Frank Beier
Professor
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Canada Research Chair in Musculoskeletal Health |
Skeletal development is a complex process that involves interactions between multiple cell types and is regulated by numerous genetic and environmental factors. Deregulation of any of these factors can lead to serious pathologies such as various forms of dwarfism (e.g. chondrodysplasias) or skeletal tumors. Moreover, improper skeletal development is directly linked to diseases of the adult skeleton such as osteoarthritis. A second line of investigation addresses the roles of transcriptional regulators of chondrocyte differentiation. In particular, we are interested in members of the nuclear receptor family, such as glucocorticoid receptor and RORalpha. We are using genetically altered mice in conjunction with microarray analyses and cell biological approaches to identify the roles and target genes of these transcription factors in skeletal development. More recently, we have expanded these studies to explore epigenetic mechanisms involved in cartilage gene expression and to examine of the roles of nuclear receptors in the pathogenesis of osteoarthritis. These studies are also funded by CIHR. Our third area of interest are the molecular mechanisms involved in the progression of osteoarthritis. Through microarray analyses we have identified several pathways (such as TGFalpha-EGFR signaling) that possible contribute to osteoarthritis. We are now testing the function of some of these pathways using genetic and surgical models of osteoarthritis, together with cell and organ culture and biochemical techniques. In particular, we are testing whether drugs that modulate activity of these pathways present suitable approaches to halt or slow osteoarthritis progression in animal models. These studies are supported by CIHR and the National Institutes of Health (NIH, US).
The majority of our skeleton - for example the ribs, vertebrae and the bones of our limbs - form through the process of endochondral ossification in which the later bone is first laid down as a cartilage model. The cells of the cartilage, the chondrocytes, control the length, shape and function of endochondral bones. Our lab is interested in the signaling pathways and molecular mechanisms that regulate the biology of chondrocytes and other skeletal cells. In this context, we follow three overlapping areas of research.
One focus of the lab is the role of intracellular signaling pathways in chondrocytes. We have demonstrated important functions for signaling molecules of the Rho GTPase and several kinase families (e.g. MAP, PI3K/AKT, GSK-3) in the control of chondrocyte proliferation and differentiation. Current projects address the function of selected signaling molecules in cartilage in vivo and the elucidation of their mechanisms of action (such as effects on gene expression and cytoskeletal organization). We are especially interested in the interactions of chondrocytes with other cell types, including endothelial and perichondral cells as well as osteoblasts and osteoclasts. We utilize knockout mice, organ and cell cultures coupled to a large variety of molecular and cellular assays in these studies. These studies are funded by the Canadian Institutes of Health Research (CIHR).
Gillespie, J.R., Ulici, V., Dupuis, H., Higgs, A., DiMattia, A., Patel, S., Woodgett, J.R., and Beier, F. (2011). Deletion of Glycogen Synthase Kinase-3β in Cartilage Results in Up-Regulation of Glycogen Synthase Kinase-3a Protein Expression. Endocrinology, Epub Feb. 15, 2011. Stanton, L-A., Li, J.R., and Beier, F. (2010). PPAR gamma2 expression in growth plate chondrocytes is regulated by p38 and GSK-3. J. Cell. Mol. Medicine 14, 242-256.
Appleton, C.T.G., Usmani, S.E., Mort, J., and Beier, F. (2010). RhoA/ROCK and MEK/ERK mediation of transforming growth factor alpha signaling in articular cartilage degeneration. Lab. Invest. 90, 20 -30.
James, C.G., Stanton, L.-A., Agoston, H., Ulici, V., Underhill, T.M., and Beier, F. (2010). Genome-wide analyses of gene expression during mouse endochondral ossification. PLoS ONE 5, e8693.
Ulici, V., James, C.G., Hoenselaar, K., and Beier, F. (2010). Genome-wide analyses of PI3 kinase target genes in chondrocytes. PLoS ONE 5, e8866.
Yan, Q., Feng, Q., and Beier, F. (2010). Endothelial nitric oxide synthase deficiency results in reduced chondrocyte proliferation and endochondral bone growth. Arthr. & Rheum. 62, 2013-2022.
Ulici, V., Hoenselaar, K.D., Agoston, H., McErlain, D.D., Umoh, J., Chakrabarti, S., Holdsworth, D.W., and Beier, F. (2009). The role of Akt1 in terminal stages of endochondral bone formation: angiogenesis and ossification. Bone 45, 1133-1145.
Woods, A., Wang, G., James, C.G., Dupuis, H., and Beier, F. (2009). Microarray analyses of chondrocyte gene expression in response to manipulation of the actin cytoskeleton: Identification of a central role of RORα signaling. J. Cell. Mol. Med., 13, 3497-3516.
Solomon, L., Li, J., Bérubé, N.G., and Beier, F. (2009). Loss of ATRX function in cartilage results in only minor skeletal defects. PLoS ONE 4, e7106.
Ulici, V., Hoenselaar, K.D., Gillespie, J.R., and Beier, F. (2008). The PI3K pathway regulates endochondral bone growth through control of hypertrophic chondrocyte differentiation. BMC Dev. Biol. 8:40.
Appleton, C.T.G., Pitelka, V., Henry, J., and Beier, F. (2007). Chondrocyte gene expression in a surgical rodent model of Osteoarthritis. Arthritis & Rheumatism 56, 1854-1868.
Wang, G., Woods, A., Agoston, H., Ulici, V., Glogauer, M., and Beier, F. (2007). Genetic ablation of Rac1 in cartilage results in chondrodysplasia. Dev. Biol. 306, 612-623.
Woods, A., Wang, G., Dupuis, H., Shao, Z., and Beier, F. (2007). Rac1 signaling stimulates N-Cadherin expression, mesenchymal condensation and chondrogenesis. J. Biol. Chem. 282, 23500-23508.
Appleton, C.T.G., Usmani, S.E., Bernier, S.M., Aigner, T., and Beier, F. (2007). Transforming growth factor alpha suppression of articular chondrocyte phenotype and Sox9 expression in a rat model of osteoarthritis. Arthritis & Rheumatism 56, 3693-3705.
