[Frontiers in Bioscience S4, 251-268, January 1, 2012]

TGF-b signaling in cartilage homeostasis and osteoarthritis

Kenneth W Finnson1, Yoon Chi1, George Bou-Gharios3 Andrew Leask2, Anie Philip1

1Division of Plastic Surgery, Department of Surgery, Montreal General Hospital, McGill University, Montreal, QC, H3G 1A4 Canada, 2Division of Oral Biology, Department of Dentistry, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Building, London ON N6A 5C1 Canada, 3Kennedy Institute of Rheumatology, Imperial College London, London, W6 8LH, UK

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Overview of TGF-b signaling
3.1. TGF-b family
3.2. TGF-b synthesis and activation of latent TGF-b
3.3. TGF-b receptors and signaling pathways
3.4. Regulation of TGF-b signaling
3.4.1. Extracellular control
3.4.2. Intracellular control
4. TGF-b action in cartilage
5. Deregulation of TGF-b signaling in osteoarthritis
5.1. TGF-b isoform expression
5.2. TGF-b activation
5.3. TGF-b receptor expression
5.4. Smad2/3 signaling
5.5. Smad1/5 signaling
5.6. Smad7/Smurf2 activity
5.7. Non-Smad pathways
5.8. TGF-b co-receptors
6. TGF-b signaling pathway as a therapeutic target for osteoarthritis
7. Concluding Remarks
8. References

1. ABSTRACT

Healthy cartilage is maintained by a delicate balance between the anabolic and catabolic activities of articular chondrocytes. This involves actions of numerous cytokines and growth factors that regulate the synthesis and degradation of extracellular matrix components which maintain the functional integrity of the joint. An imbalance between the activities of these anabolic and catabolic factors leads to cartilage degradation resulting in osteoarthritis (OA), a chronic degenerative joint disorder characterized by destruction of articular cartilage, alterations of subchondral bone and synovial fibrosis. Among the cytokines and growth factors that have been studied in the context of cartilage homeostasis and OA, transforming growth factor-beta-b (TGF-b) has emerged as an important molecule that plays a critical role in the development, growth, maintenance and repair of articular cartilage. Deregulation of its signaling and responses has been shown to be involved in OA. Several components of the TGF-b pathway, including extracellular, cell surface and intracellular molecules, display altered expression or action in OA. In this review, we discuss the regulatory mechanisms of TGF-b signaling and link these mechanisms to cartilage function, highlighting the important role of TGF-b in maintaining cartilage function and integrity. We also summarize the alterations in the molecular events of TGF-b signaling and responses that may contribute to OA progression and discuss the potential of targeting the TGF-b signaling pathway for the development of novel therapies for OA.