Rheumatology Commons^™

Decreased Expression Of Caveolin 1 In Patients With Systemic Sclerosis: Crucial Role In The Pathogenesis Of Tissue Fibrosis., Francesco Del Galdo, Federica Sotgia, Cecilia J. De Almeida, Jean-Francois Jasmin, Megan Musick, Michael P. Lisanti, Sergio A. Jimenez

Department of Medicine Faculty Papers

OBJECTIVE: Recent studies have implicated caveolin 1 in the regulation of transforming growth factor beta (TGFbeta) downstream signaling. Given the crucial role of TGFbeta in the pathogenesis of systemic sclerosis (SSc), we sought to determine whether caveolin 1 is also involved in the pathogenesis of tissue fibrosis in SSc. We analyzed the expression of CAV1 in affected SSc tissues, studied the effects of lack of expression of CAV1 in vitro and in vivo, and analyzed the effects of restoration of caveolin 1 function on the fibrotic phenotype of SSc fibroblasts in vitro.

METHODS: CAV1 expression in tissues was analyzed by …

Statins And The Vasculopathy Of Systemic Sclerosis: Potential Therapeutic Agents?, Chris T. Derk, Sergio A. Jimenez

Department of Medicine Faculty Papers

It has been postulated that endothelial cell injury is the initiating event in the pathogenesis of systemic sclerosis, causing attraction, attachment, migration and infiltration of activated T-cells and subsequent production of cytokines and growth factors. As a result of the action of these cytokines and growth factors, chemoattraction of fibroblasts into the vessel wall and transdifferentiation of resident fibroblasts and smooth muscle cells into myofibroblasts occur leading to fibrosis and exaggerated collagen deposition in the vessel wall. To date, the therapeutic options for the vasculopathy of systemic sclerosis have been limited to drugs that cause vasodilation and inhibit platelet aggregation …

Transcriptional Inhibition Of Type I Collagen Gene Expression In Scleroderma Fibroblasts By The Antineoplastic Drug Ecteinascidin 743., Natalia Louneva, Biagio Saitta, David J Herrick, Sergio A. Jimenez

Department of Medicine Faculty Papers

We previously showed that COL1A1 expression is up-regulated at the transcriptional level in systemic sclerosis (SSc) fibroblasts and that the CCAAT-binding factor (CBF) is involved in this increased expression. Ecteinascidin 743 (ET-743) is a chemotherapeutic agent that binds with sequence specificity to the minor groove of DNA and inhibits CBF-mediated transcriptional activation of numerous genes. Therefore, we examined the effects of ET-743 on the increased COL1A1 expression in SSc fibroblasts. The drug caused a potent and dose-dependent inhibition of type I collagen biosynthesis, which reached 70-90% at 700 pM without affecting cell viability. The same drug concentration caused 60-80% reduction …

Detection And Characterization Of Sp1 Binding Activity In Human Chondrocytes And Its Alterations During Chondrocyte Dedifferentiation., Rita M. Dharmavaram, Gang Liu, Sheryl D. Mowers, Sergio A. Jimenez

Department of Medicine Faculty Papers

We have detected DNA binding activity for a synthetic oligonucleotide containing an Sp1 consensus sequence in nuclear extracts from human chondrocytes. Changes in the levels of Sp1 oligonucleotide binding activity were examined in nuclear extracts from freshly isolated human chondrocytes, from chondrocytes that had been cultured under conditions that allowed the maintenance of a chondrocyte-specific phenotype on plastic dishes coated with the hydrogel poly(2-hydroxyethyl methacrylate), and from chondrocytes induced to dedifferentiate into fibroblast-like cells by passage in monolayer culture on plastic substrata. It was observed that Sp1 binding was 2-3-fold greater in nuclear extracts from dedifferentiated chondrocytes than in nuclear …

Increased Alpha 1(I) Procollagen Gene Expression In Tight Skin (Tsk) Mice Myocardial Fibroblasts Is Due To A Reduced Interaction Of A Negative Regulatory Sequence With Ap-1 Transcription Factor., Neena Philips, Reza I. Bashey, Sergio A. Jimenez

Department of Medicine Faculty Papers

The TSK mouse, a model of fibrosis, displays exaggerated connective tissue accumulation in skin and visceral organs including the heart. To study the mechanisms of myocardial fibrosis in TSK mice, we established several strains of TSK mice myocardial fibroblasts in culture and examined the regulation of collagen gene expression in these cells. These strains displayed increased collagen gene expression in comparison with myocardial fibroblasts established from normal mice. On an average, the TSK myocardial fibroblast cultures showed a 4-fold increase in collagen synthesis and 4.4- and 3.6-fold increases, respectively, in alpha 1(I) and alpha 1(III) collagen mRNA steady state levels. …

Regulation Of Human Lung Fibroblast Alpha 1(I) Procollagen Gene Expression By Tumor Necrosis Factor Alpha, Interleukin-1 Beta, And Prostaglandin E2., Arturo Diaz, Elena Munoz, Rosemary Johnston, Joseph H. Korn, Sergio A. Jimenez

Department of Medicine Faculty Papers

We investigated the participation of prostaglandin (PG) E2 in the regulation of the alpha 1(I) procollagen gene expression by tumor necrosis factor alpha (TNF alpha), and interleukin-1 beta (IL-1 beta) in normal adult human lung fibroblasts. TNF alpha (100 units/ml) and IL-1 beta (100 units/ml) stimulated the production of PGE2 and caused a dose-dependent inhibition of up to 54 and 66%, respectively, of the production of type I procollagen. Preincubation of cultures with indomethacin partially reversed the inhibition of procollagen production induced by the cytokines. Cytokine-stimulated endogenous fibroblast PG accounted for 35 and 68% of the inhibition induced by TNF …

Alternative Splicing Of Human Prostaglandin G/H Synthase Mrna And Evidence Of Differential Regulation Of The Resulting Transcripts By Transforming Growth Factor Beta 1, Interleukin 1 Beta, And Tumor Necrosis Factor Alpha., Arturo Diaz, Anthony M. Reginato, Sergio A. Jimenez

Department of Medicine Faculty Papers

Prostaglandin G/H synthase (PGG/HS) is the rate-limiting enzyme in the conversion of arachidonic acid to prostaglandins and thromboxanes. We screened a human lung fibroblast cDNA library with an ovine PGG/HS cDNA and isolated a 2.3-kilobase clone (HCO-T9). Sequence analysis of this clone showed that (a) it contained the entire translated region of PGG/HS and (b) it displayed an in-frame splicing of the last 111 base pairs encoded by exon 9, which resulted in the elimination of the N-glycosylation site at residue 409. Polymerase chain reaction amplification with specific oligonucleotides of reverse-transcribed mRNA from diverse human tissues and cultured cells yielded …

Transforming Growth Factor-Beta Stimulation Of Lung Fibroblast Prostaglandin E2 Production., Arturo Diaz, John Varga, Sergio A. Jimenez

Department of Medicine Faculty Papers

Transforming growth factor-beta (TGF beta) stimulated the production of total protein, collagen, and fibronectin by normal human lung fibroblasts. The stimulatory response was maximal at 100 pM TGF beta and reversed toward control at higher concentrations. Inhibition of fibroblast prostaglandin (PG) synthesis enhanced TGF beta-induced stimulation of total protein, collagen, and fibronectin production and reversed the negative slope of the dose-response curve at high concentrations of TGF beta. Determination of the steady-state levels of Types I and III procollagens and fibronectin mRNAs employing specific cDNA probes demonstrated that inhibition of fibroblast PG production increased the stimulatory effect of TGF beta …