11β-hydroxysteroid dehydrogenase type 1 selective inhibitor BVT.2733 protects osteoblasts against endogenous glucocorticoid induced dysfunction

Lin Wu; Hanmei Qi; Yi Zhong; Shan Lv; Jing Yu; Juan Liu; Long Wang; Jianhua Bi; Xiaocen Kong; Wenjuan Di; Juanmin Zha; Feng Liu; Guoxian Ding

doi:10.1507/endocrj.EJ12-0376

ORIGINALS

11β-hydroxysteroid dehydrogenase type 1 selective inhibitor BVT.2733 protects osteoblasts against endogenous glucocorticoid induced dysfunction

Lin Wu, Hanmei Qi, Yi Zhong, Shan Lv, Jing Yu, Juan Liu, Long Wang, Jianhua Bi, Xiaocen Kong, Wenjuan Di, Juanmin Zha, Feng Liu, Guoxian Ding

Author information

Lin Wu
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
Hanmei Qi
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
Yi Zhong
Department of Pharmaceutical Chemistry, China Pharmaceutical University, Nanjing, People’s Republic of China
Shan Lv
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
Jing Yu
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
Juan Liu
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
Long Wang
Department of Endocrinology, Third Affiliated Hospital of Suzhou University, Changzhou, Jiangsu Province, People’s Republic of China
Jianhua Bi
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
Xiaocen Kong
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
Wenjuan Di
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
Juanmin Zha
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
Feng Liu
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
Guoxian Ding
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China

Keywords: BVT.2733, 11β-hydroxysteroid dehydrogenase type 1, Senile osteoporosis, MC3T3-E1 preosteoblast, Lentivirus

JOURNAL FREE ACCESS

2013 Volume 60 Issue 9 Pages 1047-1058

DOI https://doi.org/10.1507/endocrj.EJ12-0376

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Abstract

Pharmacologic glucocorticoids (GCs) inhibit osteoblast function and induce osteoporosis. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) may play a role in osteoporosis as it regulates GC action at a pre-receptor level by converting inactive GC to its active form. Further, 11β-HSD1 was found increasingly expressed in bone with age. In spite of these obervations, its function in senile osteoporosis remains uncertain. In this study we constructed a lentiviral vector overexpressing mouse 11β-HSD1 and then MC3T3-E1 preosteoblast cells were infected by the negative control lentivirus and 11β-HSD1-overexpressing lentivirus, respectively. The mRNA and protein levels of 11β-HSD1 were significantly increased in MC3T3-E1 cells that were infected by 11β-HSD1-overexpressing lentivirus compared to the cells infected by the negative control lentivirus. The osteogenic differentiation of MC3T3-E1 preosteoblast cells was dramatically suppressed by 11β-HSD1 overexpression under the reductase substrate dehydrocorticosterone (DHC). The inhibition effect was similar to the inhibition of osteogenesis by over-dose GCs, including ALP activity, the ultimate calcium nodus formation as well as the expression of the osteogenic genes such as ALP, BSP, OPN and OCN. However, with addition of BVT.2733, a selective inhibitor of 11β-HSD1, all of the above osteogenic repression effects by 11β-HSD1 overexpression were reversed. Furthermore, a GC receptor antagonist RU486 also showed the similar effect, preventing inhibition of osteogenesis by 11β-HSD1 overexpression. These results demonstrated that the specific 11β-HSD1 inhibitor BVT.2733 can reverse the suppression effect towards osteogenic differentiation in 11β-HSD1 overexpressed MC3T3-E1 cells. Inhibition of 11β-HSD1 can be a new therapeutic strategy for senile osteoporosis.

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