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Roberto Civitelli, MD Professor of Medicine, Orthopedic Surgery,
and Cell Biology and Physiology
Dr. Civitelli received his medical degree and completed his residency in internal medicine at Siena University School of Medicine, Siena, Italy. He moved to Washington University in 1985 to serve a fellowship in Endocrinology and Metabolism. In addition to his research laboratory, he directs the division's Clinical Research Unit. His entire career has been dedicated to the study of bone homeostasis at the bench and in the clinic. He has received many awards for his research contributions, including the Fuller Albright Award from the American Society for Bone and Mineral Research. He has served on grant review panels for NIH, NASA and other international agencies; is a member of the Editorial Board of the Journal of Bone and Mineral Research, and is the current Editor of Calcified Tissue International. Research Interests The skeletal tissue is continuously remodeled throughout life, its structure being determined by concurrent genetic, environmental, hormonal, and mechanical factors. Most metabolic bone diseases, such as osteoporosis, are the result of an imbalance between bone resorption and formation, with the former prevailing. 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. We are currently focusing on understanding 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, which form intercellular channels that allow direct cell-cell communication via transfer of ions and small solutes. We have found that 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. Using in vivo models of osteoblast specific connexin gene deletion, we found that gap junctional communication is required for proper bone mass development and maintenance, and for full osteogenic response to bone anabolic factors, including pharmacological agents and mechanical factors. We have also found that gap junctional communication regulates osteoblast gene expression by modulating the activity of specific transcription factors on osteoblast-specific promoters. 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 and abnormal development of osteoprogenitors from bone marrow stem cells. In vivo nterference with cadherin/b-catenin interactions reduces mesenchymal osteogenic commitment, favoring adipogenesis. We are pursuing the mechanism by which cadherins modulate the b-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. Understanding the molecular mechanisms of cell-cell interactions will disclose new potential therapeutic targets for bone anabolism. Civitelli Lab 
Recent Publications Armamento-Villareal R, Villareal DT, Avioli LV, Civitelli, R: Estrogen status and heredity are major determinants of premenopausal bone mass. J Clin Invest 1992; 90: 2464-2471. Civitelli R, Beyer EC, Warlow PM, Robertson AJ, Geist ST, Steinberg TH: Connexin43 mediates direct intercellular communication in human osteoblastic cell networks. J Clin Invest 1993; 91:1888-1896. Lecanda F, Towler DA, Ziambaras K, Cheng S-L, Koval M, Steinberg TH, Civitelli R: Gap junctional communication modulates gene expression in osteoblastic cells. Mol Biol Cell 1998; 9:2249-2258. Lecanda F, Warlow PM, Sheikh S, Steinberg TH, Civitelli R: Connexin43 deficiency causes delayed ossification, craniofacial abnormalities and osteoblast dysfunction. J Cell Biol 2000; 151: 931-943. Shin C-S, Lecanda F, Sheikh S, Weitzmann L, Cheng S-L, Civitelli R: The relative abundance of different cadherins defines differentiation of mesenchymal precursors into osteogenic, myogenic, or adipogenic pathways. J Cell Biochem 2000; 78: 566-577. Civitelli R, Pilgram TK, Dotson M, Muckerman J, Lewandowski N, Armamento-Villareal R, Yokoyama-Crothers N, Kardaris E, Hauser J, Cohen S, Hildebolt CF: Hormone/estrogen replacement therapy improves alveolar and postcranial bone density in postmenopausal women. Arch Int Med 2002; 162:1409-1415. Civitelli R, Lecanda F, J¿rgensen N, Steinberg TH: Intercellular junctions and cell-cell communication. In: Bilezikian J, Raisz L, Rodan G, (Eds.), Principles of Bone Biology, 2nd edition, Academic Press, San Diego, CA. 2002; 287-302. Stains JP, Lecanda F, Screen J, Towler DT, Civitelli R: Gap junctional communication modulates transcription by altering recruitment of Sp1 and Sp3 to connexin response elements in osteoblast promoters. J Biol Chem 2003; 278:24377-24387. Castro CHM, Shin CS, Stains JP, Cheng S-L, Sheikh S, Mbalaviele G, Szejnfeld VL, and Civitelli R: Targeted expression of a dominant negative N-cadherin in 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. Mbalaviele G, Sheikh S, Stains JP, Salazar VS, Cheng SL, Chen D, Civitelli R: _-catenin and BMP-2 synergize to promote osteoblast differentiation and new bone formation. J Cell Biochem 2005; 385:613-623. Stains JP, Civitelli R: Cell-cell interactions in regulating osteogenesis and osteoblast function. Birth Defects Res C: Embryo Today 2005; 75:72-80.
Division of Bone & Mineral Diseases
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