Subject(s)
Abdominal Pain/etiology , Amish , Hypercholesterolemia/complications , Intestinal Diseases/complications , Lipid Metabolism, Inborn Errors/complications , Phytosterols/adverse effects , Retroperitoneal Fibrosis/etiology , Xanthomatosis/etiology , Abdominal Pain/diagnosis , Abdominal Pain/drug therapy , Amish/genetics , Anticholesteremic Agents/therapeutic use , Azetidines/therapeutic use , Biopsy , Diagnosis, Differential , Ezetimibe , Female , Humans , Hypercholesterolemia/diagnosis , Hypercholesterolemia/drug therapy , Hypercholesterolemia/genetics , Intestinal Diseases/diagnosis , Intestinal Diseases/drug therapy , Intestinal Diseases/genetics , Lipid Metabolism, Inborn Errors/diagnosis , Lipid Metabolism, Inborn Errors/drug therapy , Lipid Metabolism, Inborn Errors/genetics , Phytosterols/genetics , Predictive Value of Tests , Retroperitoneal Fibrosis/diagnosis , Retroperitoneal Fibrosis/drug therapy , Retroperitoneal Space , Tomography, X-Ray Computed , Treatment Outcome , Xanthomatosis/diagnosis , Xanthomatosis/drug therapy , Young AdultABSTRACT
Extracellular matrix deposition and tissue scarring characterize the process of fibrosis. Transforming growth factor beta (TGFß) 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 TGFß in an IGFBP-3-dependent manner. TGFß 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, TGFß and IGFBP-3.
Subject(s)
Fibrosis/genetics , Fibrosis/metabolism , Gene Expression Regulation , Insulin-Like Growth Factor Binding Protein 3/metabolism , Syndecan-2/genetics , Cells, Cultured , Enzyme Activation , Gene Expression Regulation/drug effects , Gene Silencing , Humans , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Skin/metabolism , Skin/pathology , Syndecan-2/metabolism , Time Factors , Transforming Growth Factor beta1/pharmacologyABSTRACT
Familial Mediterranean fever (FMF) is the autoinflammatory disease and hereditary periodic fever syndrome that most commonly affects people of Eastern Mediterranean origin. It is characterized by recurrent self-limited attacks of fever and serositis, with an increase in acute-phase reactant markers, and is transmitted in an autosomal recessive pattern. Inflammation shifts the hemostatic mechanisms favoring thrombosis. There are few reports of an increased risk of hypercoagulability in patients with FMF in the absence of amyloidosis and nephrotic syndrome. In this case report, we describe a 43-year-old Turkish patient who presented with right-sided pleuritic chest pain and pulmonary embolism. The patient described having prior similar attacks of serositis, but had never been diagnosed with FMF. Further workup revealed an increase in acute phase reactants, negative hypercoagulability studies and heterozygosity for the M694V mutation in the pyrin (MEFV) gene. We identified untreated FMF and chronic inflammation as his only risk factor for pulmonary embolism. With this case report, we support recent studies that have demonstrated that inflammation may lead to prothrombotic states in patients with FMF.
Subject(s)
Familial Mediterranean Fever/complications , Pulmonary Embolism/diagnosis , Pulmonary Embolism/etiology , Acetaminophen/therapeutic use , Adult , Analgesics, Non-Narcotic/therapeutic use , Anticoagulants/therapeutic use , Chest Pain/drug therapy , Chest Pain/etiology , Colchicine/therapeutic use , Diagnosis, Differential , Familial Mediterranean Fever/diagnosis , Familial Mediterranean Fever/drug therapy , Follow-Up Studies , Heparin/therapeutic use , Humans , Male , Pulmonary Embolism/drug therapy , Serositis/diagnosis , Serositis/drug therapy , Serositis/etiology , Tubulin Modulators/therapeutic use , Turkey , Warfarin/therapeutic useABSTRACT
We have previously shown that insulin-like growth factor (IGF) binding protein- 5 (IGFBP-5) is overexpressed in lung fibrosis and induces the production of extracellular matrix components, such as collagen and fibronectin, both in vitro and in vivo. The exact mechanism by which IGFBP-5 exerts these novel fibrotic effects is unknown. We thus examined the signaling cascades that mediate IGFBP-5-induced fibrosis. We demonstrate for the first time that IGFBP-5 induction of extracellular matrix occurs independently of IGF-I, and results from IGFBP-5 activation of MAPK signaling, which facilitates the translocation of IGFBP-5 to the nucleus. We examined the effects of IGFBP-5 on early growth response (Egr)-1, a transcription factor that is central to growth factor-mediated fibrosis. Egr-1 was up-regulated by IGFBP-5 in a MAPK-dependent manner and bound to nuclear IGFBP-5. In fibroblasts from Egr-1 knockout mice, induction of fibronectin by IGFBP-5 was abolished. Expression of Egr-1 in these cells rescued the extracellular matrix-promoting effects of IGFBP-5. Moreover, IGFBP-5 induced cell migration in an Egr-1-dependent manner. Notably, Egr-1 levels, similar to IGFBP-5, were increased in vivo in lung tissues and in vitro in primary fibroblasts of patients with pulmonary idiopathic fibrosis. Taken together, our findings suggest that IGFBP-5 induces a fibrotic phenotype via the activation of MAPK signaling and the induction of nuclear Egr-1 that interacts with IGFBP-5 and promotes fibrotic gene transcription.
