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. The fundamental premise that drives our research efforts is that intercellular communication and signaling among bone cells via gap junctions and paracrine factors is necessary to maximize bone response to local, systemic and mechanical stimuli. Alterations of such mechanisms contribute to bone demineralization that occurs in many metabolic bone diseases, in particular, osteoporosis.

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 causes structural changes similar to those seen in aging and disuse osteoporosis, altering bone sensitivity to mechanical load. We also recently found that another bone cell connexin, connexin45 (Gjc1) has opposite function on osteoclastogenesis, and Gjc1 ablation in bone forming cells results in high bone mass. To translate such discoveries to human pathobiology, we have generated mouse models carrying Gja1 mutations that recapitulate the human disease oculodentodigital dysplasia, where gap junctional communication is defective, or phenocopy traits seen in recessive craniometaphyseal dysplasia. We are currently working on the molecular mechanisms by which different Gja1 mutations lead to different skeletal phenotypes, and how connexin45 and connexin43 interact in forming gap junctions and in modulating cell-cell communication with the ultimate goal of harnessing such biological mechanisms for therapeutic targeting.

Bone cells also express several members of the cadherin superfamily of cell adhesion molecules. Genetic deletion of N-cadherin and cadherin-11 causes osteopenia owing to an osteoblast defect, though the two cadherins serve specific functions in bone homeostasis. In particular, we have discovered that N-cadherin has a dual role in osteogenic cells, contributing to maintain the osteogenic precursor pool but also restraining full osteogenic differentiation via interfering with Wnt signaling. We have also discovered that N-cadherin in osteolineage cells modulates the growth of extracellular tumors, and unexpectedly found cells with an osteogenic signature in the tumor microenvironment. Current projects are designed to determine the role of N-cadherin in extraskeletal tumor microenvironment cells and to devise strategies to interfere with this newly discovered function of N-cadherin in cancer.

Selected Publications:

Fontana F, Hickman-Brecks CL, Salazar VS, Revollo L, Abou-Ezzi G, Grimston SK, Jeong SY, Watkins M, Fortunato M, Alippe Y, Link DC, Mbalaviele G, Civitelli R. (2017). N-cadherin Regulation of Bone Growth and Homeostasis Is Osteolineage Stage-Specific. Journal of Bone and Mineral Research, 32(6):1332-1342. PMCID: PMC5466462.

Grimston SK, Fontana F, Watkins M, Civitelli R. (2017). Heterozygous deletion of both sclerostin (Sost) and connexin43 (Gja1) genes in mice is not sufficient to impair cortical bone modeling. PLoS One. 12(11):e0187980. PMCID: PMC5693294.

Revollo L, Kading J, Jeong SY, Li J, Salazar V, Mbalaviele G, Civitelli R. (2015). N-cadherin restrains PTH activation of Lrp6/β-catenin signaling and osteoanabolic action. Journal of Bone and Mineral Research. 2015; 30:274-285. PMCID: PMC4315770.

Salazar VS, Zarkadis N, Huang L, Norris J, Grimston SK, Mbalaviele G, Civitelli R. (2013). Embryonic ablation of osteoblast Smad4 interrupts matrix synthesis in response to canonical wnt signaling and causes an osteogenesis imperfecta-like phenotype. Journal of Cell Science, 126:4974-4984. PMCID: PMC3820242.

Grimston SK, Watkins MP, Brodt MD, Silva MJ, Civitelli R. (2012) Enhanced periosteal and endocortical responses to axial tibial compression loading in conditional connexin43 deficient mice. PLoS One, 7(9):e44222. PCMID: PMC3438198.

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, 51(4):787-94. PCMID: PMC3432742.

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.

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.

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.

Last Updated: 8/1/2018 9:28:50 AM

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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