[Frontiers in Bioscience 7, d1231-1246, May 1, 2002]

HOMEOSTASIS OF EXTRACELLULAR MATRIX BY TGF-BETA AND LEFTY

Siamak Tabibzadeh

Dept of OB/GYN and Fetomaternal Medicine, Stony Brook University, Stony Brook, NY 11794

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. TGF-beta superfamily
4. Role of TGF-beta in homeostasis of ECM
5. TGF-beta as a prime mediator of fibrosis
5.1. Bleomycin induced lung fibrosis
5.2. Carbon tetrachloride induced liver fibrosis
6. Role of TGF-beta in tumor progression
7. Role of CTGF in homeostasis of ECM
8. TGF-beta signaling
9. Regulation of TGF-beta actions
10. Lefty is an inhibitor of TGF-beta signaling
11. Lefty inhibits deposition of collagen in vivo
11.1. Lefty inhibits collagen and CTGF mRNA expression in vivo
11.2. Lefty induces collagenolytic and elastolytic activities in vivo
12. Lefty is over-expressed in human cancers
13. Potential treatment strategies
14. Conclusions
15. References

1. ABSTRACT

Both normal and neoplastic tissues have a stroma comprised of fibroblasts which deposit an extracellular matrix (ECM) enriched in collagen. In most normal tissues, the synthesis and breakdown of the ECM is maintained at a low level. However, in normal adult tissues such as endometrium, and in rapidly growing embryonic and neoplastic tissues, there is a significant increase in the synthesis and/or breakdown of ECM. The homeostasis of the ECM is maintained by a molecular repertoire which appears to consist of TGF-beta and lefty. TGF-beta acts as a pro-fibrogenic cytokine by increasing the synthesis of collagen and decreasing the degradation of ECM. Physiologic levels of TGF-beta maintains tissue homeostasis and aberrant over-expression of TGF-beta leads to tissue fibrosis. TGF-beta acts through a core Smad signaling pathway which is initiated by the binding of homo-dimeric TGF-beta protein to two type I and II receptors. The constitutively active receptor type II leads to phosphorylation of receptor type I which, in turn, causes the R-Smads to get phosphorylated. The downstream gene transcriptional activity of this event includes significant increase in connective tissue growth factor (CTGF) and collagen mRNA synthesis which leads to deposition of collagen in tissues. Lefty inhibits Smad2 phosphorylation initiated by TGF-beta or its receptor and prevents CTGF promoter activity driven by TGF-beta. Moreover, lefty inhibits CTGF and collagen mRNA synthesis and increases collagenolysis and elastolysis and as a result of these actions, lefty significantly reduces the amount of collagen deposited in tissues. Thus, TGF-beta and lefty might coordinately participate in the homeostasis of ECM in tissues.