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.
Highlights
The process of fibrosis is characterized by activation and proliferation of fibroblasts, and excessive deposition of extracellular matrix (ECM) that produces abnormal scarring of tissues leading to organ failure
Insulin like growth factor binding protein-3 (IGFBP-3) was silenced in primary lung fibroblasts using sequence-specific siRNA, cells were stimulated with Transforming growth factor beta (TGFb) to assess which genes require IGFBP-3 for induction by TGFb
Since both TGFb and IGFBP-3 are implicated in the development of fibrosis, and both of these factors induce expression of SDC2 mRNA (Figure 1A), we assessed SDC2 protein levels in primary lung fibroblasts stimulated with TGFb and in which IGFBP-3 expression and induction by TGFb were silenced
Summary
The process of fibrosis is characterized by activation and proliferation of fibroblasts, and excessive deposition of extracellular matrix (ECM) that produces abnormal scarring of tissues leading to organ failure. Transforming growth factor beta (TGFb) is one of the most studied pro-fibrotic factors. It has been implicated in the pathogenesis of liver, kidney, lung and skin fibrosis [1]. TGFb induces mesenchymal cell proliferation, increased ECM production and a fibrotic response in various tissues [2]. We and others have shown that TGFb induces Insulin like growth factor binding protein-3 (IGFBP-3) mRNA and protein expression [3], [4], [5], [6], [7], [8]. We demonstrated a time-dependent increase in IGFBP-3 secretion in response to TGFb stimulation of primary lung fibroblasts [8]. We have shown that IGFBP-3 contributes to ECM deposition in primary fibroblasts and increases dermal and collagen bundle thickness in a human ex vivo skin explant model [8], [12], [13]
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