The National Research Centre for Endocrinology, ul. Dmitria Uljanova, 11, Moscow, Russia, 117036.
Federal Research and Clinical Center FMBA of Russia, Moscow, Russia.
Osteoporos Int. 2018 Jan;29(1):211-221. doi: 10.1007/s00198-017-4241-7. Epub 2017 Oct 4.
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.
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).
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.
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.
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.
本研究旨在通过测量库欣病（CD）患者蝶鞍骨（蝶鞍）骨样本中选定的 mRNA 和 microRNA（miR）水平，评估慢性糖皮质激素（GC）过量对骨骼的反应。
从 16 例临床和生化证据确凿的 CD 患者和 10 例临床无功能垂体腺瘤（NFPA）患者的蝶骨中获得骨样本，这些患者通过性别、年龄和体重指数进行匹配。定量聚合酶链反应（qPCR）用于检测已知参与骨重塑调节的基因（mRNA 和 miR）的表达，这些基因基于动物和细胞培养研究。
皮质醇过多与参与成骨细胞功能和成熟的基因下调有关（ACP5、ALPL、BGLAP、COL1A1、COL1A2、BMP2、RUNX2、TWIST1）。GC 过量导致 Wnt 信号通路拮抗剂（Dkk1、SOST）的表达增加，以及已知抑制成骨细胞形成的 miR 水平发生变化（miR-125b-5p、miR-218-5p、miR-34a-5p、miR-188-3p、miR-199a-5p），p<0.05，q<0.1。有趣的是，在长期皮质醇过多的情况下发现了代偿机制：Wnt10b、LRP5 和 LRP6 的上调；SFRP4 的下调；涉及成骨细胞形成的 miR 变化（miR-210-5p、miR-135a-5p、miR-211、miR-23a-3p、miR-204-5p）；以及与破骨细胞生成相关的基因下调。这些变化都没有阻止骨形成的抑制。
人类内源性 GC 过多通过上调 Wnt 信号通路拮抗剂和调节参与间充质干细胞分化的 miR 来抑制骨形成。Wnt 信号通路拮抗剂和 miR 似乎是治疗糖皮质激素诱导性骨质疏松症的有前途的研究靶点。
