MicroRNA functions in osteogenesis and dysfunctions in osteoporosis

Abstract

MicroRNAs (miRNAs) are critical post-transcriptional regulators of gene expression that control osteoblast mediated bone formation and osteoclast-related bone remodeling. Deregulation of miRNA mediated mechanisms is emerging as an important pathological factor in bone degeneration (eg, osteoporosis) and other bone-related diseases. MiRNAs are intriguing regulatory molecules that are networked with cell signaling pathways and intricate transcriptional programs through ingenuous circuits with remarkably simple logic. This overview examines key principles by which miRNAs control differentiation of osteoblasts as they evolve from mesenchymal stromal cells during osteogenesis, or of osteoclasts as they originate from monocytic precursors in the hematopoietic lineage during osteoclastogenesis. Of particular note are miRNAs that are temporally upregulated during osteoblastogenesis (eg, miR-218) or osteoclastogenesis (eg, miR-148a). Each miRNA stimulates differentiation by suppressing inhibitory signaling pathways ('double-negative' regulation). The excitement surrounding miRNAs in bone biology stems from the prominent effects that individual miRNAs can have on biological transitions during differentiation of skeletal cells and correlations of miRNA dysfunction with bone diseases. MiRNAs have significant clinical potential which is reflected by their versatility as disease-specific biomarkers and their promise as therapeutic agents to ameliorate or reverse bone tissue degeneration.

Figure 1. MicroRNAs stimulate osteoblast and osteoclast differentiation through ‘double negative’ circuits

MicroRNAs control osteoblastogenesis (A) and osteoclastogenesis (B) through regulatory circuits in which microRNA interactions with the 3′UTRs of target mRNAs suppress (‘first negative’) the translation of proteins that inhibit (‘second negative’) the differentiation of osteoblasts or osteoclasts. Panels A and B illustrate two proposed circuits for either bone forming or bone promoting cells. Multiple other molecular circuits are known (or otherwise likely to exist) that may cross-regulate the factors shown in the diagram.

Figure 1. MicroRNAs stimulate osteoblast and osteoclast differentiation through ‘double negative’ circuits

MicroRNAs control osteoblastogenesis (A) and osteoclastogenesis (B) through regulatory circuits in which microRNA interactions with the 3′UTRs of target mRNAs suppress (‘first negative’) the translation of proteins that inhibit (‘second negative’) the differentiation of osteoblasts or osteoclasts. Panels A and B illustrate two proposed circuits for either bone forming or bone promoting cells. Multiple other molecular circuits are known (or otherwise likely to exist) that may cross-regulate the factors shown in the diagram.