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.
|LeBlanc, Kimberly T; Walcott, Marie E; Gaur, Tripti et al. (2015) Runx1 Activities in Superficial Zone Chondrocytes, Osteoarthritic Chondrocyte Clones and Response to Mechanical Loading. J Cell Physiol 230:440-8|
|Tye, Coralee E; Gordon, Jonathan A R; Martin-Buley, Lori A et al. (2015) Could lncRNAs be the missing links in control of mesenchymal stem cell differentiation? J Cell Physiol 230:526-34|
|Lopez-Camacho, Cesar; van Wijnen, Andre J; Lian, Jane B et al. (2014) Core binding factor ? (CBF?) is retained in the midbody during cytokinesis. J Cell Physiol 229:1466-74|
|Gordon, Jonathan A R; Lisle, Jennifer W; Alman, Benjamin A et al. (2014) Disruption of crosstalk between mesenchymal stromal and tumor cells in bone marrow as a therapeutic target to prevent metastatic bone disease. J Cell Physiol 229:1884-6|
|Gordon, Jonathan A R; Montecino, Martin A; Aqeilan, Rami I et al. (2014) Epigenetic pathways regulating bone homeostasis: potential targeting for intervention of skeletal disorders. Curr Osteoporos Rep 12:496-506|
|Barutcu, A Rasim; Tai, Phillip W L; Wu, Hai et al. (2014) The bone-specific Runx2-P1 promoter displays conserved three-dimensional chromatin structure with the syntenic Supt3h promoter. Nucleic Acids Res 42:10360-72|
|Zaidi, Sayyed K; Grandy, Rodrigo A; Lopez-Camacho, Cesar et al. (2014) Bookmarking target genes in mitosis: a shared epigenetic trait of phenotypic transcription factors and oncogenes? Cancer Res 74:420-5|
|Wu, Hai; Whitfield, Troy W; Gordon, Jonathan A R et al. (2014) Genomic occupancy of Runx2 with global expression profiling identifies a novel dimension to control of osteoblastogenesis. Genome Biol 15:R52|
|Tai, Phillip W L; Zaidi, Sayyed K; Wu, Hai et al. (2014) The dynamic architectural and epigenetic nuclear landscape: developing the genomic almanac of biology and disease. J Cell Physiol 229:711-27|
|Tai, Phillip W L; Wu, Hai; Gordon, Jonathan A R et al. (2014) Epigenetic landscape during osteoblastogenesis defines a differentiation-dependent Runx2 promoter region. Gene 550:1-9|
Showing the most recent 10 out of 206 publications