Bone formation is a regulated and ordered developmental process that requires the biosynthetic and metabolic functions of osteoblasts. This program since its inception 18 years ago has advanced our understanding of cellular and molecular mechanisms that regulate osteoblast proliferation and differentiation, including the characterization of distinct stages of osteoblast phenotype maturation. We identified Runx2 as a transcription factor essential for osteogenic differentiation that integrates developmental signaling pathways and is a novel epigenetic regulator of cell fate determination. MicroRNAs control gene expression programs by altering both the levels and translational potential of mRNAs. One of our major discoveries in the current period is the critical role of microRNAs in controlling osteoblast lineage-commitment and maturation, as well as osteogenic signaling pathways that regulate bone mass (Li et al., Proc. Natl. Acad. Sci., 2008;Li et al, J. Biol. Chem., 2009). Our preliminary data indicate that Runx2 may regulate the expression of microRNAs that attenuate key biological pathways necessary for bone formation. Therefore, our central hypothesis is that microRNAs control commitment and differentiation of osteoblasts at key developmental transitions for regulating bone formation and that a subset of these miRs is mechanistically linked to Runx2. Consequently, we propose that developmentally expressed microRNAs can provide a novel strategy for treating skeletal disorders. In the proposed studies, we will (i) characterize how microRNAs control development of the osteoblast phenotype, (ii) analyze the function of Runx2 dependent microRNAs, and (iii) characterize skeletal phenotypes in mice defective in producing mature microRNAs in osteoblasts. The significance of our studies is the definition of mechanistic linkages among microRNAs, osteogenic signaling pathways and Runx2 in controlling osteoblast differentiation that will provide innovative insight into the molecular basis of bone formation. The principal impact of our identification of microRNAs that are rate-limiting for bone anabolic effects is the potential to develop microRNA-based pre-translational approaches as a novel dimension for clinical applications to modulate bone mass in patients.
MicroRNAs have emerged as key regulators of biological cell lineage commitment and differentiation and apoptosis and are also associated with numerous disease states (cancer, fibrosis, arthritis). This recently appreciated level of post-transcriptional control has been minimally studied in relation to normal bone development and turnover. Identification of bone- related miRs and their targets for control of osteoblast growth and differentiation will lead to novel approaches for treating bone diseases.
|Tye, Coralee E; Boyd, Joseph R; Page, Natalie A et al. (2018) Regulation of osteogenesis by long noncoding RNAs: An epigenetic mechanism contributing to bone formation. Connect Tissue Res 59:35-41|
|Tracy, Kirsten M; Tye, Coralee E; Ghule, Prachi N et al. (2018) Mitotically-Associated lncRNA (MANCR) Affects Genomic Stability and Cell Division in Aggressive Breast Cancer. Mol Cancer Res 16:587-598|
|Tracy, Kirsten M; Tye, Coralee E; Page, Natalie A et al. (2018) Selective expression of long non-coding RNAs in a breast cancer cell progression model. J Cell Physiol 233:1291-1299|
|Wu, Hai; Gordon, Jonathan A R; Whitfield, Troy W et al. (2017) Chromatin dynamics regulate mesenchymal stem cell lineage specification and differentiation to osteogenesis. Biochim Biophys Acta Gene Regul Mech 1860:438-449|
|Zheng, Leilei; Tu, Qisheng; Meng, Shu et al. (2017) Runx2/DICER/miRNA Pathway in Regulating Osteogenesis. J Cell Physiol 232:182-91|
|Tasadduq, Raazia; Gordon, Jonathan; Al-Ghanim, Khalid A et al. (2017) Ethanol Extract of Cissus quadrangularis Enhances Osteoblast Differentiation and Mineralization of Murine Pre-Osteoblastic MC3T3-E1 Cells. J Cell Physiol 232:540-547|
|Tai, Phillip W L; Wu, Hai; van Wijnen, André J et al. (2017) Genome-wide DNase hypersensitivity, and occupancy of RUNX2 and CTCF reveal a highly dynamic gene regulome during MC3T3 pre-osteoblast differentiation. PLoS One 12:e0188056|
|Hurd, Lauren M; Thacker, Mihir M; Okenfuss, Ericka et al. (2017) Aneurysmal bone cysts and pathologic fracture associated with supernumerary ring chromosome 6 in two unrelated patients. Am J Med Genet A 173:3205-3210|
|VanOudenhove, Jennifer J; Medina, Ricardo; Ghule, Prachi N et al. (2017) Precocious Phenotypic Transcription-Factor Expression During Early Development. J Cell Biochem 118:953-958|
|Dudakovic, Amel; Gluscevic, Martina; Paradise, Christopher R et al. (2017) Profiling of human epigenetic regulators using a semi-automated real-time qPCR platform validated by next generation sequencing. Gene 609:28-37|
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