Jiawei Hu3Rong Li4Yun Liu5Guoxing Zhu6Xiaoxu Rong7Department of Orthopedics, The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214000, ChinaDepartment of Orthopedics, Yixin Shanjuan Orthopaedic Hospital, YiXing, Jiangsu, 214000, ChinaDepartment of Orthopedics, The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214000, ChinaDepartment of Orthopedics, The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214000, ChinaDepartment of Pharmacy, The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214000, ChinaDepartment of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, 300350 ChinaDepartment of Orthopedics, The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214000, China; Corresponding authors.Department of Orthopedics, The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214000, China; Corresponding authors.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.http://www.sciencedirect.com/science/article/pii/S0753332220301694GlucocorticoidGlucocorticoid-induced osteoporosisGlucocorticoid receptorOsteoblastBone |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yu Jiang Yajun Lu Xu Jiang Jiawei Hu Rong Li Yun Liu Guoxing Zhu Xiaoxu Rong |
spellingShingle |
Yu Jiang Yajun Lu Xu Jiang Jiawei Hu Rong Li Yun Liu Guoxing Zhu Xiaoxu Rong Glucocorticoids induce osteoporosis mediated by glucocorticoid receptor-dependent and -independent pathways Biomedicine & Pharmacotherapy Glucocorticoid Glucocorticoid-induced osteoporosis Glucocorticoid receptor Osteoblast Bone |
author_facet |
Yu Jiang Yajun Lu Xu Jiang Jiawei Hu Rong Li Yun Liu Guoxing Zhu Xiaoxu Rong |
author_sort |
Yu Jiang |
title |
Glucocorticoids induce osteoporosis mediated by glucocorticoid receptor-dependent and -independent pathways |
title_short |
Glucocorticoids induce osteoporosis mediated by glucocorticoid receptor-dependent and -independent pathways |
title_full |
Glucocorticoids induce osteoporosis mediated by glucocorticoid receptor-dependent and -independent pathways |
title_fullStr |
Glucocorticoids induce osteoporosis mediated by glucocorticoid receptor-dependent and -independent pathways |
title_full_unstemmed |
Glucocorticoids induce osteoporosis mediated by glucocorticoid receptor-dependent and -independent pathways |
title_sort |
glucocorticoids induce osteoporosis mediated by glucocorticoid receptor-dependent and -independent pathways |
publisher |
Elsevier |
series |
Biomedicine & Pharmacotherapy |
issn |
0753-3322 |
publishDate |
2020-05-01 |
description |
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. |
topic |
Glucocorticoid Glucocorticoid-induced osteoporosis Glucocorticoid receptor Osteoblast Bone |
url |
http://www.sciencedirect.com/science/article/pii/S0753332220301694 |
work_keys_str_mv |
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