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Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, Florida, USA
1Correspondence: Department of Cell Biology and Anatomy, RMSB 2030 A, University of Miami School of Medicine, 1600 NW 10th Ave., Miami, FL 33136, USA. E-mail: ggrotend{at}miami.edu
Fibroblast proliferation, differentiation into myofibroblasts, and increased collagen synthesis are key events during both normal wound repair and fibrotic lesion formation. Here we report that these biological responses to TGF-ß by fibroblasts are regulated via a CTGF-dependent pathway in concert with either EGF or IGF-2. Our studies indicate these responses to TGF-ß are mutually exclusive, and cells that are proliferating do not express 
-SMA or elevated levels of collagen synthesis. Cells expressing -SMA do not exhibit DNA synthesis but do coexpress higher levels of types I and III collagen mRNA. Thus, fibroblast proliferation and differentiation are controlled by combinatorial signaling pathways involving not only components of the TGF-ß/CTGF pathway, but also signaling events induced by EGF and IGF-2-activated receptors. Collectively, our studies indicate TGF-ß functions as a classic embryonic inducer, initiating a cascade that is controlled by other factors in the cellular environment. We propose a model for this process with regard to wound repair and fibrotic lesion formation that is likely applicable to other instances of CTGF action during embryogenesis.—Grotendorst, G. R., Rahmanie, H., Duncan, M. R. Combinatorial signaling pathways determine fibroblast proliferation and myofibroblast differentiation.
Key Words: myofibroblasts • TGF-ß • CTGF • fibrotic tissue
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