Congenital and acquired bone diseases constitute a major public health issue. Research conducted in the last decades has led to improved preventive and therapeutic interventions, but the diseases continue today to cause disability, morbidity and mortality at a high rate. More research is therefore needed to further decipher disease mechanisms and develop better interventions. This project is designed to contribute to this effort by increasing current knowledge of the molecular regulation of skeletal stem cells (SSCs) and their osteoblastic descendants. We will test the hypothesis that SOXC transcription factors critically control bone formation from development onwards by directing SSCs and pre-osteoblasts to express a wide array of genes that ensure their self-renewal and inhibit their osteoblastic differentiation. This hypothesis is supported by preliminary evidence that the SOXC genes, i.e., Sox4, Sox11, and Sox12, are actively expressed in SSCs and early osteoblastic cells in the mouse, and that both their specific co-inactivation and the overexpression of SOX11 in SSCs result in underdeveloped bone in embryos and in low bone mass in adult mice. This hypothesis is also supported by published evidence that SOX4 is a candidate gene for osteoporosis and low bone mass in humans and that SOX11 heterozygous mutations cause characteristic dysmorphic features.
Two specific aims are proposed to test this hypothesis.
Aim 1 is to use SOXC loss-of-function and gain-of-function mouse models to definitively assess the importance of SOXC genes in osteogenesis throughout life.
Aim 2 is to use cutting- edge molecular and functional approaches to identify the transcriptional targets of SOXC proteins in SSCs and pre-osteoblasts, and the importance of these targets in mediating the roles of SOXC proteins in these cells. Altogether, it is expected that new knowledge acquired upon completion of this project will significantly deepen current understanding of SSC and skeleton regulation from development to late adulthood and will thereby spark novel ideas and provide new means to better understand and treat bone diseases.
This project is designed to fill gaps in our current understanding of the genetic mechanisms that drive progenitor/stem cells and bone-forming cells in developing and adult bones. It will use cutting-edge approaches in vivo and in vitro to test the hypothesis that the closely related SOXC transcription factors critically control cell self-renewal and the pace of osteoblastic differentiation. Successful achievement of this project should have major public health impact by providing novel insights into mechanisms that could be disrupted in inherited and acquired bone diseases and by suggesting improved strategies to prevent and treat these diseases.
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| Liu, Chia-Feng; Angelozzi, Marco; Haseeb, Abdul et al. (2018) SOX9 is dispensable for the initiation of epigenetic remodeling and the activation of marker genes at the onset of chondrogenesis. Development 145: |
| Sarvestani, Samaneh K; Signs, Steven A; Lefebvre, Veronique et al. (2018) Cancer-predicting transcriptomic and epigenetic signatures revealed for ulcerative colitis in patient-derived epithelial organoids. Oncotarget 9:28717-28730 |
| Ferguson, James; Devarajan, Mahima; DiNuoscio, Gregg et al. (2018) PRC2 Is Dispensable in Vivo for ?-Catenin-Mediated Repression of Chondrogenesis in the Mouse Embryonic Cranial Mesenchyme. G3 (Bethesda) 8:491-503 |
