Runx2 is a scaffolding protein that interacts with proteins representing many different functional classes,including chromatin remodeling factors, proteins coupled to cell growth control, differentiation of osteoblastsand production of bone matrix, as well as those proteins that transduce developmental signaling pathwaysfor bone formation. We have established that Runx2 recruits to its subnuclear domains associated with thenuclear matrix, intracellular mediators of signaling pathways that are both positive and negative regulators ofbone formation, including Smads in response to BMP/TGF(3, and YAP, a WW domain protein in response toSrc signaling. We have defined specific point mutations in the Runx2 protein that can disrupt these criticalinteractions between Runx2 and Smad and Runx2 with WW domain proteins, which include a growingnumber of factors that influence Runx2 activity on target genes. These point mutations allow us to addressthe in vivo significance of these interactions in nuclear microenvironments in mouse knock-in models. Ourdiscovery of miRNAs that affect osteoblast differentiation leads us to address how micro-RNAs (miRNA) thattarget Runx2 and Runx2 co-factors regulate bone formation through modification of the proteins that formRunx2 coregulatory complexes in the nucleus. Project 2 will now pursue how these multiple signalingpathways which converge on Runx2 are regulated during osteoblast differentiation for the control of boneformation. We will 1) characterize Runx2-Smad target genes and regulatory complexes required to completethe BMP2 osteogenic signal; 2) characterize the biological mechanisms and signaling pathways influencingthe organization of WW coregulatory proteins with Runx2 to control osteogenesis;
and Aim 3) investigatehow miRNA candidates that target Runx2 and coregulatory factors regulate osteogenesis.Clinical Relevance: There is a pressing need to develop anabolic therapies for treating bone loss inosteoporosis from the aging skeleton or induced secondary to a metabolic bone disorder. Our studies willdefine novel targets that produce new bone in response to BMPs, shift the stem cell differentiation towardsthe osteoblast lineage and identify miRNA regulators of bone formation. Each of these represents potentialtherapeutic applications to stimulate osteoblast differentiation and bone formation. For example, siRNA andmiRNA technologies are being developed for in vivo application. Anabolic therapies that are safer thanhormone treatments could be developed for stimulating bone formation.
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