Roles of Noncoding RNA in Bone Regeneration

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This renewal grant application represents a deepened extension of the current grant (DE25681) focusing on the bone-enhancing effects of microRNA (miR)-335-5p, first identified and characterized in our laboratory. We have published over 9 peer-reviewed papers and won many prizes and awards in reporting the results. We have recently reported our new discovery of the function of miR-335-5p in inhibiting osteoclast differentiation and bone resorption. We further found that miR-335-5p exerts its inhibitory effect through its binding to the 3’UTR elements of igsf3 (immunoglobulin superfamily, member 3). Igsf3’s increased expression during the process of osteoclast differentiation is reversely correlated with the expression of miR-335-5p. This new discovery together with the well-characterized anabolic osteogenic effect of miR-335-5p, has led us to speculate that miR-335-5p is a potent pharmaceutical candidate for treating osteoporosis and its related bone disorders, where the balance between bone formation and resorption is disturbed. At present, osteoporosis treatments include anti-resorptive drugs and anabolic bone-forming drugs. However, these drugs target either the bone-resorption or bone-formation pathway, but not both. Many protein-based therapies have the disadvantages including side-effects and the high cost. We have generated both miR-335-5p gene knockout (loss-of-function) and overexpression (gain-of-function) mice. These two mouse lines will provide the most advanced and sophisticated approaches for gene manipulation to achieve our research purposes. Collaborating with scientists and bioengineers at the New Jersey Institute of Technology, we have developed novel and cutting-edge targeted nanoparticles for the first time to precisely deliver miR-335-5p to the target cells where it can exert its dual-effects in both bone-resorption and bone-formation pahways. Aim 1. To explore the molecular mechanism of the newly discovered function of miR-335-5p in suppressing osteoclast activity and bone resorption; Aim 2. To use our newly generated miR-335-5p gene knockout and overexpression mice to characterize the multilayered functions of miR-335-5p in bone metabolism; Aim 3. To apply newly developed targeted nanoparticles to deliver miR-335-5p to specific cell types and determine its therapeutic effects on bone wound healing and reversal of osteoporosis. We will determine the therapeutic effects of miR-335-5p given effective concentration, optimal frequency, and accurate duration of administration to maximize its functions at both cellular and organismal levels. This renewal project is conceptually, technically, and interventionally innovative. The advantageous features of miRNA-based therapy will allow this translational study to shift the paradigm in understanding, treating and ultimately curing osteoporosis and its related bone disorders. An interdisciplinary team of investigators with complementary and synergistic skills will conduct the studies (Jake Chen – experimental pathology and bone biology; Qisheng Tu – cell and molecular biology; Xiaoyang Xu – biomaterials and drug delivery).