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 bone cell interactions in bone and within the cancer microenvironment, and the cross-regulation of bone and energy metabolism, with the ultimate purpose of devising mechanisms by which such interactions can be modified for therapeutic targeting. The fundamental premise that drives our research efforts is that intercellular communication and signaling among bone cells via cell-cell adhesion, gap junctions, and paracrine factors is necessary to maximize bone response to local, systemic, and mechanical stimuli, and to modulate cancer growth in bone and extraskeletal tumors.

Bone forming cells, osteoblasts, express abundant gap junction proteins, primarily connexin43 (Cx43). Conditional deletion of the Cx43 gene (Gja1) in bone cells increases osteoclastogenesis, decreases mineralization and bone strength, and causes structural changes similar to those seen in aging and disuse osteoporosis. Cx43 is also present in the adipogenic lineage, which share common precursors with osteolineage cells. We find that Cx43 in adipocyte precursors facilitates fat tissue accumulation upon high calorie intake. Another bone cell connexin, connexin45 (Cx45) has opposite function on osteoclastogenesis, and Cx45 gene (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 and Gjc1 conditional knockouts and mutations that recapitulate human diseases. We are currently working on the molecular mechanisms by which connexin45 and connexin43 interact in modulating cell-cell communication in bone modeling and remodeling, and how connexin43 modulate adipogenesis and glucose homeostasis. Targeting of Cx43 (and Cx45) may represent a novel approach to improve bone mass and mitigate obesity.

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. Our lab 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 extraskeletal tumors, and unexpectedly found that cells with an osteogenic signature are present in the tumor microenvironment. Current projects are designed to determine the role of N-cadherin in tumor microenvironment cells and to devise strategies to interfere with this newly discovered function of N-cadherin in cancer.

Mentorship and Commitment to Diversity Statement:
Our laboratory is fully committed to mentoring and training a diverse and inclusive workforce. For over 3 decades, our lab has welcomed and supported trainees from all the 5 continents, from widely diverse backgrounds, cultures, languages and personal experiences.  Such diversity has contributed to create a culture of inclusiveness, mutual respect, positive curiosity and sharing of each other’s lifetime journeys. Such diversity is a defining feature of our environment as a small lab community within the larger Musculoskeletal Research Center at Washington University. As the founder and director of an institutional training program, I am fully committed to the mentoring of the next generation of scientists and physicians in the musculoskeletal field, and this extends to all laboratory members, students, post-docs, technicians, staff scientist and junior faculty. 

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: 3/22/2021 1:32:03 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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