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

Proulx ST, Kwok E, You Z, Papuga MO, Beck CA, Shealy DJ, Calvi LM, Ritchlin CT, Awad HA, Boyce BF, Xing L, Schwarz EM. Elucidating bone marrow edema and myelopoiesis in murine arthritis using contrast-enhanced magnetic resonance imaging. Arthritis Rheum. 2008 Jul;58(7):2019-2029.

Zhu M, Chen M, Zuscik M, Wu Q, Wang YJ, Rosier RN, O'Keefe RJ, Chen D. Inhibition of beta-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum. 2008 Jul;58(7):2053-2064.

Zhang X, Awad HA, O’Keefe RJ, Guldberg RE, Schwarz EM. A perspective: engineering periosteum for structural bone graft healing. Clin Orthop Relat Res. 2008 Aug;466(8):1777-1787.

Kaback LA, Soung DY, Naik A, Geneau G, Schwarz EM, Rosier RN, O’Keefe RJ, Drissi H. Teriparatide (1-34 human PTH) regulation of osterix during fracture repair. J Cell Biochem. 2008 May 20. [Epub ahead of print]

Tsutsumi R, Hock C, Bechtold CD, Proulx ST, Bukata SV, Ito H, A Awad H, Nakamura T, O’Keefe RJ, Schwarz EM. Differential effects of biologic versus bisphosphonate inhibition of wear debris-induced osteolysis assessed by longitudinal micro-CT. J Orthop Res. 2008 Apr 10. [Epub ahead of print]

Xie C, Xue M, Wang Q, Schwarz EM, O’Keefe RJ, Zhang X. Tamoxifen-inducible CreER-mediated gene targeting in periosteum via bone-graft transplantation. J Bone Joint Surg Am. 2008 Feb;90 Suppl 1:9-13.

Zhang Q, Guo R, Schwarz EM, Boyce BF, Xing L. TNF inhibits production of stromal cell-derived factor 1 by bone stromal cells and increases osteoclast precursor mobilization from bone marrow to peripheral blood. Arthritis Res Ther. 2008;10(2):R37. Epub 2008 Mar 27.

Yao Z, Xing L, Qin C, Schwarz EM, Boyce BF. Osteoclast precursor interaction with bone matrix induces osteoclast formation directly by an interleukin-1-mediated autocrine mechanism. J Biol Chem. 2008 Apr 11;283(15):9917-9924.

Zuscik MJ, Ma L, Buckley T, Puzas JE, Drissi H, Schwarz EM, O’Keefe RJ. Lead induces chondrogenesis and alters transforming growth factor-beta and bone morphogenetic protein signaling in mesenchymal cell populations. Environ Health Perspect. 2007 Sep;115(9):1276-1282.

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.

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.