Chronic inflammation, such as that seen in rheumatoid arthritis (RA), periprosthetic osteolysis, massive allografting and infections are accompanied by irreversible cartilage and bone destruction. These complications are exacerbated by exposure to environmental agents such as lead and cigarette smoke, which can inhibit skeletal repair, such as fracture healing.

      Over the last decade there has been remarkable progress towards our understanding of the mechanisms responsible for this process. Much of this information was derived from studies that used transgenic and knockout mice. These have demonstrated the importance of the tumor necrosis factor-alpha (TNFα) and receptor activator of NFκB ligand (RANKL) signal transduction pathways in the induction cytokines, adhesion molecules, oxygenases, matrix metaloprotease (MMPs) and osteoclast activity. We have developed a mouse model of fracture healing, which we used to demonstrate the ill effects of lead exposure.

      We are now working on translational approaches to further elucidate the cellular and molecular mechanism responsible for bone erosion and defective skeletal repair. These studies stress novel biologic and gene therapy strategies to inhibit these pathways. Our goal is to the develop new therapies to treat these bone diseases.

Recent Publications

Ho, H., X. Lu, P. Sime, R. Phipps, E. Schwarz, R. O’Keefe, H. Awad, and M. Zuscik. 2007. Exposure of mice to cigarette smoke causes a reduction in bone volume, density and femoral biomechanical rigidity. Trans Ortho Res Soc:54. [Abstract]

Puzas, J., R. Ubayawardena, K. Hochberg, T. Sheu, E. Schwarz, R. O’Keefe, R. Rosier, and M. Zuscik. 2006. Mechanisms of lead-induced osteoarthritis. Trans Ortho Res Soc. [Abstract]

Lu, X., L. Yanoso, E. M. Schwarz, R. J. O’Keefe, R. N. Rosier, J. E. Puzas, H. Awad, and M. J. Zuscik. 2006. Nicotine enhances cartilage formation and delays callus remodeling durning facture healing in mice. J. Bon. Min. Res. 21:S337. [Abstract]

Maloney, M. D., J. J. Goater, R. Parsons, H. Ito, R. J. O’Keefe, P. T. Rubery, M. H. Drissi, and E. M. Schwarz. 2006. Safety and efficacy of ultraviolet-a light-activated gene transduction for gene therapy of articular cartilage defects. J Bone Joint Surg Am 88:753-761.

Ito, H., M. Koefoed, P. Tiyapatanaputi, K. Gromov, J. J. Goater, J. Carmouche, X. Zhang, P. T. Rubery, J. Rabinowitz, R. J. Samulski, T. Nakamura, K. Soballe, J. O’Keefe R, B. F. Boyce, and E. M. Schwarz. 2005. Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy. Nature Medicine 11:291-297.

Carmouche, J. J., J. E. Puzas, X. Zhang, P. Tiyapatanaputi, D. A. Cory-Slechta, R. Gelein, M. Zuscik, R. N. Rosier, B. F. Boyce, J. O’Keefe R, and E. M. Schwarz. 2005. Lead exposure inhibits fracture healing and is associated with increased chondrogenesis, delay in cartilage mineralization, and a decrease in osteoprogenitor frequency. Environ Health Perspect 113:749-755.

Koefoed, M., H. Ito, K. Gromov, D. G. Reynolds, H. A. Awad, P. T. Rubery, M. Ulrich-Vinther, K. Soballe, R. E. Guldberg, A. S. Lin, J. O’Keefe R, X. Zhang, and E. M. Schwarz. 2005. Biological Effects of rAAV-caAlk2 Coating on Structural Allograft healing. Mol Ther 12:212-218.

Ritchlin, C. T., S. A. Haas-Smith, P. Li, D. G. Hicks, and E. M. Schwarz. 2003. Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J Clin Invest 111:821-831.

Zhang, X., E. M. Schwarz, D. A. Young, J. E. Puzas, R. N. Rosier, and R. J. O’Keefe. 2002. Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. J Clin Invest 109:1405-1415.

Zuscik, M. J., D. B. Pateder, J. E. Puzas, E. M. Schwarz, R. N. Rosier, and R. J. O’Keefe. 2002. Lead alters parathyroid hormone-related peptide and transforming growth factor-beta1 effects and AP-1 and NF-kappaB signaling in chondrocytes. J Orthop Res 20:811-818.