MiR-708 promotes steroid-induced osteonecrosis of femoral head, suppresses osteogenic differentiation by targeting SMAD3

Abstract

Steroid-induced osteonecrosis of femoral head (ONFH) is a serious complication of glucocorticoid (GC) use. We investigated the differential expression of miRs in the mesenchymal stem cells (MSCs) of patients with ONFH, and aimed to explain the relationship between GC use and the development of MSC dysfunction in ONFH. Cells were collected from bone marrow of patients with ONFH. Samples were assigned to either GCs Group or Control Group at 1:1 matched with control. We then used miRNA microarray analysis and real-time PCR to identify the differentially expressed miRs. We also induced normal MSCs with GCs to verify the differential expression above. Subsequently, we selected some of the miRs for further studies, including miRNA target and pathway prediction, and functional analysis. We discovered that miR-708 was upregulated in ONFH patients and GC-treated MSCs. SMAD3 was identified as a direct target gene of miR-708, and functional analysis demonstrated that miR-708 could markedly suppress osteogenic differentiation and adipogenesis differentiation of MSCs. Inhibition of miR-708 rescued the suppressive effect of GC on osteonecrosis. Therefore, we determined that GC use resulted in overexpression of miR-708 in MSCs, and thus, targeting miR-708 may serve as a novel therapeutic biomarker for the prevention and treatment of ONFH.

Overactivated autophagy contributes to steroid-induced avascular necrosis of the femoral head

“…Osteonecrosis can result in debilitation and adversely affect the quality of life, frequently requiring surgical intervention. Thus far, there are no effective preventive measures for SANFH (14). Although multiple theories underlying this complication have been proposed, no pathophysiologic mechanism has been identified as the etiology for the development of osteonecrosis of the femoral head (15).…”

Emerging roles of MicroRNAs in osteonecrosis of the femoral head

“…Knockdown of miR-708 also rescued the suppressive effect of glucocorticoid on osteonecrosis. 33 These data suggested that glucocorticoid might result in miR-708 overexpression to mediate its ONFH-promoting effect. This miRNA may thus act as a new therapeutic target for the prevention and treatment of ONFH.…”

“…[45][46][47] Hao et al 33 found that the expression of miR-708 was significantly upregulated in glucocorticoid-treated and ONFH patients' mesenchymal stem cells. In addition, they found that Smad3 (small mothers against decapentaplegic 3) was a direct target of miR-708.…”

“…53,54 miRNAs were found to play crucial pathogenic roles in ONFH, 33,34 especially through interacting with transcription factors involved in adipogenesis, osteogenesis and angiogenesis ( Figure 1). An increasing number of studies have also hinted at their potential therapeutic roles in ONFH.…”

“…[30][31][32] Recently, several studies suggested that miRNAs play important roles in the development of ONFH. [33][34][35] Nevertheless, an in-depth appraisal of the related literature is still lacking.…”