|University of Rochester|
School of Medicine & Dentistry
|Molecular Toxicology & Environmental Medicine Cluster|
|Ph.D. Program in Toxicology|
|Regis J. OKeefe|
Professor of Orthopaedics
B.A. 1981 (Yale University)
M.D. 1985 (Harvard Medical School)
Ph.D. 2000 (University of Rochester)
Molecular Mechanisms of Lead in Chondrocyte Differentiation and Skeletal Development.
Our research is part of a comprehensive cartilage cell and molecular biology program designed to identify the intracellular signals and pathways important in chondrocyte differentiation. Lead is one of the most important environmental toxicants and we have found that this ion has specific effects on important intracellular signaling pathways in chondrocytes. The work is conducted in the Center for Musculoskeletal Research, which is one of the six Aab Institutes for Biological Sciences, areas of special research focus at this university.
Long bone growth depends on an ordered sequence of maturational changes by growth plate chondrocytes. The changes include large increases in cellular volume, alkaline phosphatase activity, and alterations in matrix synthesis. The differentiation process is regulated by a complex interaction between several important local growth factors, including PTHrP, bone morphogenetic protein-6, and indian hedge hog. Our laboratory studies the intracellular signaling pathways stimulated by these factors and how the cell integrates such signals into an expression of cellular phenotype and specific state of differentiation.
Using several exquisite in vitro and in vivo models of chondrocyte differentiation, we have found that ionic lead, at physiologically relevant concentrations, alters specific signaling pathways in chondrocytes. For example, while lead alone does not alter AP-1 mediated transcription, it enhances the stimulatory effect of PTHrP on AP-1 mediated transcription. In contrast, lead has a direct inhibitory effect on NFkB signaling, an effect that is not altered by PTHrP treatment.
These findings of altered intracellular signaling have general importance for our understanding of lead toxicity in all tissues, as well as specific importance in cartilage. Children poisoned with lead have decreased growth and altered morphology of the growth plate. Our studies are designed to determine the molecular events involved in lead toxicity in the hopes of finding potential therapeutic targets that might reduce lead toxicity. This will improve bone development and reparative bone formation in conditions such as skeletal trauma. It may also suggest important targets in other tissues affected by lead toxicity.
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, OKeefe 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, OKeefe 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, OKeefe 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]
Chen M, Zhu M, Awad H, Li TF, Sheu TJ, Boyce BF, Chen D, O'Keefe RJ. Inhibition of beta-catenin signaling causes defects in postnatal cartilage development. J Cell Sci. 2008 May 1;121(Pt 9):1455-1465.
Xie C, Xue M, Wang Q, Schwarz EM, OKeefe 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.
Zuscik MJ, Hilton MJ, Zhang X, Chen D, OKeefe RJ. Regulation of chondrogenesis and chondrocyte differentiation by stress. J Clin Invest. 2008 Feb;118(2):429-438. Review.
Zuscik MJ, Ma L, Buckley T, Puzas JE, Drissi H, Schwarz EM, OKeefe 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.
Wang Q, Wei X, Zhu T, Zhang M, Shen R, Xing L, OKeefe RJ, Chen D. 2007. Bone Morphogenetic Protein 2 Activates Smad6 Gene Transcription through Bone-specific Transcription Factor Runx2. J Biol Chem. Apr 6;282(14):10742-8.
Chen M, Lichtler AC, Sheu TJ, Xie C, Zhang X, O'Keefe RJ, Chen D. 2007. Generation of a transgenic mouse model with chondrocyte-specific and tamoxifen-inducible expression of Cre recombinase. Genesis. Jan;45(1):44-50.
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Revised July 18 2008 (vgl)