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.

Recent Publications

Wang Q, Wei X, Zhu T, Zhang M, Shen R, Xing L, O’Keefe 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.

Schwarz EM, Looney RJ, Drissi MH, O'Keefe RJ, Boyce BF, Xing L, Ritchlin CT. 2006. Autoimmunity and bone. Ann N Y Acad Sci. Apr;1068:275-83.

Robertson G, Xie C, Chen D, Awad H, Schwarz EM, O’Keefe RJ, Guldberg RE, Zhang X. 2006. Alteration of femoral bone morphology and density in COX-2-/- mice. Bone. May 25;

Li TF, Chen D, Wu Q, Chen M, Sheu TJ, Schwarz EM, Drissi H, Zuscik M, O’Keefe RJ. 2006. TGF-beta stimulates cyclin D1 expression through activation of beta -catenin signaling in chondrocytes. J Biol Chem. 2006 May 10

Shen R, Wang X, Drissi H, Liu F, O’Keefe RJ, Chen D. 2006. Cyclin d1-cdk4 induce runx2 ubiquitination and degradation. J Biol Chem. Jun 16;281(24):16347-16353.

Maloney MD, Goater JJ, Parsons R, Ito H, O’Keefe RJ, Rubery PT, Drissi MH, Schwarz EM. 2006. Safety and efficacy of ultraviolet-a light-activated gene transduction for gene therapy of articular cartilage defects. J Bone Joint Surg Am. Apr;88(4):753-761.

Dong YF, Soung do Y, Schwarz EM, O’Keefe RJ, Drissi H. 2006. Wnt induction of chondrocyte hypertrophy through the Runx2 transcription factor. J Cell Physiol. Jul;208(1):77-86.

Nishio Y, Dong Y, Paris M, O’Keefe RJ, Schwarz EM, Drissi H. 2006. Runx2-mediated regulation of the zinc finger Osterix/Sp7 gene. Gene. May 10;372:62-70.

Li TF, Darowish M, Zuscik MJ, Chen D, Schwarz EM, Rosier RN, Drissi H, O’Keefe RJ. 2006. Smad3-deficient chondrocytes have enhanced BMP signaling and accelerated differentiation. J Bone Miner Res. Jan;21(1):4-16.

Looney RJ, Schwarz EM, Boyd A, O’Keefe RJ. 2006. Periprosthetic osteolysis: an immunologist's update. Curr Opin Rheumatol. Jan;18(1):80-87. Review.

Wang Y, Belflower RM, Dong YF, Schwarz EM, O’Keefe RJ, Drissi H. 2005. Runx1/AML1/Cbfa2 Mediates Onset of Mesenchymal Cell Differentiation Toward Chondrogenesis. J Bone Miner Res. 2005 Sep;20(9):1624-1636

Koefoed M, Ito H, Gromov K, Reynolds DG, Awad HA, Rubery PT, Ulrich-Vinther M, Soballe K, Guldberg RE, Lin AS, O’Keefe RJ, Zhang X, Schwarz EM. 2005. Biological effects of rAAV-caAlk2 coating on structural allograft healing. Mol Ther. Aug;12(2):212-218.

Dong Y, Drissi H, Chen M, Chen D, Zuscik MJ, Schwarz EM, O’Keefe RJ. 2005. Wnt-mediated regulation of chondrocyte maturation: modulation by TGF-beta. J Cell Biochem. Aug 1;95(5):1057-1068.

Soloviev A, Schwarz EM, Darowish M, O’Keefe RJ. 2005. Sphingomyelinase mediates macrophage activation by titanium particles independent of phagocytosis: A role for free radicals, NFkappaB, and TNFalpha. J Orthop Res. Jun 8; [Epub ahead of print]

Wei X, Zhang X, Zuscik MJ, Drissi MH, Schwarz EM, O'Keefe RJ. 2005. Fibroblasts express RANKL and support osteoclastogenesis in a COX-2-dependent manner after stimulation with titanium particles. J Bone Miner Res. Jul;20(7):1136-1148

Carmouche JJ, Puzas JE, Zhang X, Tiyapatanaputi P, Cory-Slechta DA, Gelein R, Zuscik M, Rosier RN, Boyce BF, O'Keefe RJ, Schwarz EM. Lead exposure inhibits fracture healing and is associated with increased chondrogenesis, delay in cartilage mineralization, and a decrease in osteoprogenitor frequency. Environ Health Perspect. Jun;113(6):749-755.

Gordon AH, O'Keefe RJ, Schwarz EM, Rosier RN, Puzas JE. 2005. Nuclear factor-kappaB-dependent mechanisms in breast cancer cells regulate tumor burden and osteolysis in bone. Cancer Res. 2005 Apr 15;65(8):3209-3217.

Li TF, Zuscik MJ, Ionescu AM, Zhang X, Rosier RN, Schwarz EM, Drissi H, and O’Keefe RJ. 2004. PGE2 inhibits chondrocyte differentiation through PKA and PKC signaling. Exp Cell Res. Oct 15;300(1):159-169

Ferguson CM, Schwarz EM, Puzas JE, Zuscik MJ, Drissi H, and O’Keefe RJ. 2004. Transforming growth factor-beta1 induced alteration of skeletal morphogenesis in vivo. J Orthop Res. Jul;22(4):687-696.

Zuscik MJ, Baden JF, Wu Q, Sheu TJ, Schwarz EM, Drissi H, O’Keefe RJ, Puzas JE, and Rosier RN. 2004. 5-azacytidine alters TGF-beta and BMP signaling and induces maturation in articular chondrocytes. J Cell Biochem. May 15;92(2):316-331.

Ionescu AM, Drissi H, Schwarz EM, Kato M, Puzas JE, McCance DJ, Rosier RN, Zuscik MJ, and O’Keefe RJ. 2004. CREB Cooperates with BMP-stimulated Smad signaling to enhance transcription of the Smad6 promoter. J Cell Physiol. Mar;198(3):428-440.