MicroRNA‑4327 regulates TGF‑β1 stimulation of matrix metalloproteinase‑13 expression via CREB‑binding protein‑mediated Runx2 acetylation in human osteoblasts

Transforming growth factor beta 1 (TGF-β1), a multifunctional cytokine, induces the expression of bone remodeling gene matrix metalloproteinase-13 (MMP-13). CREB-binding protein (CBP), a co-activator and runt-related transcription factor 2 (RUNX2), a bone transcription factor, play critical roles in regulating bone-remodeling genes. Recent advances in non-coding RNAs have revealed the significance of MicroRNAs (miRNAs) and their target genes in bone physiology. The present study hypothesized that TGF-β1 stimulated MMP-13 expression by downregulating CBP-targeting miRNAs and activating CBP-mediated RUNX2 acetylation in human osteoblastic cells. TGF-β1-downregulated miRNAs that potentially target CBP were identified. Among these miRNAs, TGF-β1 significantly downregulated miR-4327 in these cells. TGF-β1 stimulated CBP, acetylated RUNX2 and MMP-13 protein expression levels in human osteoblastic cells and this effect was decreased by overexpressing miR-4327 in these cells. In human osteoblastic cells, miR-4327 was found to directly bind to the 3'-untranslated region of CBP using a dual-luciferase gene reporter assay. Thus, the present study indicated that the TGF-β1/miR-4327/CBP/RUNX2 plays a key role in MMP-13 expression, suggesting the clinical relevance of this axis for treating bone-related disorders.

CREB-binding protein; matrix metalloproteinase-13; miRNA-4327; runt-related transcription factor 2; transforming growth factor-β1.