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Biomedical subjects

Joseph H Korn

Publications and source records attributed to Joseph H Korn.

15 recordsLinked to original sources
PubMed2007

Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192.

OBJECTIVE: To evaluate CAT-192, a recombinant human antibody that neutralizes transforming growth factor beta1 (TGFbeta1), in the treatment of early-stage diffuse cutaneous systemic sclerosis (dcSSc). METHODS: Patients with SSc duration of <18 months were randomly assigned to the placebo group or to 1 of 3 CAT-192 treatment groups: 10 mg/kg, 5 mg/kg, 0.5 mg/kg. Infusions were given on day 0 and weeks 6, 12, and 18. The primary objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of CAT-192. Secondary outcomes included the modified Rodnan skin thickness score (MRSS), the Scleroderma Health Assessment Questionnaire, assessment of organ-based disease, serum levels of soluble interleukin-2 receptor, collagen propeptides (N propeptide of type I [PINP] and type III collagen), and tissue levels of messenger RNA for procollagens I and III and for TGFbeta1 and TGFbeta2. RESULTS: Forty-five patients were enrolled. There was significant morbidity and mortality, including 1 death in the group receiving 0.5 mg/kg of CAT-192 and 3 deaths in the group receiving 5 mg/kg of CAT-192. There were more adverse events and more serious adverse events in patients receiving CAT-192 than in those receiving placebo, although these events were not more frequent in the high-dose treatment group. The MRSS improved in all groups during the study, but there was no evidence of a treatment effect for CAT-192. Improvement in the MRSS correlated with the disease duration (r = -0.54, P = 0.0008). Changes in the PINP level from baseline correlated with changes in the MRSS (r = 0.37, P = 0.027). CONCLUSION: We report the first evaluation of a systemically administered and repeatedly dosed anti-TGFbeta1 drug. In this pilot study, CAT-192, in doses up to 10 mg/kg, showed no evidence of efficacy. The utility of clinical and biochemical outcome measures and the feasibility of multicenter trials of early dcSSc were confirmed.

Adult↗
PubMed2006

Durometry for the assessment of skin disease in systemic sclerosis.

OBJECTIVE: To examine the validity of a durometer to objectively measure skin hardness in systemic sclerosis (SSc), and to compare digital durometry with the modified Rodnan skin score (MRSS) and ultrasonography. METHODS: Patients with SSc and healthy controls underwent durometry measurements in 3 assessments: a Latin square experiment to establish durometry's intra- and interobserver reliability compared with skin scoring (5 SSc, 1 control); a longitudinal cohort to assess sensitivity to change in skin hardness (13 SSc, 5 controls); and an ultrasound cohort to evaluate correlation between durometry, ultrasound-measured skin thickness, and clinical skin scoring (30 SSc, 12 controls). RESULTS: Intraobserver reproducibility was higher for durometry than for clinical skin scoring (intraclass correlation coefficient [ICC] 0.97 versus 0.85), whereas interobserver reproducibility was similar (0.75 versus 0.73). Interobserver reproducibility of durometry was good for all body areas (ICC 0.61-0.85), but for skin scoring it was moderate in the legs (0.51) and poor in the abdomen (0.08), feet (0.09), and fingers (0.27). Durometry scores correlated with clinical skin scores (Latin square: r = 0.44, P = 0.03; longitudinal cohort: r = 0.81, P < 0.001) and ultrasound-measured skin thickness (hands: r = 0.58, forearms: r = 0.63, upper arms: r = 0.40; P < or = 0.001 for all). Uninvolved skin in patients with SSc was harder than skin from controls (mean +/- SD 23 +/- 7 durometer units [DU] versus 19 +/- 6 DU; P < 0.0001). Finally, there was a strong correlation between change in MRSS and change in durometry score (r = 0.77, P = 0.002). CONCLUSION: Durometer-measured skin hardness correlates well with MRSS and ultrasound-measured skin thickness, provides greater reliability than MRSS, and is sensitive to changes in skin hardness over time. Durometry should be considered for use in clinical therapeutic SSc trials.

Arm↗
PubMed2006

Cartilage oligomeric matrix protein is overexpressed by scleroderma dermal fibroblasts.

Cartilage oligomeric matrix protein (COMP) is an extracellular glycoprotein that belongs to the thrombospondin gene family. It is found predominantly in cartilage, tendon, ligament, and bone. Mutations in the COMP gene have been linked to the development of pseudoachondroplasia and multiple epiphysial dysplasia. COMP influences the organization of collagen fibrils by interacting with collagens I, II and IX. Gene expression profiling of cultured skin fibroblasts suggested that COMP mRNA levels were elevated in scleroderma. We therefore examined COMP expression in SSc and normal skin biopsies. Immunohistochemistry confirmed that COMP protein accumulates in SSc but not normal skin, with SSc skin showing striking deposition in the papillary and deeper dermis. Significant staining was also seen in non-lesional skin from patients. Due to its involvement in the development of fibrosis, TGFbeta was examined for a possible role in regulating COMP expression. Cultured SSc fibroblasts demonstrated greater staining for COMP compared to normal controls prior to stimulation, and TGFbeta-1 induced a large increase in mRNA and protein. Murine fibroblasts engineered to overexpress human COMP demonstrated increased levels of fibronectin and collagen in the extracellular matrix. Taken together, these data demonstrate that COMP is overexpressed in SSc skin and cultured fibroblasts possibly due to autocrine TGFbeta stimulation, and COMP overexpression is sufficient to stimulate excess matrix deposition. By interactions with other matrix proteins and cells, COMP may play a role in pathogenic matrix deposition.

Animals↗
PubMed2005

Increased expression of type I collagen induced by microfibril-associated glycoprotein 2: novel mechanistic insights into the molecular basis of dermal fibrosis in scleroderma.

OBJECTIVE: Mutations in fibrillin 1, a key component of extracellular microfibrils, are associated with connective tissue disorders such as Marfan's syndrome or skin fibrosis in the tight skin mouse model of scleroderma. Previous studies have suggested that fibrillin 1 mediates skin fibrosis via its interface with associated microfibrillar proteins and type I collagen; in particular, microfibril-associated glycoprotein 2 (MAGP-2), an extracellular matrix protein that binds to fibrillins and the alphavbeta3 integrin, is increased in TSK mouse and human scleroderma skin. Because the function of MAGP-2 in the biologic processes of the matrix remains unknown, this study investigated whether MAGP-2 regulates type I collagen. METHODS: Fibroblast cultures conditionally overexpressing MAGP-2 were developed. Cells were analyzed by Western blotting, Northern blotting, pulse-chase analysis, and immunofluorescence to assess the effect of MAGP-2 on type I collagen. RESULTS: Cells overexpressing MAGP-2 formed increased MAGP-2 matrix and showed a 3-fold increase in intracellular type I procollagen. This increase was associated with increased levels of type I collagen in the medium and matrix. Increased type I collagen colocalized with the MAGP-2 matrix. MAGP-2 overexpression had no effect on type I procollagen messenger RNA, but markedly increased the half-life of type I procollagen. MAGP-2 induced type I collagen even under conditions in which no MAGP-2 matrix was detectable, and did not require the presence of the RGD motif of MAGP-2 in its integrin-binding site. CONCLUSION: This study shows that MAGP-2 stabilizes type I procollagen, identifying an important function of MAGP-2 in extracellular matrix homeostasis. It also suggests that MAGP-2 might mediate skin fibrosis in TSK mice and in patients with scleroderma.

Animals↗
PubMed2005

Scleroderma fibroblasts demonstrate enhanced activation of Akt (protein kinase B) in situ.

Recent studies suggest that, in addition to activation and hypersecretion of matrix components, fibroblasts from patients with systemic sclerosis (SSc) are relatively resistant to apoptosis. Transforming growth factor-beta (TGF)-beta is strongly implicated in the pathogenesis of SSc and we and others have shown that TGF-beta can activate Akt, a kinase with potent anti-apoptotic effects. To determine whether Akt was activated in SSc, we quantified phospho-Akt expression in skin fibroblasts in vitro by western blot analysis and a functional kinase assay. In addition, the relative proportion of fibroblasts containing activated Akt in was quantified by immunohistochemistry on skin sections insitu. Analysis of Akt phosphorylation of skin fibroblasts in vitro suggested increased phosphorylation of Akt, and evaluation of skin sections by immunohistochemistry revealed significantly higher percentages of fibroblasts that stained for phospho-Akt compared with controls (78% +/- 14.0% vs 13% +/- 9%, p < 0.001). In addition, co-incident staining of phospho-Akt and alpha-smooth muscle actin was observed in some fibroblasts. These findings indicate that Akt is activated insitu in skin fibroblasts from patients with SSc. Akt activation may contribute to resistance to apoptosis, selection of disease-inducing fibroblasts, and, possibly, myofibroblasts.

Apoptosis↗
PubMed2005

Responsiveness of the SF-36 and the Health Assessment Questionnaire Disability Index in a systemic sclerosis clinical trial.

OBJECTIVE: This study compares the responsiveness to change of the Medical Outcomes Study Short Form Health Survey (SF-36), a measure of health related quality of life (HRQOL), and the Health Assessment Questionnaire Disability Index (HAQ-DI), a function instrument, in a randomized clinical trial for treatment of systemic sclerosis (SSc). METHODS: A phase 2/3, multicenter, prospective, placebo controlled trial was conducted to evaluate human recombinant relaxin treatment in patients with diffuse SSc over 24 weeks. At baseline, subjects had stable, moderately severe, diffuse SSc of disease duration < or = 5 years, modified Rodnan skin score > or = 20, serum creatinine < 2.0 mg/dl, percentage forced vital capacity (% FVC) predicted > or = 50%, and % DLCO predicted > or = 40% and were not receiving concomitant disease modifying therapies. Internal consistency reliability of multi-item scales was estimated using Cronbach's alpha. Responsiveness to change of the SF-36 and HAQ-DI was computed between Weeks 0 and 24. Subjects were classified as unchanged or having a meaningful change in 4 different external measures: Change in (1) skin score > or = 30%; (2) % FVC predicted of > or = 15%; (3) self-reported patient global assessment by visual analog scale (VAS) > or = 20%; and (4) physician global assessment by VAS of > or = 20%. Responsiveness indices were computed and Cohen's effect size criteria were used to assess the magnitude of change. RESULTS: A total of 239 patients participated in this trial, with 196 completing the 24 week trial. Cronbach's alpha for the SF-36 scales ranged from 0.76 to 0.93 and for the HAQ-DI ranged from 0.69 to 0.91 (good to excellent). The SF-36 had a larger magnitude of responsiveness in overall disease (patient and physician global assessment) compared to the HAQ-DI, while the HAQ-DI had a larger magnitude of responsiveness in clinical measures (i.e., change in skin score and % FVC predicted) than the SF-36. CONCLUSION: These data support inclusion of both the SF-36 and HAQ-DI as outcome measures in future clinical trials of diffuse SSc.

Adult↗
PubMed2004

Mutant fibrillin 1 from tight skin mice increases extracellular matrix incorporation of microfibril-associated glycoprotein 2 and type I collagen.

OBJECTIVE: Skin fibrosis in the TSK mouse, a model of skin fibrosis seen in systemic sclerosis (SSc), is caused by a large in-frame duplication in the Fbn1 gene, tsk-Fbn1. We investigated whether tsk-Fbn1 might cause dermal fibrosis by affecting Fbn1 and associated extracellular matrices. We also studied whether deposition of microfibril-associated glycoprotein 2 (MAGP-2), a protein that is associated with fibrillin 1, was altered in the skin of patients with SSc. METHODS: An in vitro model of the TSK mouse was created by conditionally expressing tsk-Fbn1 in mouse embryonic fibroblasts (MEFs). Cell cultures were examined by immunofluorescence and Western and Northern blotting to determine the effect of tsk-Fbn1 on the structure, expression, and deposition of fibrillin 1 (Fbn-1), type I collagen, and MAGP-2. The skin of TSK mice and SSc patients was analyzed by immunohistochemistry for MAGP-2 expression. RESULTS: Expression of tsk-Fbn1 in cultured MEF cells altered the morphology of Fbn-1 fibers and increased the deposition of type I collagen into the extracellular matrix (ECM) without concomitantly changing messenger RNA expression, secretion, or processing of type I procollagen. Moreover, MEF cells expressing tsk-Fbn1 showed increased MAGP-2 matrix. MAGP-2 was increased in the dermis of TSK mice. Fibrotic SSc skin also showed higher levels of MAGP-2 in the dermis than nonfibrotic SSc skin and normal skin. CONCLUSION: Tsk-Fbn1 altered ECM organization and caused fibrosis by affecting the deposition of MAGP-2 or other Fbn-1-associated proteins. Alterations in microfibril structure or deposition might contribute to fibrosis in SSc.

Animals↗
PubMed2004

Fibulin-2 and fibulin-5 alterations in tsk mice associated with disorganized hypodermal elastic fibers and skin tethering.

The Tight skin (Tsk) mouse is an important model of skin fibrosis that occurs in systemic sclerosis. These mice develop skin tethering and thickening associated with expression of a mutant fibrillin-1 gene. We show that Tsk fibrillin-1 leads to marked alterations in elastic fibers of the hypodermis of Tsk animals. In Tsk mice, a prominent elastic fiber layer found normally at the interface between hypodermal muscle and connective tissue was absent from an early age. The lack of elastic fibers at the hypodermal muscle-connective tissue (M-CT) interface was associated with a loss of staining for fibulin-5 in the same region. These mice also formed disorganized elastic fibers throughout hypodermal connective tissue as they aged. The increased elastic fibers in Tsk hypodermal connective tissue was associated with increased fibrillin-1 and fibulin-2 matrices. These results suggest that Tsk fibrillin-1 causes skin tethering by altering matrix protein composition in Tsk hypodermal connective tissues. The closely parallel alterations in elastogenesis associated with increased fibulin-2 in hypodermal connective tissues and decreased fibulin-5 at the hypodermal M-CT interface suggest that these proteins mediate the effect of Tsk-fibrillin-1 on elastogenesis.

Animals↗
PubMed2003

Fibrosis in scleroderma.

The pathogenesis of fibrosis in scleroderma involves a complex set of interactions between the fibroblast and its surroundings. Multiple fibrotic pathways are activated for reasons that are not completely clear, but involve immune activation, microvascular damage, and fibroblast transformation into the myofibroblast. Differential proliferation and apoptosis preserve the myofibroblast phenotype rather that leading to a selective depletion of activated fibroblasts after an acute injury has healed. Disproportionate fibroblast activity could result from a combination of possible cellular and matrix defects that include fibrillin protein abnormalities, autoantibody formation, type II immune response, excessive endothelial reaction to injury, and excessive fibroblast response to TGF-beta. Development of therapies that are targeted to correcting these abnormalities will eventually lead to effective treatment for the fibrotic complications of scleroderma.

Fibroblasts↗
PubMed2003

Scleroderma: a treatable disease.

Many effective treatments for scleroderma have emerged in recent years, including bosentan, an endothelin receptor antagonist, and epoprostenol, a prostacyclin, both of which target vasoconstriction. Cyclophosphamide may soon be proven effective against interstitial lung disease.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Measuring disease activity and functional status in patients with scleroderma and Raynaud's phenomenon.

OBJECTIVE: To document disease activity and functional status in patients with scleroderma (systemic sclerosis [SSc]) and Raynaud's phenomenon (RP) and to determine the sensitivity to change, reliability, ease of use, and validity of various outcome measures in these patients. METHODS: Patients with SSc and moderate-to-severe RP participating in a multicenter RP treatment trial completed daily diaries documenting the frequency and duration of RP attacks and recorded a daily Raynaud's Condition Score (RCS). Mean scores for the 2-week periods prior to baseline (week 0), end of trial (week 6), and posttrial followup (week 12) were calculated. At weeks 0, 6, and 12, physicians completed 3 global assessment scales and performed clinical assessments of digital ulcers and infarcts; patients completed the Health Assessment Questionnaire (HAQ), the Arthritis Impact Measurement Scales 2 (AIMS2) mood and tension subscales, 5 specific SSc/RP-related visual analog scales (VAS), and 3 other VAS global assessments. We used these measures to document baseline disease activity and to assess their construct validity, sensitivity to change, and reliability in trial data. RESULTS: Two hundred eighty-one patients (248 women, 33 men; mean age 50.4 years [range 18-82 years]) from 14 centers participated. Forty-eight percent had limited cutaneous SSc; 52% had diffuse cutaneous SSc. Fifty-nine patients (21%) had digital ulcers at baseline. Patients had 3.89 +/- 2.33 (mean +/- SD) daily RP attacks (range 0.8-14.6), with a duration of 82.1 +/- 91.6 minutes/attack. RCS for RP activity (possible range 0-10) was 4.30 +/- 1.92. HAQ scores (0-3 scale) indicated substantial disability at baseline (total disability 0.86, pain 1.19), especially among the subscales pertaining to hand function (grip, eating, dressing). AIMS2 mood and tension scores were fairly high, as were many of the VAS scores. Patients with digital ulcers had worse RCS, pain, HAQ disability (overall, grip, eating, and dressing), physician's global assessment, and tension, but no significant difference in the frequency of RP, duration of RP, patient's global assessment, or mood, compared with patients without digital ulcers. VAS scores for digital ulcers as rated by the patients were not consistent with the physician's ratings. Factor analysis of the 18 measures showed strong associations among variables in 4 distinct domains: disease activity, RP measures, digital ulcer measures, and mood/tension. Reliability of the RCS, HAQ pain and disability scales, and AIMS2 mood and tension subscales was high. The RP measures demonstrated good sensitivity to change (effect sizes 0.33-0.76). CONCLUSION: Our findings demonstrate that the significant activity, disability, pain, and psychological impact of RP and digital ulcers in SSc can be measured by a small set of valid and reliable outcome measures. These outcome measures provide information beyond the quantitative metrics of RP attacks. We propose a core set of measures for use in clinical trials of RP in SSc patients that includes the RCS, patient and physician VAS ratings of RP activity, a digital ulcer/infarct measure, measures of disability and pain (HAQ), and measures of psychological function (AIMS2).

Affect↗
PubMed2002

Transforming growth factor beta induces fibroblast fibrillin-1 matrix formation.

OBJECTIVE: Fibrillin, an extracellular matrix protein implicated in dermal fibrosis, is increased in the reticular dermis of systemic sclerosis (SSc) skin. We undertook this study to investigate the hypothesis that transforming growth factor beta (TGFbeta) or other cytokines regulate fibrillin matrix formation by normal and SSc fibroblasts. We further investigated the mechanism of TGFbeta-induced fibrillin fibrillogenesis and its relationship to myofibroblasts. METHODS: Fibrillin and fibronectin matrix deposition and alpha-smooth muscle actin expression by fibroblast cultures from normal and SSc skin treated with TGFbeta or other cytokines were analyzed by immunofluorescence. Supernatant and extracellular matrix from normal and SSc fibroblasts treated with or without TGFbeta were evaluated by Western blot and Northern blot for fibrillin protein and messenger RNA (mRNA) expression, respectively. RESULTS: Immunofluorescence demonstrated increased fibrillin matrix formation by normal and scleroderma fibroblasts after TGFbeta treatment. Other cytokines, including tumor necrosis factor alpha, interleukin-1beta (IL-1beta), IL-4, granulocyte-macrophage colony-stimulating factor, and platelet-derived growth factor, did not affect fibrillin fibrillogenesis. Fibrillin matrix formed in proximity to myofibroblasts and independently of up-regulation of fibronectin matrix or cell number. Western blot analysis of extracellular matrix confirmed increased fibrillin after TGFbeta stimulation of normal or scleroderma fibroblasts. However, TGFbeta did not alter the expression of either soluble fibrillin protein or fibrillin mRNA. CONCLUSION: Our data show that TGFbeta induces fibrillin protein incorporation into the extracellular matrix without affecting fibrillin gene expression or protein synthesis, suggesting that fibrillin matrix assembly is regulated extracellularly. TGFbeta might increase fibrillin matrix by activating myofibroblasts. Such TGFbeta-mediated effects could account for the increased fibrillin matrix observed in SSc skin.

Cells, Cultured↗
PubMed2002

Apoptosis and myofibroblasts in the pathogenesis of systemic sclerosis.

Tissue fibrosis is the result of a complex series of events focusing on regulation of fibroblast proliferation, synthesis of extracellular matrix, and apoptosis. Transforming growth factor-beta is important for the stimulation of the fibrotic response by promoting the production of extracellular matrix proteins, by promoting the differentiation of the myofibroblast cell morphology, and by protecting these cells against apoptotic stimuli. Other cytokines such as interleukin-1 may have stimulatory and counter-regulatory effects on fibrosis. The effects of these signaling molecules depend on cellular environment and are organ specific. Furthermore, intercellular interactions and cell-matrix interactions can stimulate or inhibit the apoptotic pathway. Through selective inhibition of apoptosis in myofibroblasts, fibrosis can become dysregulated and lead to diseases such as systemic sclerosis.

Animals↗
PubMed2002

Cytokine directed therapy in scleroderma: rationale, current status, and the future.

The hallmark of scleroderma is cutaneous and visceral fibrosis characterized and by increased biosynthesis of multiple matrix proteins by interstitial fibroblasts. Studies over recent years have delineated pathways involved in promoting matrix synthesis and elucidated the molecular pathways of regulation. Central to the regulation of fibrosis are extracellular mediators, called cytokines, which are elaborated by a variety of cells, including those in the immune system, vascular cells, and fibroblasts themselves. The concept that inhibiting or promoting the action of these naturally occurring profibrotic or antifibrotic molecules, respectively, is a rational therapeutic approach to treating scleroderma and other fibrotic diseases finds support in animal studies and anticytokine therapy conducted in relation to rheumatoid arthritis and other disorders. This review looks at cytokines known or thought to play a role in scleroderma and/or other fibrotic states and at potential therapy directed at these mediators. Potential targets for therapy include transforming growth factor beta (TGF-beta), connective tissue growth factor (CTGF), IL-4, IL-13, MCP-1, and endothelin, among others.

Animals↗