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Endocrinology Vol. 141, No. 12 4728-4735
Copyright © 2000 by The Endocrine Society

ARTICLES

Smad2 and 3 Mediate Transforming Growth Factor-ß1-Induced Inhibition of Chondrocyte Maturation1

Cristin M. Ferguson, Edward M. Schwarz, Paul R. Reynolds, J. Edward Puzas, Randy N. Rosier and Regis J. O’Keefe

Department of Orthopaedics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Address all correspondence and requests for reprints to: Regis J. O’Keefe, M.D., Box 665, Department of Orthopaedics, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642. E-mail: regis_okeefe{at}urmc.rochester.edu

Transforming growth factor-ß (TGF-ß) is a multifunctional regulator of a variety of cellular functions, including proliferation, differentiation, matrix synthesis, and apoptosis. In growth plate chondrocytes, TGF-ß slows the rate of maturation. Because the current paradigm of TGF-ß signaling involves Smad proteins as downstream regulators of target genes, we have characterized their role as mediators of TGF-ß effects on chondrocyte maturation. Both Smad2 and 3 translocated to the nucleus upon TGF-ß1 signaling, but not upon BMP-2 signaling. Cotransfection experiments using the TGF-ß responsive and Smad3 sensitive p3TP-Lux luciferase reporter demonstrated that wild-type Smad3 potentiated, whereas dominant negative Smad3 inhibited TGF-ß1 induced luciferase activity. To confirm the role of Smad2 and 3 as essential mediators of TGF-ß1 effects on chondrocyte maturation, we overexpressed both wild-type and dominant negative Smad2 and 3 in virally infected chondrocyte cultures. Overexpression of both wild-type Smad2 and 3 potentiated the inhibitory effect of TGF-ß on chondrocyte maturation, as determined by colx and alkaline phosphatase activity, whereas dominant negative Smad2 and 3 blocked these effects. Wild-type and dominant negative forms of Smad3 had more pronounced effects than Smad2. Our results define Smad2 and 3 as key mediators of the inhibitory effect of TGF-ß1 signaling on chondrocyte maturation.




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