Roberto Civitelli, MD

Sydney M. and Stella H. Schoenberg Professor of Medicine | Chief, Division of Bone and Mineral Diseases | Professor of Orthopaedic Surgery and of Cell Biology and Physiology

Research Interests

Cell-cell communication in bone

Overview of research activity: The skeletal tissue is continuously remodeled throughout life, its structure being determined by concurrent genetic, environmental, hormonal, and mechanical factors. Bone remodeling is orchestrated by the coordinated action of different cells types, osteoblasts, osteoclasts, osteocytes and cells of the bone marrow. Most metabolic bone diseases, such as osteoporosis, are the result of an imbalance between bone resorption and formation, with the former prevailing. A defective “coupling” between these two processes may occur via a reduced formation, an increased resorption, or both. The long term goal of the laboratory is to understand the cellular and molecular basis of this tightly regulated process, and to devise mechanisms by which the balance could be modified. Our current research interests are directed toward the biologic function of direct intercellular communication between bone cells via gap junctions and cell-to-cell contact. We have identified molecules of the connexin family of gap junction proteins in human and rodent osteoblastic cell models, including connexin43 and connexin45. These proteins form intercellular channels that allows direct cell-cell communication in osteoblastic networks via transfer of ions and small solutes. We have found that gap junctional communication regulates osteoblastic gene expression, such as osteocalcin and bone sialoprotein, via modulation of signals that flow through the intercellular channels. Such signals regulate binding of transcriptional factors to osteoblast-specific promoters, reflected by changes in basal transcriptional activity. The critical role of intercellular communication for bone formation is underscored by skeletal defects occurring in connexin43-deficient (“knock-out”) mice, primarily in areas of intramembranous ossification. Bone cells also express several members of the cadherin superfamily of cell adhesion molecules, some of which are regulated during osteoblast differentiation. We found that homotypic, calcium-dependent cell-cell adhesion is required for development of osteoblasts during bone modeling and remodeling. The fundamental hypothesis that drives our research efforts is that derangement of intercellular communication may constitute one of the pathophysiologic mechanisms of generalized demineralization that occurs in many metabolic bone diseases, most importantly osteoporosis. Regulation of osteoblast function by gap junctional communication and cell adhesion molecules, the effect of hormones and factors active on bone metabolism, including mechanical strain, on intercellular communication in osteoblastic networks, and development of in vivo models for tissue-specific gene deletions of connexins and cadherins using gene targeting technology are the current focus of the laboratory’s activity.


Washington University Physicians Network