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J. Biol. Chem., Vol. 278, Issue 42, 41227-41236, October 17, 2003

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Transforming Growth Factor--mediated Chondrogenesis of Human Mesenchymal Progenitor Cells Involves N-cadherin and Mitogen-activated Protein Kinase and Wnt Signaling Cross-talk^*

Richard Tuli   ¶, Suraj Tuli , Sumon Nandi , Xiaoxue Huang , Paul A. Manner  ||, William J. Hozack , Keith G. Danielson , David J. Hall  and Rocky S. Tuan   || **

From the Cartilage Biology and Orthopaedics Branch, NIAMS, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, the Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and the ^||Department of Orthopaedic Surgery, George Washington University, Washington, D. C. 20037

The multilineage differentiation potential of adult tissue-derived mesenchymal progenitor cells (MPCs), such as those from bone marrow and trabecular bone, makes them a useful model to investigate mechanisms regulating tissue development and regeneration, such as cartilage. Treatment with transforming growth factor- (TGF-) superfamily members is a key requirement for the in vitro chondrogenic differentiation of MPCs. Intracellular signaling cascades, particularly those involving the mitogen-activated protein (MAP) kinases, p38, ERK-1, and JNK, have been shown to be activated by TGF-s in promoting cartilage-specific gene expression. MPC chondrogenesis in vitro also requires high cell seeding density, reminiscent of the cellular condensation requirements for embryonic mesenchymal chondrogenesis, suggesting common chondro-regulatory mechanisms. Prompted by recent findings of the crucial role of the cell adhesion protein, N-cadherin, and Wnt signaling in condensation and chondrogenesis, we have examined here their involvement, as well as MAP kinase signaling, in TGF-1-induced chondrogenesis of trabecular bone-derived MPCs. Our results showed that TGF-1 treatment initiates and maintains chondrogenesis of MPCs through the differential chondro-stimulatory activities of p38, ERK-1, and to a lesser extent, JNK. This regulation of MPC chondrogenic differentiation by the MAP kinases involves the modulation of N-cadherin expression levels, thereby likely controlling condensation-like cell-cell interaction and progression to chondrogenic differentiation, by the sequential up-regulation and progressive down-regulation of N-cadherin. TGF-1-mediated MAP kinase activation also controls WNT-7A gene expression and Wnt-mediated signaling through the intracellular -catenin-TCF pathway, which likely regulates N-cadherin expression and subsequent N-cadherin-mediated cell-adhesion complexes during the early steps of MPC chondrogenesis.

Received for publication, May 20, 2003 , and in revised form, July 30, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported in part by a Percival E. and Ethel Brown Foerderer Foundation fellowship from Thomas Jefferson University.

^** To whom correspondence should be addressed: Cartilage Biology and Orthopaedics Branch, NIAMS, National Institutes of Health, Bldg. 50, Rm. 1503, 50 South Dr., MSC 8022, Bethesda, MD 20892-8022. Tel.: 301-451-6854; Fax: 301-435-8017; E-mail: Tuanr{at}mail.nih.gov.

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