期刊
JOURNAL OF CELL BIOLOGY
卷 179, 期 6, 页码 1311-1323出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200704042
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- NCI NIH HHS [R01 CA034282, CA34282] Funding Source: Medline
- NIAMS NIH HHS [AR49698, P01 AR049698] Funding Source: Medline
The conjunctive presence of mechanical stress and active transforming growth factor beta 1 (TGF-beta 1) is essential to convert fibroblasts into contractile myofibroblasts, which cause tissue contractures in fibrotic diseases. Using cultured myofibroblasts and conditions that permit tension modulation on the extracellular matrix (ECM), we establish that myofibroblast contraction functions as a mechanism to directly activate TGF-beta 1 from self-generated stores in the ECM. Contraction of myofi broblasts and myofibroblast cytoskeletons prepared with Triton X-100 releases active TGF-beta 1 from the ECM. This process is inhibited either by antagonizing integrins or reducing ECM compliance and is independent from protease activity. Stretching myofibroblast-derived ECM in the presence of mechanically apposing stress fibers immediately activates latent TGF-beta 1. In myofibroblast-populated wounds, activation of the downstream targets of TGF-beta 1 signaling Smad2/3 is higher in stressed compared to relaxed tissues despite similar levels of total TGF-beta 1 and its receptor. We propose activation of TGF-beta 1 via integrin-mediated myofibroblast contraction as a potential checkpoint in the progression of fibrosis, restricting autocrine generation of myofibroblasts to a stiffened ECM.
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