Noncanonical transforming growth factor beta signaling in scleroderma fibrosis.
OBJECTIVE
Persistent transforming growth factor beta (TGF-beta) signaling is the major factor contributing to scleroderma (SSc) fibrosis. This review will summarize recent progress on the noncanonical TGF-beta signaling pathways and their role in SSc fibrosis.


RESULTS
Canonical TGF-beta signaling involves activation of the TGF-beta receptors and downstream signal transducers Smad2/3. The term noncanonical TGF-beta signaling includes a variety of intracellular signaling pathways activated by TGF-beta independently of Smad2/3 activation. There is evidence that these pathways play important role in SSc fibrosis. In a subset of SSc fibroblasts, a multiligand receptor complex consisting of TGF-beta and CCN2 receptors drives constitutive activation of the Smad1 pathway. CCN2 is also a primary effector of this pathway, thus establishing an autocrine loop that amplifies TGF-beta signaling. SSc fibroblasts also demonstrate reduced expression of endogenous antagonists of TGF-beta signaling including transcriptional repressors, Friend leukemia integration-1 and perixosome proliferator-activated receptor-gamma, as well as inhibitor of Smad3 phosphorylation, PTEN. PTEN is a key mediator of the cross-talk between the sphingosine kinase and the TGF-beta pathways.


CONCLUSIONS
Discovery of the role of noncanonical TGF-beta signaling in fibrosis offers new molecular targets for the antifibrotic therapies. Due to the heterogeneous nature of SSc, knowledge of these pathways could help to tailor the therapy to the individual patient depending on the activation status of a specific profibrotic pathway.
Trojanowska
Maria
M
Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina 29425, USA. trojanme@musc.edu
D000818:Animals; D019898:Autocrine Communication; D003094:Collagen / Q000235:genetics; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D008954:Models, Biological; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000099157:Sphingosine Kinase
D003094:Collagen; D055513:Connective Tissue Growth Factor; D051059:PTEN Phosphohydrolase; D017853:Phosphotransferases (Alcohol Group Acceptor); D051898:Smad1 Protein; D016212:Transforming Growth Factor beta; D000099157:Sphingosine Kinase; C526317:CCN2 protein, human; C497399:SMAD1 protein, human; C494929:PTEN protein, human