Roberto Civitelli, MD
Chief, Division of Bone and Mineral Diseases and Sydney M & Stella H Schoenberg Professor of Medicine
Sydney M. and Stella H. Schoenberg Chair in Medicine, 2003
Fuller Albright Young Investigator Award, American Society for Bone and Mineral Research, 1994
John M. Kinney International Award for Nutrition and Metabolism, 1992
Elizabeth Winston Lanier Award; Kappa Delta Award for Outstanding Orthopedic Research, 1991
Bone and Mineral Diseases
Paget’s Disease of Bone
Metabolic Bone Diseases
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 ablation of the connexin43 gene (Gja1) in mice leads to skeletal abnormalities similar to those seen in the human disease oculodentodigital dysplasia, a genetic disorder caused by Gja1 mutations.
Conditional deletion of Gja1 after birth results in a high bone turnover state with osteopenia and decreased bone strength. It also renders the skeleton insensitive to mechanical loading and unloading, causing structural changes similar to those seen in aging and disuse osteoporosis. Gap junctional communication regulates osteoblast gene expression by modulating the activity of transcription factors on specific response elements. Bone cells also 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 due to an osteoblast defect, though the two cadherins serve specific functions in bone homeostasis.
Since interference with cadherin/β-catenin interactions reduces mesenchymal osteogenic commitment, favoring adipogenesis, we are currently pursuing the mechanisms by which cadherins modulate the β-catenin pathway as an osteoinductive signaling system. We also find that the pro-osteogenic action of β-catenin requires interaction with the BMP-2/4 pathway, and more specifically, with Smad4. Work is ongoing to address the molecular mechanisms of this signaling cross-talk for osteogenesis. The fundamental hypothesis that drives our research efforts is that derangement of intercellular communication and/or signaling among bone cells via surface molecules may contribute to bone demineralization that occurs in many metabolic bone diseases, in particular, osteoporosis.
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.
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.
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.
Salazar VS, Mbalaviele G, Civitelli R. The pro-osteogenic action of β-catenin requires interaction with BMP signaling, but not Tcf/Lef transcriptional activity. J Cell Biochem 2008 104:942-952.
Di Benedetto A, Watkins M, Grimston S, Salazar V, Donsante C, Mbalaviele G, Radice GL, Civitelli R. N-cadherin and cadherin-11 modulate postnatal bone growth and osteoblast differentiation by distinct mechanisms. J Cell Sci 2010 (In Press).
DBBS Graduate Program Affiliation
- Molecular Cell Biology
- Molecular Genetics and Genomics
Professional Societies and Organizations
- American Society for Bone and Mineral Research
- The Endocrine Society
- International Bone and Mineral Society
- The American Physiological Society
- The International Society for Clinical Densitometry
- American Society for Cell Biology
- American Society for Clinical Investigation
- Association of American Physicians