Roberto Civitelli, M.D.

Internal Medicine
Bone & Mineral Diseases
Cell Biology and Physiology
Orthopaedic Surgery

Molecular Cell Biology Program
Molecular Genetics and Genomics Program

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, primarily connexin43. Conditional deletion of the connexin43 gene (Gja1) in bone cells results in a high bone turnover state driven by increased osteoclastogenesis, decreased mineralization and bone strength. It also renders the skeleton more sensitive to mechanical loading and unloading, causing structural changes similar to those seen in aging and disuse osteoporosis, and in the human disease oculodentodigital dysplasia, a disorder caused by Gja1 mutations. We are currently focusing on the molecular mechanisms by which connexins modulate skeletal homeostasis and bone modeling during adaptive responses to hormonal and mechanical stimuli.

Bone cells also express several members of the cadherin superfamily of cell adhesion molecules. Genetic deletion of N-cadherin and cadherin-11 causes osteopenia due to an osteoblast defect, though the two cadherins serve specific functions in bone homeostasis. Since interference with cadherin/beta-catenin interactions reduces mesenchymal osteogenic commitment, favoring adipogenesis, we are currently pursuing the mechanisms by which cadherins modulate the Wnt/beta-catenin pathway as an osteoinductive signaling system.

We also find that the pro-osteogenic action of beta-catenin requires interaction with the BMP-2/4 pathway, and more specifically, with Smad4. Ongoing work to address the molecular mechanisms of this signaling cross-talk for osteogenesis reveal that Smad4 deficiency multiple signaling pathways critical for osteogenesis, resulting in abnormalities remidful of osteogenesis imperfecta and cleidocranial dysplasia.

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.

Selected Publications:

Watkins MP, Norris JY, Grimston SK, Zhang X, Phipps RJ, Ebetino FH, Civitelli R. (2012). Bisphosphonates improve trabecular bone mass and normalize cortical thickness in ovariectomized, osteoblast connexin43 deficient mice. Bone, [E-pub ahead of print]. PCMID: in progress.

Greenbaum AM, Revollo LD, Woloszynek JR, Civitelli R, Link DC. (2012). N-cadherin in osteolineage cells is not required for maintenance of hematopoietic stem cells. Blood, 120(2):295-302. PMCID: PMC3398761.

Grimston SK, Goldberg DB, Watkins M, Brodt MD, Silva MJ, Civitelli R. (2011) Connexin43 deficiency reduces the sensitivity of cortical bone to the effects of muscle paralysis. Journal of Bone and Mineral Research, 26(9):2151-60. PMCID:PMC3306012.

Watkins M, Grimston SK, Norris JY, Guillotin B, Shaw A, Beniash E, Civitelli R. (2011). Osteoblast connexin43 modulates skeletal architecture by regulating both arms of bone remodeling. Molecular Biology of the Cell, 22(8):1240-51. PMCID: PMC3078079.

Di Benedetto A, Watkins M, Grimston S, Salazar V, Donsante C, Mbalaviele G, Radice GL, Civitelli R. (2010) N-cadherin and cadherin-11 modulate postnatal bone growth and osteoblast differentiation by distinct mechanisms. Journal of Cell Science, 123(Pt 15):2640-8. PMCID: PMC2908051.

Salazar VS, Mbalaviele G, Civitelli R. (2008). The pro-osteogenic action of β-catenin requires interaction with BMP signaling, but not Tcf/Lef transcriptional activity. Journal of Cellular Biochemistry, 104:942-952.

Chung DJ, Castro CHM, Watkins M, Stains JP, Chung MY, Szejnfeld VL, Willecke K, Theis M, Civitelli R. (2006). Low peak bone mass and attenuated response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43. Journal of Cell Science, 119:4187-4198.

Stains JP, Civitelli R. (2005) Gap junctions regulate extracellular signal-regulated kinase signaling to affect gene transcription in osteoblasts. Molecular Biology of the Cell, 16:64-72.

Castro CHM, Shin CS, Stains JP, et al. (2004). Targeted expression of a dominant negative N-cadherinin vivo delays peak bone mass and increases adipogenesis. Journal of Cell Science, 117:2853 2864.

Last Updated: 8/14/2012 4:23:15 PM

Cross-section of a mouse tibia labeled with calcein (yellow) and alizarin red (red) to show new bone formation on the endocortical and periosteal surfaces.
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