Combinatorial signaling pathways determine fibroblast proliferation and myofibroblast differentiation.
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-beta by fibroblasts are regulated via a CTGF-dependent pathway in concert with either EGF or IGF-2. Our studies indicate these responses to TGF-beta are mutually exclusive, and cells that are proliferating do not express alpha-SMA or elevated levels of collagen synthesis. Cells expressing alpha-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-beta/CTGF pathway, but also signaling events induced by EGF and IGF-2-activated receptors. Collectively, our studies indicate TGF-beta 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
Gary R
GR
Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, Florida 33136, USA. ggrotend@miami.edu
Rahmanie
Hamed
H
Duncan
Matthew R
MR
D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line / Q000166:cytology / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D055513:Connective Tissue Growth Factor; D004261:DNA Replication / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000494:pharmacology / Q000502:physiology*; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology / Q000502:physiology*; D007668:Kidney; D032446:Myoblasts / Q000166:cytology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D014945:Wound Healing / Q000502:physiology*
D000199:Actins; C526317:CCN2 protein, human; C526316:CCN2 protein, rat; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D004815:Epidermal Growth Factor; D007335:Insulin-Like Growth Factor II; D003094:Collagen