Smad2 and 3 mediate transforming growth factor-β1-induced inhibition of chondrocyte maturation

被引：44

作者：

Ferguson, CM ^{[1
]}

Schwarz, EM ^{[1
]}

Reynolds, PR ^{[1
]}

Puzas, JE ^{[1
]}

Rosier, RN ^{[1
]}

O'Keefe, RJ ^{[1
]}

机构：

[1] Univ Rochester, Sch Med & Dent, Dept Orthopaed, Rochester, NY 14642 USA

来源：

ENDOCRINOLOGY | 2000年 / 141卷 / 12期

关键词：

D O I：

10.1210/endo.141.12.7848

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Transforming growth factor-beta (TGF-beta) is a multifunctional regulator of a variety of cellular functions, including proliferation, differentiation, matrix synthesis, and apoptosis. In growth plate chondrocytes, TGF-beta slows the rate of maturation. Because the current paradigm of TGF-beta signaling involves Smad proteins as downstream regulators of target genes, we have characterized their role as mediators of TGF-beta effects on chondrocyte maturation. Both Smad2 and 3 translocated to the nucleus upon TGF-beta1 signaling, but not upon BMP-2 signaling. Cotransfection experiments using the TGF-beta responsive and Smad3 sensitive p3TP-Lux luciferase reporter demonstrated that wild-type Smad3 potentiated, whereas dominant negative Smad3 inhibited TGF-beta1 induced luciferase activity. To confirm the role of Smad2 and 3 as essential mediators of TGF-beta1 effects on chondrocyte maturation, we overexpressed both wild-type and dominant negative Smad2 and 3 in virally infected chondrocyte cultures. Overexpression of both wildtype Smad2 and 3 potentiated the inhibitory effect of TGF-beta 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 farms of Smad3 had more pronounced effects than Smad2. Our results define Smad2 and 3 as key mediators of the inhibitory effect of TGF-beta1 signaling on chondrocyte maturation.

引用

页码：4728 / 4735

页数：8

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