Syndecan-2 is a novel target of insulin-like growth factor binding protein-3 and is over-expressed in fibrosis

• Published in: PloS one 2012-08, Vol.7 (8), p.e43049
• Main Authors: Ruiz, Ximena D, Mlakar, Logan R, Yamaguchi, Yukie, Su, Yunyun, Larregina, Adriana T, Pilewski, Joseph M, Feghali-Bostwick, Carol A
• Format: Article
• Language: English
• Subjects: Analysis; Biology; Cell adhesion & migration; Cell culture; Cell growth; Cell proliferation; Cells, Cultured; Critical care; Deposition; Enzyme Activation; Extracellular matrix; Fibroblasts; Fibrosis; Fibrosis - genetics; Fibrosis - metabolism; Gene expression; Gene Expression Regulation - drug effects; Gene Silencing; Genes; Heparan sulfate; Humans; Insulin; Insulin-Like Growth Factor Binding Protein 3 - metabolism; Insulin-like growth factor-binding protein 3; Insulin-like growth factors; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Lung diseases; Lungs; MAP kinase; Medical research; Medicine; Mesenchyme; mRNA; Organ culture; Pathogenesis; Patients; Phosphorylation; Protein binding; Protein kinase; Protein kinases; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins; Pulmonary fibrosis; Respiratory tract diseases; RNA; Scars; Scleroderma; Scleroderma (Disease); Skin; Skin - metabolism; Skin - pathology; Syndecan; Syndecan-2 - genetics; Syndecan-2 - metabolism; Systemic sclerosis; Time Factors; Tissues; Transforming Growth Factor beta1 - pharmacology; Transforming growth factor-b; Transforming growth factors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0043049

Extracellular matrix deposition and tissue scarring characterize the process of fibrosis. Transforming growth factor beta (TGFβ) and Insulin-like growth factor binding protein-3 (IGFBP-3) have been implicated in the pathogenesis of fibrosis in various tissues by inducing mesenchymal cell proliferation and extracellular matrix deposition. We identified Syndecan-2 (SDC2) as a gene induced by TGFβ in an IGFBP-3-dependent manner. TGFβ induction of SDC2 mRNA and protein required IGFBP-3. IGFBP-3 independently induced production of SDC2 in primary fibroblasts. Using an ex-vivo model of human skin in organ culture expressing IGFBP-3, we demonstrate that IGFBP-3 induces SDC2 ex vivo in human tissue. We also identified Mitogen-activated protein kinase-interacting kinase (Mknk2) as a gene induced by IGFBP-3. IGFBP-3 triggered Mknk2 phosphorylation resulting in its activation. Mknk2 independently induced SDC2 in human skin. Since IGFBP-3 is over-expressed in fibrotic tissues, we examined SDC2 levels in skin and lung tissues of patients with systemic sclerosis (SSc) and lung tissues of patients with idiopathic pulmonary fibrosis (IPF). SDC2 levels were increased in fibrotic dermal and lung tissues of patients with SSc and in lung tissues of patients with IPF. This is the first report describing elevated levels of SDC2 in fibrosis. Increased SDC2 expression is due, at least in part, to the activity of two pro-fibrotic factors, TGFβ and IGFBP-3.