Skeletogenesis in the limbs, trunk and other sites involves endochondral and intramembranous ossifications. While much is known about these processes at the embryological, histological and biochemical levels, relatively little is known at the molecular level. In Preliminary Studies, we describe the cloning of avian C-1-1, an alternatively spliced form of the ets transcription factor ERG-3. We find that C-1-1 is expressed in permanent articular chondrocytes while ERG-3 is expressed in prehypertrophic growth plate chondrocytes in the developing chick skeleton. Virally driven constitutive expression of C-1-1 blocks chondrocyte maturation and endochondral ossification, while constitutive expression of ERG-3 favors maturation. These and other results lead to our central hypothesis that C-1-1 and ERG-3 are involved and have distinct roles in skeletogenesis and skeletal function. Specifically, we propose (a) to determine whether constitutive expression of C-1-1 or ERG-3 affects skeletogenesis differentially by changing the expression of potential downstream effectors, including Indian hedgehog, PTH-RP, PTH-RP receptor or the bone factor CBFA1, (b) to determine the developmental consequences of ERG inhibition caused by antisense strategies or gene ablation obtained by homologous recombination in mice, and (c) to determine how C-1-1 and ERG-3 differentially regulate gene transcription in chondrocytes and whether they may do so by specific interactions with ets DNA motifs and other transcription factors such as ETS-2 and AP-1 complexes. To achieve these goals, we will use viral expression vectors, cell cultures, in vivo chick embryo manipulation, recombinant proteins, protein-protein and protein-DNA interaction assays, in situ hybridization and gene ablation. The results of the project will provide key information on molecular mechanisms regulating the formation of articular cartilage, long bones and other elements, and will point to molecular defects that may underlie congenital and acquired conditions of skeletogenesis and skeletal function in the growing organism and adult.
| Looney, Agnieszka P; Han, Rong; Stawski, Lukasz et al. (2017) Synergistic Role of Endothelial ERG and FLI1 in Mediating Pulmonary Vascular Homeostasis. Am J Respir Cell Mol Biol 57:121-131 |
| Usami, Yu; Gunawardena, Aruni T; Iwamoto, Masahiro et al. (2016) Wnt signaling in cartilage development and diseases: lessons from animal studies. Lab Invest 96:186-96 |
| Candela, Maria Elena; Wang, Chao; Gunawardena, Aruni T et al. (2016) Alpha 5 Integrin Mediates Osteoarthritic Changes in Mouse Knee Joints. PLoS One 11:e0156783 |
| Ohta, Yoichi; Okabe, Takahiro; Larmour, Colleen et al. (2015) Articular cartilage endurance and resistance to osteoarthritic changes require transcription factor Erg. Arthritis Rheumatol 67:2679-90 |
| Han, Rong; Pacifici, Maurizio; Iwamoto, Masahiro et al. (2015) Endothelial Erg expression is required for embryogenesis and vascular integrity. Organogenesis 11:75-86 |
| Decker, Rebekah S; Koyama, Eiki; Pacifici, Maurizio (2015) Articular Cartilage: Structural and Developmental Intricacies and Questions. Curr Osteoporos Rep 13:407-14 |
| Candela, Maria Elena; Yasuhara, Rika; Iwamoto, Masahiro et al. (2014) Resident mesenchymal progenitors of articular cartilage. Matrix Biol 39:44-9 |
| Decker, Rebekah S; Koyama, Eiki; Enomoto-Iwamoto, Motomi et al. (2014) Mouse limb skeletal growth and synovial joint development are coordinately enhanced by Kartogenin. Dev Biol 395:255-67 |
| Candela, Maria Elena; Cantley, Leslie; Yasuaha, Rika et al. (2014) Distribution of slow-cycling cells in epiphyseal cartilage and requirement of ?-catenin signaling for their maintenance in growth plate. J Orthop Res 32:661-8 |
| Decker, Rebekah S; Koyama, Eiki; Pacifici, Maurizio (2014) Genesis and morphogenesis of limb synovial joints and articular cartilage. Matrix Biol 39:5-10 |
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