Syndecan-2 Is a Novel Target of Insulin-Like Growth Factor Binding Protein-3 and Is Over-Expressed in Fibrosis

Abstract

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.

Matrix Metalloproteinases as Therapeutic Targets for Idiopathic Pulmonary Fibrosis

“…IGFBP-3 has been strongly linked to the pathogenesis of IPF and other fibrosing conditions (58). TGF-β increases IGFBP-3 secretion by fibroblasts, and IGFBP-3 serves as a downstream modulator of TGF-β by inducing fibroblast production of syndecan-2 and regulating TGF-β induction of syndecan -in human fibroblasts (59). Syndecan-2 promotes cell signaling, proliferation, migration, and cytoskeletal organization, cell-matrix interactions and ECM assembly (60)(61)(62).…”

Up-Regulation of Heparan Sulfate 6-O-Sulfation in Idiopathic Pulmonary Fibrosis

“…In lung homogenates and in lavage fluid from patients with IPF, HSPG family members, such as syndecan-1 and syndecan-2, are up-regulated (16,17). TGF-b1 induces syndecan-2 expression in primary human lung fibroblasts (17).…”

“…In lung homogenates and in lavage fluid from patients with IPF, HSPG family members, such as syndecan-1 and syndecan-2, are up-regulated (16,17). TGF-b1 induces syndecan-2 expression in primary human lung fibroblasts (17). Syndecan-4 expression is up-regulated in bleomycin-induced lung injury, and syndecan-4 null mice exhibit a dysregulated inflammatory response, increased myofibroblast recruitment, and interstitial fibrosis after bleomycin administration (18).…”

Cellular interactions in the pathogenesis of interstitial lung diseases

“…IGFBP-3 independently induces syndecan-2 (SDC2) and regulates transforming growth factor (TGF)-β induction of SDC2 in primary human fibroblasts from IPF and SSc-PF patients [18].…”

“…in part by the expression of the scavenger receptor CD163, the IL-1RII decoy receptor and mannose receptors, and by increased IL-10, C-C chemokine ligand (CCL) 18 and pulmonary activation-regulated chemokine (PARC) production [87]. Different ILDs, including IPF and SSc-ILD, share the increased production of CCL18, a chemokine produced mainly by antigen-presenting cells that is chemotactic predominantly for T-lymphocytes, as a common mechanism, and CCL18 produced by alveolar macrophages promotes collagen production by lung fibroblasts [88].…”