A large body of evidence suggests that bone is a dynamic tissue that can heal spontaneously following injury. However, this regenerative process often fails in the geriatric population contributing to widespread aging- related injuries to the musculoskeletal system. Inhibition of mRNA translation by microRNAs (miRNAs) has emerged as an important regulator of osteogenic signaling pathways. Accordingly, miRNA dysregulation has been implicated in the onset and progression of osteoporosis and osteoarthritis. These findings provide a rational basis for the development of novel bone bioengineering therapies that target specific miRNAs in a spatially and temporally controlled fashion. Among its members, miR-29b-1-3p is considered a mature dominant miRNA species that facilitates osteogenic differentiation of human mesenchymal stem/stromal cells (MSCs). In contrast, little is known about miR-29b-1-5p, the other mature miRNA expressed from the same precursor, which until recently was thought of as a byproduct. We have preliminary evidence that miR-29b-1- 5p is anti-osteogenic and that MSCs isolated from geriatric patients exhibit elevated levels of miR-29b-1-5p compared to adult MSCs, while the expression of miR-29b-1-3p is unchanged. These novel findings suggest a pathogenic role for miR-29b-1-5p in aging-related defects in osteogenesis and bone regeneration. Based on these findings, we hypothesize that the miR-29b-1-5p/miR-29b-1-3p ratio increases with age thereby tilting the scale towards anti-osteogenic characteristics. We further hypothesize that inhibitors of miR-29b-1-5p (anti- miRNA therapy) would be effective in reversing anti-osteogenic effects and promoting bone regeneration with progressing age. In this proposal, we aim to elucidate the molecular basis by which miR-29b-1-5p suppresses osteogenic gene targets and disrupts osteogenic differentiation of MSCs with aging, and to determine the effects of altering miR-29b-1-5p levels on MSC-mediated local bone formation in vivo using novel polymer hydrogels. To address these aims, we will use a variety of molecular cell biology and functional assays prior to employing an established orthotopic bone injury model. These studies will provide preclinical evidence for the therapeutic potential of miR-29b-1-5p inhibitors to promote bone regeneration and also for an effective and improved delivery system for anti-miRNA therapy.
Given the worldwide epidemic of skeletal injuries, particularly in the geriatric population, a thorough understanding of the basic gene-regulatory mechanisms governing bone regeneration is of critical importance. Numerous studies suggest that microRNA dysregulation plays an important role in the development of aging- related osteoporosis and osteoarthritis, and that microRNA therapy may be clinically useful for the treatment of these debilitating disorders. In this proposal, we focus on a particular microRNA (miR-29b-1-5p) elevated with aging and aim to investigate the underlying mechanisms by which miR-29b-1-5p suppresses bone formation, and if anti-miR-29b-1-5p therapy is effective in reversing these negative effects for the treatment of critical-size bone defects.
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