Research Abstract:
The long-term goal of the laboratory is to understand the cellular and molecular basis of the bone remodeling process, and to devise mechanisms by which this balance can be modified. Our current research is focused on how bone cells function in a social context, via intercellular communication through gap junctions and direct cell-to-cell contact. Bone forming cells, osteoblasts, express abundant gap junction proteins, connexin43 and connexin45. An optimal degree of gap junctional communication is necessary for normal osteoblast function, as genetic deficiency of connexin43 in mice leads to skeletal abnormalities and delayed ossification at birth. Furthermore, gap junctional communication regulates osteoblast gene expression by modulating the activity of transcription factors on specific response elements. Using in vivo models of osteoblast specific connexin gene deletion, we are analyzing the role of gap junctional communication in bone mass development and maintenance, and in response to pharmacological agents and mechanical factors. Bone cells express several members of the cadherin superfamily of cell adhesion molecules, and we have found that N-cadherin and cadherin-11 constitute a surface bimolecular fingerprinting that defines osteogenic cells. Genetic deletion of these cadherins causes osteopenia, and interference with cadherin/-catenin interactions reduces mesenchymal osteogenic commitment, favoring adipogenesis. We are pursuing the mechanisms by which cadherins modulate the -catenin pathway as an osteoinductive signaling system. The fundamental hypothesis that drives our research efforts is that derangement of intercellular communication and/or signaling via surface molecules may contribute to bone demineralization that occurs in many metabolic bone diseases, in particular, osteoporosis.
Selected Publications:
Grimston SK, Brodt MJ, Silva MJ, Civitelli R. Attenuated response to in vivo mechanical loading in mice with conditional osteoblast ablation of the Connexin43 gene (Gja1). J. Bone Miner. Res. 2008 23:879-886.
Chung DJ, Castro CHM, Watkins M, Stains JP, Chung MY, Szejnfeld VL, Willecke K, Theis M, Civitelli R. Low peak bone mass and attenuated response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43. J. Cell Sci. 2006 119:4187-4198.
Mbalaviele G. Shin CS, Civitelli R: Cell-cell adhesion and signaling via cadherins. Connecting bone cells in their microenvironment. J. Bone Miner. Res. 2006 21:1821-1827.
Stains JP, Civitelli R. Gap junctions regulate extracellular signal-regulated kinase signaling to affect gene transcription in osteoblasts. Mol. Biol Cell 2005 16:64-72.
Castro CHM, Shin CS, Stains JP, et al. Targeted expression of a dominant negative N-cadherinin vivo delays peak bone mass and increases adipogenesis. J Cell Sci 2004 117:2853 2864.
Last Updated: 08/06/2008 |