MicroRNA-106b inhibits osteoclastogenesis and osteolysis by targeting RANKL in giant cell tumor of bone

Abstract

Giant cell tumor (GCT) of bone consists of three major cell types: giant cells, monocytic cells, and stromal cells. From microarray analysis, we found that miR-106b was down-regulated in GCT clinical samples and further determined by fluorescence in situ hybridization. In addition, the expression of novel potential target of miR-106b, RANKL, was elevated in GCT along with previously determined targets in other tumors such as IL-8, MMP2 and TWIST. In a RANKL 3′UTR luciferase reporter assays, agomiR-106b repressed the luciferase activity and the effect was eliminated when the targeting site in the reporter was mutated, suggesting a direct regulation of miR-106b on RANKL mRNA. Moreover, overexpression of miR-106b in GCTSCs through TALEN-mediated site-specific knockin clearly inhibited osteoclastogenesis and osteolysis. By grafting the GCT onto the chick CAM, we confirmed the inhibitory effect of miR-106b on RANKL expression and giant cell formation. Furthermore, in an OVX mouse model, silencing of miR-106b increased RANKL protein expression and promoted bone resorption, while up-regulation of miR-106b inhibited bone resorption. These results suggest that miR-106b is a novel suppressor of osteolysis by targeting RANKL and some other cytokines, which indicates that miR-106b may be a potential therapeutic target for the treatment of GCT.

Icariin attenuates titanium particle‐induced inhibition of osteogenic differentiation and matrix mineralization via miR‐21‐5p

“…Icariin has been demonstrated to play an important role in osteogenic differentiation (Cao et al, ; Wu et al, ). It has been reported that miRNAs are associated with the osteogenic differentiation, osteoclastogenesis and osteolysis (Wang et al, ; Huang et al, ; Miller et al, ). Icariin elevates miR‐21 levels and inhibits apoptosis in embryos (Zhang et al, ).…”

Differential expression of filamin B splice variants in giant cell tumor cells

“…Overexpression of RANKL in GCT microenvironment stimulates the secretion of tumor necrosis factor-α (TNF-α) and interleukin-1β from giant cells, which in turn induces GCT stromal cell proliferation. RANKL is also an important signaling pathway which plays a vital role in osteoclastogenesis and bone resorption (22,23). Bone resorption is necessary for the establishment and promotion of tumor metastasis in the bone (24,25).…”

MicroRNAs in Bone Diseases: Progress and Prospects

“…GCTBs are characterized by the presence of numerous multinucleated osteoclastlike giant cells distributed among mononuclear stromal cells [31]. GCTBs are also characterized by extensive bone resorption, which results in regional pain and bone destruction, mostly occurring in distal femur, proximal tibia, distal radius, and sacrum [32,33]. Histologically, GCTBs can be classified into three main types, which are osteoclast-like multinucleated giant cells, monocytic round cells, and spindle-like stromal cells [34].…”