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01-01-2018 | Original Article

Effects of endogenous hypercortisolism on bone mRNA and microRNA expression in humans

Authors: Z. E. Belaya, T. A. Grebennikova, G. A. Melnichenko, A. G. Nikitin, A. G. Solodovnikov, O. I. Brovkina, A. U. Grigoriev, L. Y. Rozhinskaya, I. I. Dedov

Published in: Osteoporosis International | Issue 1/2018

Abstract

Summary

Hypercortisolism in humans suppresses osteoblastogenesis and osteoblast function through the upregulation of Wnt-signaling antagonists (sclerostin, Dkk1) and changes in microRNAs levels (miR-125b-5p, miR-218-5p, miR-34a-5p, miR-188-3p, miR-199a-5p) which are associated with mesenchymal stem-cell commitment to adipocytes or cartilage cells over the osteoblasts.

Introduction

The purpose of this study was to evaluate the responses of bone to chronic glucocorticoid (GC) excess by measuring the levels of selected mRNA and microRNA (miR) in bone samples of patients with Cushing’s disease (CD).

Methods

Bone samples were obtained during transsphenoidal adenomectomy from the sphenoid bone (sella turcica) from 16 patients with clinically and biochemically evident CD and 10 patients with clinically non-functioning pituitary adenomas (NFPA) matched by sex, age, and body mass index. Quantitative polymerase chain reactions (qPCR) were used to examine the expression of genes (mRNA and miRs) known to be involved in bone remodeling regulation based on studies in animals and cell culture.

Results

Hypercortisolism was associated with the downregulation of genes involved in osteoblast function and maturation (ACP5, ALPL, BGLAP, COL1A1, COL1A2, BMP2, RUNX2, TWIST1). An excess of GC caused increased expression of Wnt-signaling antagonists (Dkk1, SOST) and changes in the levels of miRs that are known to suppress osteoblastogenesis (miR-125b-5p, miR-218-5p, miR-34a-5p, miR-188-3p, miR-199a-5p) p < 0.05, q < 0.1. Interestingly, compensatory mechanisms were found in long-term hypercortisolism: upregulation of Wnt10b, LRP5, and LRP6; downregulation of SFRP4; changes in miRs involved in osteoblastogenesis (miR-210-5p, miR-135a-5p, miR-211, miR-23a-3p, miR-204-5p); and downregulation of genes associated with osteoclastogenesis. None of these changes prevented the suppression of bone formation.

Conclusions

An excess of endogenous GC in humans suppresses bone formation through the upregulation of Wnt-signaling antagonists and dysregulation of miRs involved in mesenchymal stem-cell commitment. Both Wnt-signaling antagonists and miRs seem to be promising targets for further research in therapeutic intervention in glucocorticoid-induced osteoporosis.

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Title: Effects of endogenous hypercortisolism on bone mRNA and microRNA expression in humans
Authors: Z. E. Belaya
T. A. Grebennikova
G. A. Melnichenko
A. G. Nikitin
A. G. Solodovnikov
O. I. Brovkina
A. U. Grigoriev
L. Y. Rozhinskaya
I. I. Dedov
Publication date: 01-01-2018
Publisher: Springer London
Published in: Osteoporosis International / Issue 1/2018
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-017-4241-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Effects of endogenous hypercortisolism on bone mRNA and microRNA expression in humans

Abstract

Summary

Introduction

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Summary

Introduction

Methods

Results

Conclusions

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