MiR 376c inhibits osteoblastogenesis by targeting Wnt3 and ARF‐GEF‐1 ‐facilitated augmentation of beta‐catenin transactivation

Abstract

Wnt signaling pathway plays important role in all aspects of skeletal development which include chondrogenesis, osteoblastogenesis, and osteoclastogenesis. Induction of the Wnt-3 signaling pathway promotes bone formation while inactivation of the pathway leads to bone related disorders like osteoporosis. Wnt signaling thus has become a desired target to treat osteogenic disorders. MicroRNAs (miRNAs) represent an important category of elements that interact with Wnt signaling molecules to regulate osteogenesis. Here, we show that miR-376c, a well-characterized tumor suppressor which inhibits cell proliferation and invasion in osteosarcoma by targeting to transforming growth factor-alpha, suppresses osteoblast proliferation, and differentiation. Over-expression of miR-376c inhibited osteoblast differentiation, whereas inhibition of miR-376c function by antimiR-376c promoted expression of osteoblast-specific genes, alkaline phosphatase (ALP) activity, and matrix mineralization. Target prediction analysis tools and experimental validation by luciferase 3' UTR reporter assay along with qRT-PCR identified Wnt-3 and ARF-GEF-1 as direct targets of miR-376c. It was seen that over-expression of miR-376c leads to repression of canonical Wnt/β-catenin signaling. Our overall results suggest that miR-376c targets Wnt-3 and ARF-GEF-1 suppresses ARF-6 activation which prevents the release of β-catenin and its transactivation thereby inhibiting osteoblast differentiation. Although miR-376c is known to be a tumor repressor; we have identified a second complementary function of miR-376c where it inhibits Wnt-3-mediated osteogenesis and promotes bone loss.

Characterization of the chondrogenic and osteogenic potential of male and female human muscle‐derived stem cells: Implication for stem cell therapy

“…WNT3A expression was variable between cell populations and passages, although WNT3A was expressed significantly more in young female 1 hMDSCs compared to young male 1 hMDSCS . Our in vitro histology, however, demonstrated that young male 1 hMDSCs were more osteogenic than young female 1 hMDSCs.…”

Bioinformatics analysis and identification of circular RNAs promoting the osteogenic differentiation of human bone marrow mesenchymal stem cells on titanium treated by surface mechanical attrition

“…In the predicted ceRNA networks, one combination of circ-GNB5, circ-HERC1, circ-KMT2A, circ-LTBP2, hsa-miR-24-3p and the Wnt3 gene, another comprised of circ-LTBP2, circ-MCF2L2, circ-MDN1, circ-MYH9, circ-PLPPR4, circ-RAB31, circ-SMARCH2, circ-SPEG, circ-SYNM, circ-TANGO6, hsa-miR-5195-3p and the Wnt4, IGF1 genes, the third consists of circ-ADAMTS13, circ-ARHGAP32, circ-BRPF3, circ-CARD8, circ-CCDC88C, circ-COL4A2, circ-DGKD, circ-DIP2C, circ-DYNC1H1, circ-FAT3, circ-LTBP2, hsa-let-7b-5p and CHRD, three networks communicated with each other through the core hub circ-LTBP2. Based on the previous prediction, it's target mRNAs including wnt3, wnt4, CBFB, IGF1 and CHRD are recognized osteogenic marker genes (Kureel et al, 2017;Qin et al, 2015;Lindsey, Rundle & Mohan, 2018). What's more, circ-LTBP2 has not been reported yet.…”

miR‑429 inhibits osteosarcoma progression by targeting HOXA9 through suppressing Wnt/β‑catenin signaling pathway

“…Increasing evidence shows that Wnt/β-catenin axis was regulated, for example, by miR-25, -376c, -21, -34a miRNAs in OS progression (43)(44)(45). Wnt/β-catenin signaling pathway modulates various genes that in turn regulate a diversity of cell functions such as proliferation, differentiation and morphogenesis, and β-catenin was proved to enhance progression, invasion and tumorigenesis in cancers (46).…”