Fibulin-1c regulates transforming growth factor-β activation in pulmonary tissue fibrosis.

Tissue remodeling/fibrosis is a major feature of all fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). It is underpinned by accumulating extracellular matrix (ECM) proteins. Fibulin-1c (Fbln1c) is a matricellular ECM protein associated with lung fibrosis in both humans and mice and stabilizes collagen formation. Here we discovered that Fbln1c was increased in the lung tissues of patients with IPF and experimental bleomycin-induced pulmonary fibrosis. Fbln1c-deficient (Fbln1c(-/-)) mice had reduced pulmonary remodeling/fibrosis and improved lung function after bleomycin challenge. FbInic interacted with fibronectin, periostin, and tenascin-C in collagen deposits following bleomycin challenge. In a potentially novel mechanism of fibrosis, FbInic bound to latent TGF-beta-binding protein 1(LTBP1) to induce TGF-beta activation and mediated downstream Smad3 phosphorylation/signaling. This process increased myofibroblast numbers and collagen deposition. Fbln1c and LTBP1 colocalized in lung tissues from patients with IPF. Thus, Fbln1c may be a novel driver of TGF-beta-induced fibrosis involving LTBP1 and may be an upstream therapeutic target.