Rheumatology Commons^™

Molecular Ablation Of Tgf-Beta Signaling Pathways By Tyrosine Kinase Inhibition: The Coming Of A Promising New Era In The Treatment Of Tissue Fibrosis, Joel Rosenbloom, Sergio A. Jimenez

Selected Works of Sergio Jiménez, MD, MACR

No abstract provided.

Modulation Of Tgf-Beta Signaling By Proinflammatory Cytokines In Articular Chondrocytes., Jorge A. Roman-Blas, David G. Stokes, Sergio A. Jimenez

Department of Medicine Faculty Papers

OBJECTIVE: The normal structure and function of articular cartilage are the result of a precisely balanced interaction between anabolic and catabolic processes. The transforming growth factor-beta (TGF-beta) family of growth factors generally exerts an anabolic or repair response; in contrast, proinflammatory cytokines such as interleukin 1 beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) exert a strong catabolic effect. Recent evidence has shown that IL-1beta, and TNF-alpha, and the TGF-beta signaling pathways share an antagonistic relationship. The aim of this study was to determine whether the modulation of the response of articular chondrocytes to TGF-beta by IL-1beta or TNF-alpha signaling pathways …

The Role Of Allograft Inflammatory Factor 1 In Systemic Sclerosis, Francesco Del Galdo, Carol M. Artlett, Sergio A. Jimenez

Selected Works of Sergio Jiménez, MD, MACR

ABSTRACT

Purpose: To review studies which support the hypothesis that allograft inflammatory factor-1 (AIF-1), a protein initially identified in chronically rejected cardiac allografts, may be involved in the pathogenesis of the progressive fibroproliferative vasculopathy which is a hallmark of systemic sclerosis (SSc).

Recent findings: Recent findings demonstrated elevated AIF-1 expression both in SSc affected tissues and peripheral blood mononuclear cells. A detailed immunohistopathologic study examined the tissue and cellular localization of the protein in affected SSc tissues and demonstrated its expression in the endothelium of dermal and pulmonary vessels, in the pulmonary parenchyma, and in relevant inflammatory cells including T …

Description Of Twelve Cases Of Nephrogenic Fibrosing Dermopathy And Review Of The Literature, Fabian A. Mendoza, Carol M. Artlett, Nora Sandorfi, Kevin Latinis, Sonoles Piera-Velazquez, Sergio A. Jimenez

Selected Works of Sergio Jiménez, MD, MACR

ABSTRACT

Objectives: To review the clinical and laboratory features of twelve cases of nephrogenic fibrosing dermopathy (NFD) studied at our institution and of 70 previously described cases in the literature.

Methods: Clinical evaluation and laboratory studies of twelve patients with NFD associated with chronic hemodialysis or peritoneal dialysis for end-stage renal disease and a review of 23 previous publications describing 70 patients with this disease.

Results: Eleven patients undergoing chronic hemodialysis and one patient undergoing chronic peritoneal dialysis for end-stage renal failure developed a severe and progressive cutaneous fibrotic process with woody induration of legs, thighs, hands and forearms, and …

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 …

Inhibition Of Collagen Gene Expression In Systemic Sclerosis Dermal Fibroblasts By Mithramycin, Nora Sandorfi, Natalia Louneva, Elena Hitraya, Gyorgy Hajnoczky, Biagio Saitta, Sergio A. Jimenez

Selected Works of Sergio Jiménez, MD, MACR

ABSTRACT

Introduction. The antitumor antibiotic mithramycin has also been shown to be a potent and effective inhibitor of fibrosis following glaucoma surgery. This DNA interacting drug displays high affinity binding to GC rich sequences in DNA, including those present in the promoter of the gene encoding the Α1 chain of type I collagen (COL1A1).

Objective. To evaluate the effects of mithramycin on the production of type I collagen in fibroblast cultures from patients with systemic sclerosis. Methods. Confluent cultures of dermal fibroblasts from patients with recent onset of the diffuse form of systemic sclerosis were treated with varius concentrations of …

Patient Characteristics And Clinical Management Of Patients With Shoulder Pain In U.S. Primary Care Settings: Secondary Data Analysis Of The National Ambulatory Medical Care Survey, James L. Wofford, Richard J. Mansfield, Raquel S. Watkins

Dartmouth Scholarship

Although shoulder pain is a commonly encountered problem in primary care, there are few studies examining its presenting characteristics and clinical management in this setting. We performed secondary data analysis of 692 office visits for shoulder pain collected through the National Ambulatory Medical Care Survey (Survey years 1993–2000). Information on demographic characteristics, history and place of injury, and clinical management (physician order of imaging, physiotherapy, and steroid intraarticular injection) were examined.

B-Myb Acts As A Repressor Of Human Col1a1 Collagen Gene Expression By Interacting With Sp1 And Cbf Factors In Scleroderma Fibroblasts, Lucia Cicchillitti, Sergio A. Jimenez, Arturo Sala, Biaggio Saitta

Selected Works of Sergio Jiménez, MD, MACR

We investigated the role of B-Myb, a cell-cycle-regulated transcription factor, in the expression of the alpha1 (I) pro-collagen gene (COL1A1) in scleroderma fibroblasts. Scleroderma or SSc (systemic sclerosis) is a fibrotic disease characterized by excessive production of extracellular matrix components, especially type I collagen. Northern-blot analysis showed an inverse relationship between COL1A1 mRNA expression and that of B-Myb during exponential cell growth and during quiescence in human SSc fibroblasts. Overexpression of B-Myb in SSc fibroblasts was correlated with decreased COL1A1 mRNA expression. Transient transfections localized the down-regulatory effect of B-Myb to a region containing the proximal 174 bp of the …

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 …

Are Antinuclear Antibodies And Rheumatiod Factor Positivity More Prevalent In Apparently Healthy Smokers Compared To Ex-Smokers And Never Smokers?, Susan Nyanzi

Loma Linda University Electronic Theses, Dissertations & Projects

Context: There is now consistent evidence from population and epidemiological studies that cigarette smoking is an independent risk factor for Rheumatoid Arthritis (RA), via Rheumatoid Factor (RF) production (Deighton, 1997; Saag, 1997; Silman, 1996; Uhlig, 1999; Wolfe, 2000). Antinuclear Antibodies (ANA) are another collection of autoantibodies that are being associated with smoking and RA initiation. To our knowledge, no studies have examined the effects of smoking on both ANA and RF simultaneously in healthy subjects.

Objectives: To determine whether cigarette smoking has an effect on ANA and RF positivity in healthy blood donors.

Design, Setting, Participants: This was a cross-sectional, …

Systemic Sclerosis: Current Views Of Its Pathogenesis., Chris T. Derk, Sergio A. Jimenez

Department of Medicine Faculty Papers

Systemic sclerosis (SSc) is an autoimmune disorder of unknown etiology characterized by severe and often progressive cutaneous and visceral fibrosis, pronounced alterations in the microvasculature, and numerous cellular and humoral immune abnormalities. Clinically, SSc is very heterogeneous, encompassing a spectrum ranging from mild limited forms of skin sclerosis with minimal internal organ involvement to severe skin and multiple internal organ fibrosis. Mortality and morbidity in SSc are very high and are directly related to the extent of the fibrotic and microvascular alterations. A better understanding of the pathogenesis of this incurable disorder will help to better target and design effective …

Regulation And Localization Of Endogenous Human Tristetraprolin, Anna-Marie Fairhurst, John E. Connolly, Katharine A Hintz, Nicolas J Goulding

Dartmouth Scholarship

Tumor necrosis factor (TNF) has been implicated in the development and pathogenicity of infectious diseases and autoimmune disorders, such as septic shock and arthritis. The zinc-finger protein tristetraprolin (TTP) has been identified as a major regulator of TNF biosynthesis. To define its intracellular location and examine its regulation of TNF, a quantitive intracellular staining assay specific for TTP was developed. We establish for the first time that in peripheral blood leukocytes, express

Regulation Of Human Col9a1 Gene Expression. Activation Of The Proximal Promoter Region By Sox9., Ping Zhang, Sergio A. Jimenez, David G Stokes

Department of Medicine Faculty Papers

The COL9A1 gene contains two promoter regions, one driving expression of a long alpha1(IX) chain in cartilage (upstream) and one driving expression of a shorter chain in the cornea and vitreous (downstream). To determine how the chondrocyte-specific expression of the COL9A1 gene is regulated, we have begun to characterize the upstream chondrocyte-specific promoter region of the human COL9A1 gene. Transient-transfection analyses performed in rat chondrosarcoma (RCS) cells, human chondrosarcoma (HTB) cells, and NIH/3T3 cells showed that the COL9A1 promoter was active in RCS cells but not HTB or NIH/3T3 cells. Inclusion of the first intron had no effect on promoter …

The Role Of Meat, Poultry, And Fish Consumption In The Occurrence Of Rheumatoid And Other Forms Of Arthritis, Asnake Hailu

Loma Linda University Electronic Theses, Dissertations & Projects

Rheumatoid arthritis and other forms of arthritis or rheumatism are now the leading cause of disability in the United States. The etiology and pathogenesis are less understood and available treatment options are not always satisfactory. This dissertation measures the prevalence and cumulative incidence of rheumatoid arthritis and other forms of arthritis or rheumatism, and examines any associations with current and lifetime consumption of meat, poultry, and fish (meat) using the Adventist Health Study and the Adventist Mortality Study databases. From these databases, it was possible to reconstruct a prospective cohort, obtain self-reported information on demographic characteristics, arthritis, rheumatoid arthritis, other …

Regulation Of Type-Ii Collagen Gene Expression During Human Chondrocyte De-Differentiation And Recovery Of Chondrocyte-Specific Phenotype In Culture Involves Sry-Type High-Mobility-Group Box (Sox) Transcription Factors, David G. Stokes, Gang Liu, Rita Dharmavaram, David Hawkins, Sonsoles Piera-Velazquez, Sergio A. Jimenez

Selected Works of Sergio Jiménez, MD, MACR

During ex vivo growth as monolayer cultures, chondrocytes proliferate and undergo a process of de-differentiation. This process involves a change in morphology and a change from expression of chondrocyte-specific genes to that of genes that are normally expressed in fibroblasts. Transfer of the monolayer chondrocyte culture to three-dimensional culture systems induces the cells to re-acquire a chondrocyte-specific phenotype and produce a cartilaginous-like tissue in vitro. We investigated mechanisms involved in the control of the de-differentiation and re-differentiation process in vitro. De-differentiated chondrocytes re-acquired their chondrocyte-specific phenotype when cultured on poly-(2-hydroxyethyl methacrylate) (polyHEMA) as assayed by morphology, reverse transcriptase PCR of …

Role Of Protein Kinase C-Delta In The Regulation Of Collagen Gene Expression In Scleroderma Fibroblasts, Sergio A. Jimenez, Svetlana Gaidarova, Biagio Saitta, Nora Sandorfi, David J. Herrich, Joan C. Rosenbloom, Umberto Kucich, William R. Abrams, Joel Rosenbloom

Selected Works of Sergio Jiménez, MD, MACR

Working with cultured dermal fibroblasts derived from control individuals and patients with systemic sclerosis (SSc), we have examined the effects of protein kinase C-delta (PKC-delta) on type I collagen biosynthesis and steady-state levels of COL1A1 and COL3A1 mRNAs. Rottlerin, a specific inhibitor of PKC-delta, exerted a powerful, dose-dependent inhibition of type I and type III collagen gene expression in normal and SSc cells. Optimal rottlerin concentrations caused a 70-90% inhibition of type I collagen production, a >80% reduction in COL1A1 mRNA, and a >70% reduction in COL3A1 mRNA in both cell types. In vitro nuclear transcription assays and transient transfections …

Identification Of Fetal Dna And Cells In Skin Lesions From Women With Systemic Sclerosis, Carol M. Artlett, J. Bruce Smith, Sergio A. Jimenez

Selected Works of Sergio Jiménez, MD, MACR

BACKGROUND: Systemic sclerosis is a disease of unknown origin which often occurs in women after their childbearing years. It has many clinical and histopathological similarities to chronic graft-versus-host disease. Recent studies indicate that fetal stem cells can survive in the maternal circulation for many years post partum. This finding suggests that fetal cells persisting in the maternal circulation or tissues could be involved in the pathogenesis of systemic sclerosis by initiating a graft-versus-host reaction.

METHODS: We used the polymerase chain reaction (PCR) to identify Y-chromosome sequences in DNA extracted from peripheral-blood cells and skin lesions from women with systemic sclerosis …

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 …

Stimulation Of Alpha 1(I) Procollagen Gene Expression In Nih-3t3 Cells By The Human T Cell Leukemia Virus Type 1 (Htlv-1) Tax Gene., E. Munoz, D. Suri, S. Amini, K. Khalili, Sergio A. Jimenez

Selected Works of Sergio Jiménez, MD, MACR

The mechanisms that regulate the expression of genes encoding extracellular matrix proteins in fibroblasts and other mesenchymal cells have remained elusive. Studies from several laboratories have indicated that Tax, a trans-regulatory protein from the human T cell leukemia virus type I not only augments viral gene expression but also triggers the expression of various cellular genes. Here, we examined the hypothesis that the expression of collagen genes may also be modulated by Tax. NIH-3T3 cells were simultaneously transfected with a Tax expressor plasmid and a chimeric construct containing regulatory sequences (-804 to +42 bp) of the alpha 1(I) procollagen gene …

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. …

Epidermal Growth Factor Coordinately Regulates The Expression Of Prostaglandin G/H Synthase And Cytosolic Phospholipase A2 Genes In Embryonic Mouse Cells., Kenneth P. Chepenik, Arturo Diaz, Sergio A. Jimenez

Department of Medicine Faculty Papers

Confluent, primary cultures of mouse embryo palate mesenchyme (MEPM) cells are refractory to activation of phospholipase A2 (PLA2) by the calcium ionophore A23187. However, treatment of these cultures with epidermal growth factor (EGF) permits the cells to activate PLA2 in response to A23187. We have developed this finding by exploring molecular mechanisms by which growth factors modulate mobilization and metabolism of arachidonic acid. We found chronic treatment (> 6 h) of confluent MEPM cells with EGF (a) increases their ability to metabolize exogenous arachidonic acid to prostaglandin E2 (PGE2) and (b) stimulated constitutive expression of activities of PLA2 and cyclooxygenase …

Functional Analysis Of Human Alpha 1(I) Procollagen Gene Promoter. Differential Activity In Collagen-Producing And -Nonproducing Cells And Response To Transforming Growth Factor Beta 1., Sergio A. Jimenez, John A. Varga, Anne Olsen, Liye Li, Arturo Diaz, Janet Herhal, Julie Koch

Department of Medicine Faculty Papers

To gain a further understanding of the regulation of human type I collagen gene expression under physiologic and pathologic conditions, we characterized 5.3 kilobase pairs (kb) of the human alpha 1(I) procollagen gene promoter. A series of deletion constructs containing portions of the alpha 1(I) procollagen 5'-flanking region (with end points from -5.3 kb to -84 base pairs (bp)) ligated to the chloramphenicol acetyltransferase (CAT) reporter gene were transiently transfected into NIH/3T3 cells. Maximal CAT activity was observed with constructs having 5' end points from -804 to -174 bp. A further 5' deletion to -84 bp caused a marked reduction …

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 …

The Tight Skin Mouse: Demonstration Of Mutant Fibrillin-1 Production And Assembly Into Abnormal Microfibrils, Cay M. Kielty, Michael Raghunath, Linda D. Siracusa, Michael J. Sherratt, Reiner Peters, C. Adrian Shuttleworth, Sergio A. Jimenez

Selected Works of Sergio Jiménez, MD, MACR

Mice carrying the Tight skin (Tsk) mutation harbor a genomic duplication within the fibrillin-1 (Fbn 1) gene that results in a larger than normal in-frame Fbn 1 transcript. In this study, the consequences of the Tsk mutation for fibrillin-containing microfibrils have been examined. Dermal fibroblasts from Tsk/+ mice synthesized and secreted both normal fibrillin (approximately 330 kD) and the mutant oversized Tsk fibrillin-1 (approximately 450 kD) in comparable amounts, and Tsk fibrillin-1 was stably incorporated into cell layers. Immunohistochemical and ultrastructural analyses of normal and Tsk/+ mouse skin highlighted differences in the gross organization and distribution of microfibrillar arrays. Rotary …

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 …

Regulation Of Transforming Growth Factor-Beta 1 Gene Expression By Glucocorticoids In Normal Human T Lymphocytes., O. Ayanlarbatuman, A. P. Ferrero, Arturo Diaz, Sergio A. Jimenez

Department of Medicine Faculty Papers

Glucocorticoids (GC) modulate immune function in a number of ways, including suppression of T cell proliferation and other IL-2-mediated T cell functions. These inhibitory effects are similar to those induced by transforming growth factor-beta 1 (TGF-beta 1), a cytokine with potent T cell inhibiting activities. We examined the hypothesis that GC effects may be at least partially achieved through modulation of the expression of the TGF-beta 1 gene in activated T cells. Normal T cells were cultured with or without purified phytohemagglutinin (PHA-p) and 4 beta-phorbol 12-myristate 13-acetate (PMA) in the presence or absence of the synthetic GC, dexamethasone (100-200 …

Expression Of A Human Cartilage Procollagen Gene (Col2a1) In Mouse 3t3 Cells., Leena Ala-Kokko, James Hyland, Carol Smith, Kari I. Kivirikko, Sergio A. Jimenez, Darwin J. Prockop

Department of Medicine Faculty Papers

Expression in a recombinant system has been difficult to obtain for any of the major fibrillar collagens that require processing by eight or more post-translational enzymes. Here, two DNA constructs were designed so that the promoter region of the gene for the pro-alpha 1(I) chain of human type I procollagen drove expression of the human type II procollagen gene in mouse NIH 3T3 cells, a culture line that normally synthesizes type I procollagen but not any cartilage-specific protein such as type II procollagen. Both constructs were expressed as both mRNA and protein. In clones expressing the construct at high levels, …

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 …