[Frontiers in Bioscience 10, 681-688, January 1, 2005]


Tian-Fang Li, Regis J. O'Keefe, and Di Chen

Center for Musculoskeletal Research, Department of Orthopaedics, University of Rochester School of Medicine, Rochester, NY 14642


1. Abstract
2. Introduction
3. Regulation of TGF-β Signaling
4. Smad-Dependent and -Independent Pathways
5. TGF-β and Other Signaling Cascades
6. Endochondral Bone Formation
7. Expression of TGF-β and Related Molecules in Chondrocytes
8. Function of TGF-β in Chondrocytes
9. Animal Models to Investigate the Roles of TGF-β in Chondrocytes
10. TGF-β and Runx2
11. TGF-β and Wnt Signaling
12. Acknowledgements
13. References


Transforming growth factor-beta (TGF-β) regulates a large variety of cellular activities. Binding of TGF-β to its cell surface receptor triggers several signaling cascades, among which the TGF-β-Smad pathway is the most extensively studied. TGF-β also activates protein kinases, including MAPK, PKA and PKC, and modulates gene expression via its delicate interaction with other signaling pathways. During endochondral bone formation, TGF-β acts as a potent inhibitor of the terminal differentiation of epiphyseal growth plate chondrocytes. This effect appears to be primarily mediated by Smad molecules, although MAPK-ATF2 signaling is also involved. The rate of chondrocyte maturation is tightly regulated through the interactions of Smad-mediated signaling, the Wnt signaling pathway, and the transcription factor Runx2. Improving our understanding of the exact mechanisms underlying TGF-β-mediated signaling pathways and their effects may greatly impact the diagnosis and treatment of many common orthopaedic diseases.