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

Endocrine Journal

Juanmin Zha³  Hanmei Qi³  Juan Liu³  Feng Liu³  Lin Wu³  Long Wang²  Shan Lv³  Jing Yu³  Xiaocen Kong³  Wenjuan Di³  Guoxian Ding³  Yi Zhong¹  Jianhua Bi³ 

[1] Department of Pharmaceutical Chemistry, China Pharmaceutical University, Nanjing, People’s Republic of China;Department of Endocrinology, Third Affiliated Hospital of Suzhou University, Changzhou, Jiangsu Province, People’s Republic of China;Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China

关键词: BVT.2733;    11β-hydroxysteroid dehydrogenase type 1;    Senile osteoporosis;    MC3T3-E1 preosteoblast;    Lentivirus;   

DOI  :  10.1507/endocrj.EJ12-0376

学科分类：内分泌与代谢学

来源: Japan Endocrine Society

【 摘 要 】

References(26)Cited-By(5)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.

【 授权许可】

Unknown