Parathyroid Hormone-regulation of Runx2 by MiR-290 for Matrix Metalloproteinase-13 Expression in Rat Osteoblastic Cells.

BACKGROUND: The dynamic changes that bone undergoes during the ensemble of remodeling are administered by vital factors like Runx2 (a bone transcription factor) and matrix metalloproteinases (MMPs). AIMS: Parathyroid hormone (PTH), an FDA approved drug for bone-related ailments, was seen to stimulate MMP-13 expression via Runx2 to ultimately aid in the bone remodeling process. MicroRNAs (miRNAs) have been shown to play a major role in controlling bone metabolism, and the use of miRNAs has recently become promising therapeutic avenues for the treatment of many diseases, including bone disorders. Thus, in this study, we attempted to investigate and evaluate the expression of MMP-13 via a miRNA profile targeting Runx2 under PTH-regulation in rat osteoblastic cells. METHODS: PTH stimulated the expression of MMP-13 mRNA significantly at 4 h in rat osteoblastic cells (UMR106-01). Runx2 was required for PTH-stimulation of MMP-13 expression, in silico scrutiny generated 14 unique miRNAs targeting Runx2, and among these miRNAs, miR-290 was significantly downregulated by PTH-treatment in UMR106- 01 cells and in rat primary osteoblasts. RESULTS: Overexpression of miR-290 decreased the expression of Runx2, the binding of Runx2 at the MMP-13 promoter, and the expression of MMP-13 mRNA in PTH-treated UMR106-01 cells. A dual luciferase reporter assay identified the direct targeting of Runx2 mRNA by miR-290 in these cells. CONCLUSION: Our findings indicate that the PTH-responsive miR-290 regulated Runx2- mediated MMP-13 expression in rat osteoblastic cells, suggesting miR-290 as a molecular marker or target in bone and bone-related diseases.

Histone acetyl transferases and their epigenetic impact on bone remodeling.

Bone remodeling is a complex event that maintains bone homeostasis. The epigenetic mechanism of the regulation of bone remodeling has been a major research focus over the past decades. Histone acetylation is an influential post-translational modification in chromatin architecture. Acetylation affects chromatin structure by offering binding signals for reader proteins that harbor acetyl-lysine recognition domains. This review summarizes recent data of histone acetylation in bone remodeling. The crux of this review is the functional role of histone acetyltransferases, the key promoters of histone acetylation. The functional regulation of acetylation via noncoding RNAs in bone remodeling is also discussed. Understanding the principles governing histone acetylation in bone remodeling would lead to the development of better epigenetic therapies for bone diseases.

Regulation of Runx2 by post-translational modifications in osteoblast differentiation.

Osteogenesis is the process of new bone formation where transcription factors play an important role in controlling cell proliferation and differentiation. Runt-related transcription factor 2 (Runx2), a key transcription factor, regulates the differentiation of mesenchymal stem cells into osteoblasts, which further mature into osteocytes. Runx2 acts as a modulator such that it can either stimulate or inhibit the osteoblast differentiation. A defect/alteration in the expression/activity of this gene may lead to skeletal dysplasia. Runx2 thus serves as the best therapeutic model gene for studying bone and bone-related diseases. In this review, we briefly outline the regulation of Runx2 and its activity at the post-translational levels by the virtue of phosphorylation, acetylation, and ubiquitination in controlling the bone homeostasis.

Regulation of Runx2 by MicroRNAs in osteoblast differentiation.

Bone is one of the most dynamic organs in the body that continuously undergoes remodeling through bone formation and resorption. A cascade of molecules and pathways results in the osteoblast differentiation that is attributed to osteogenesis, or bone formation. The process of osteogenesis is achieved through participation of the Wnt pathway, FGFs, BMPs/TGF-ß, and transcription factors such as Runx2 and Osx. The activity and function of the master transcription factor, Runx2, is of utmost significance as it can induce the function of osteoblast differentiation markers. A number of microRNAs [miRNAs] have been recently identified in the regulation of Runx2 expression/activity, thus affecting the process of osteogenesis. miRNAs that target Runx2 corepressors favor osteogenesis, while miRNAs that target Runx2 coactivators inhibit osteogenesis. In this review, we focus on the regulation of Runx2 by miRNAs in osteoblast differentiation and their potential for treating bone and bone-related diseases.