Regulatory effect of microRNA‐34a on osteogenesis and angiogenesis in glucocorticoid‐induced osteonecrosis of the femoral head

Abstract

Glucocorticoid-induced osteonecrosis of the femoral head (GIOFH) is a common and devastating orthopedic disease, and its underlying mechanism remains unclear. The aim of this study was to determine the role of microRNA-34a (mir-34a) in GIOFH. C57 mouse mesenchymal stem cells (mMSCs) and human umbilical vein endothelial cells (HUVECs) were cultured with dexamethasone (Dex). A total of 48 adult rats were treated with glucocorticoids, and after the onset of GIOFH, each femoral head was removed. Mir-34a mimics, an inhibitor and over-expressing lentivirus were used in vitro and in vivo, respectively. Real-time PCR, immunohistochemistry, ELISA, cell proliferation assays, osteoblastic differentiation, and endothelial activity assays were employed to evaluate the effect of mir-34a on mMSCs, osteoblasts, and vascular endothelial cells in glucocorticoid-treated mice. We found that Dex inhibited mMSC proliferation and osteoblastic differentiation, as well as the viability and activity of endothelial cells. Dex also caused osteonecrosis and decreased new vessel formation in vivo. Mir-34a alleviated the inhibitory effects of Dex on mMSCs and osteoblasts, while facilitating its inhibitory effects on endothelial cells. Mir-34a is an important regulator in osteogenesis and angiogenesis, and it might be useful as a therapeutic target for GIOFH. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:417-424, 2018.

Noncoding RNAs in Steroid-Induced Osteonecrosis of the Femoral Head

“…ey further showed that miR-181d could inhibit the differentiation of BMSCs into osteoblasts through inhibiting SMAD3. A similar result was also found in another study, in which steroid treatment could inhibit the proliferation of BMSCs and mir-34a expression, and the effect was promoted by increases in the concentration and the time of exposure [32]. Kang et al [34] proposed that mir-34a-5p is reciprocally regulated by steroids and improves the proliferation and differentiation of osteoblasts by targeting cyclin D1, CDK4, and CDK6 and JAG1/Notch signaling in mice.…”

“…Notably, the role of Notch signaling in the osteoblastic differentiation of BMSCs and bone formation has yielded conflicting results. Zha et al [32] verified the promotive effects of these factors and further indicated Runt-related transcription factor 2 (RUNX2) as a target of mir-34a to regulate osteoblastic differentiation. In addition, Hao et al [20] found that miR-708 expression is inversely correlated with osteonecrosis and that targeting miR-708 could not only promote osteogenic differentiation in vitro but also effectively antagonized the suppression effect of steroids on osteoblast and adipocyte differentiation through increasing SMAD3 expression, which may result in an interaction between SMAD3 and RUNX2, and consequent activation of the transforming growth factor-beta (TGF-β) signaling pathway.…”

“…Zha et al [32] showed that steroid administration suppressed the viability of human umbilical vein endothelial cells and vascular endothelial growth factor (VEGF) secretion in a dose-and time-dependent manner, while the mir-34a expression level was increased. ey suggested that the transfection of an mir-34a overexpressing lentivirus led to a direct and acute inhibitory effect on angiogenesis in the early stage of steroid-induced ONFH, but disturbed the normal vascular reparative process in the compensatory phase, which then indirectly aggravated ONFH (Figure 4).…”

Efficacy and safety of stem cell therapy for the early-stage osteonecrosis of femoral head: a systematic review and meta-analysis of randomized controlled trials

“…Osteonecrosis of femoral head (ONFH) is a common orthopedic disease characterized by interruption of blood supply and necrosis of the subchondral bone, subsequently leading to collapse of femoral head [1]. It is usually related to the ischemia of femoral head, increased intraosseous pressure, and metabolism disorders which break the balance between bone absorption and bone remolding.…”

Hypoxia alleviates dexamethasone-induced inhibition of angiogenesis in cocultures of HUVECs and rBMSCs via HIF-1α

“…Dexamethasone inhibits the protein expression and activity of eNOS, which is not conducive to angiogenesis and fetal development [ 14 ]. Furthermore, dexamethasone has been proven to inhibit angiogenesis by microRNA-34a, leading to femoral head necrosis [ 15 ]. In addition, dexamethasone inhibits angiogenesis by downregulating VEGF secretion to block tumor progression [ 16 ].…”