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Biomedical subjects

S B Abramson

Publications and source records attributed to S B Abramson.

At least 19 recordsLinked to original sources
PubMed2006

Classification of osteoarthritis biomarkers: a proposed approach.

OBJECTIVE: Osteoarthritis (OA) biomarkers are needed by researchers and clinicians to assist in disease diagnosis and assessment of disease severity, risk of onset, and progression. As effective agents for OA are developed and tested in clinical studies, biomarkers that reliably mirror or predict the progression or amelioration of OA will also be needed. METHODS: The NIH-funded OA Biomarkers Network is a multidisciplinary group interested in the development and validation of OA biomarkers. This review summarizes our efforts to characterize and classify OA biomarkers. RESULTS: We propose the "BIPED" biomarker classification (which stands for Burden of Disease, Investigative, Prognostic, Efficacy of Intervention and Diagnostic), and offer suggestions on optimal study design and analytic methods for use in OA investigations. CONCLUSION: The BIPED classification provides specific biomarker definitions with the goal of improving our ability to develop and analyze OA biomarkers, and to communicate these advances within a common framework.

Arthrography↗
PubMed2004

Nitric oxide sustains nuclear factor kappaB activation in cytokine-stimulated chondrocytes.

OBJECTIVE: In the current studies we have examined the effects of nitric oxide, and its redox derivatives peroxynitrite and S-nitrosothiol, S-nitrosocysteine, on nuclear factor kappaB (NF-kappaB) activation in cytokine-stimulated bovine chondrocytes. METHODS: The kinetics of NF-kappaB activation (p65 nuclear translocation) were assessed by immunofluorescence and immunoblot assays. RESULTS: We observed that the two nitric oxide redox species, peroxynitrite and S-nitrosocysteine, exert opposing effects on NF-kappaB activation. However, in lipopolysaccharide (LPS)/cytokine-stimulated chondrocytes (LPS, IL-1beta and TNF-alpha (LIT)) in the presence or absence of the NOS inhibitor L-NG-monomethyl arginine citrate (L-NMMA), the results indicate that nitric oxide causes persistent activation of NF-kappaB, most likely via generation of the free radical derivative peroxynitrite. CONCLUSION: The studies indicate that while nitric oxide is not required for immediate NF-kappaB activation in cytokine-stimulated chondrocytes, its effect is to sustain nuclear translocation of p65 and thereby provide a persistent "on signal" to NF-kappaB dependent gene transcription. Persistent activation of NF-kappaB may represent a mechanism by which nitric oxide sustains catabolic processes and promotes cartilage degeneration in osteoarthritis.

Animals↗
PubMed2002

Blocking the effects of IL-1 in rheumatoid arthritis protects bone and cartilage.

Destruction of articular joints occurs progressively in patients with rheumatoid arthritis (RA). Although the exact aetiology of RA has not been fully elucidated, a large body of evidence supports a role for interleukin-1 (IL-1) in cartilage and bone erosion. In vitro studies suggest that IL-1 can cause cartilage destruction by stimulating the release of matrix metalloproteinases and other degradative products, and it can increase bone resorption by stimulating osteoclast differentiation and activation. In animal models of RA, blocking the effects of IL-1 with either IL-1 receptor antagonist (IL-1Ra; endogenous), anti-IL-1 monoclonal antibodies, or soluble IL-1 type II receptors significantly reduced cartilage destruction and bone erosion. Gene therapy with IL-1Ra was also effective in reducing joint destruction in experimental RA and osteoarthritis (OA) models. In clinical studies, anakinra, a human recombinant IL-1 receptor antagonist (IL-1ra; exogenous), significantly slowed radiographic progression of RA relative to placebo and significantly reduced clinical symptoms when used as monotherapy or in addition to existing methotrexate therapy. These results demonstrate that blocking IL-1 protects bone and cartilage from progressive destruction in RA.

Animals↗
PubMed2002

"A system biology" approach to bioinformatics and functional genomics in complex human diseases: arthritis.

Human and other annotated genome sequences have facilitated generation of vast amounts of correlative data, from human/animal genetics, normal and disease-affected tissues from complex diseases such as arthritis using gene/protein chips and SNP analysis. These data sets include genes/proteins whose functions are partially known at the cellular level or may be completely unknown (e.g. ESTs). Thus, genomic research has transformed molecular biology from "data poor" to "data rich" science, allowing further division into subpopulations of subcellular fractions, which are often given an "-omic" suffix. These disciplines have to converge at a systemic level to examine the structure and dynamics of cellular and organismal function. The challenge of characterizing ESTs linked to complex diseases is like interpreting sharp images on a blurred background and therefore requires a multidimensional screen for functional genomics ("functionomics") in tissues, mice and zebra fish model, which intertwines various approaches and readouts to study development and homeostasis of a system. In summary, the post-genomic era of functionomics will facilitate to narrow the bridge between correlative data and causative data by quaint hypothesis-driven research using a system approach integrating "intercoms" of interacting and interdependent disciplines forming a unified whole as described in this review for Arthritis.

Animals↗
PubMed2001

Osteopontin: an intrinsic inhibitor of inflammation in cartilage.

OBJECTIVE: To identify extracellular and intraarticular matrix components that are differentially expressed in normal and osteoarthritis (OA)-affected cartilage and to investigate their functions with respect to regulation of mediators of inflammation. METHODS: Differential-display reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of a pool of messenger RNA (mRNA) from 10 human OA cartilage samples and 5 normal cartilage samples was performed using arbitrary primers. Confirmatory analysis of the up-regulated transcripts of fibronectin (FN) and osteopontin (OPN) was performed by RT-PCR of individual RNA samples from a separate set of donors. The effect of recombinant OPN (or anti-OPN antiserum) on chondrocyte function was examined by analyzing the spontaneous or interleukin-1 (IL-1)-induced release of nitric oxide (NO) and prostaglandin E2 (PGE2) from human OA-affected cartilage under ex vivo conditions. RESULTS: Up-regulation (300-700%) of FN and OPN mRNA was observed in human OA-affected cartilage as compared with normal cartilage. Functional analysis of the role of OPN in OA cartilage showed that 1) Addition of 1 microg/ml (20 nM) of recombinant OPN to human OA-affected cartilage under ex vivo conditions inhibited spontaneous and IL-1beta-induced NO and PGE2 production, and 2) neutralization of intraarticular OPN with anti-OPN antiserum augmented NO production. CONCLUSION: The data indicate that one of the functions of intraarticular OPN, which is overexpressed in OA cartilage, is to act as an innate inhibitor of IL-1, NO, and PGE2 production. These findings suggest that the production of pleiotropic mediators of inflammation that influence cartilage homeostasis, such as NO and PGE2, is regulated by the interaction of chondrocytes with differentially expressed proteins within the extracellular matrix.

Aged↗
PubMed2001

Circulating activated endothelial cells in systemic lupus erythematosus: further evidence for diffuse vasculopathy.

OBJECTIVE: In flares of systemic lupus erythematosus (SLE), endothelial cells (EC; activated by immune stimuli) are potential participants in the inflammatory processes that contribute to tissue damage. Accordingly, elevated levels of circulating endothelial cells (CEC) may be a marker for vascular injury. This study was undertaken to examine the possibility that stimulated EC are found in the circulation in patients with active SLE. METHODS: The study cohort included 38 patients with SLE and 16 healthy controls. Immunostaining was performed on mononuclear isolates, using mouse P1H12 (endothelial-specific antibody) and rabbit antinitrotyrosine (a "footprint" of a reactive form of nitric oxide [peroxynitritel). RESULTS: Levels of CEC were significantly higher in patients with active SLE compared with those in healthy controls (mean +/- SEM 32+/-7/ml versus 5+/-2/ml; P = 0.0028) and were correlated positively with plasma C3a in these patients (r = 0.81, P = 0.0008). Furthermore, CEC from these patients expressed an activated phenotype, as indicated by staining for nitrotyrosine. CONCLUSION: Elevated levels of CEC observed in patients with active SLE may represent a marker of endothelial injury. The activated phenotype of these cells suggests that they may be capable of further potentiating vascular injury by the production of inflammatory and prothrombotic mediators and engaging in heterotypic aggregation with neutrophils or platelets.

Cell Adhesion Molecules↗
PubMed2001

A randomized, double-blind, crossover clinical trial of diclofenac plus misoprostol versus acetaminophen in patients with osteoarthritis of the hip or knee.

OBJECTIVE: To perform a randomized, double-blind, crossover clinical trial of diclofenac + misoprostol versus acetaminophen in ambulatory patients with osteoarthritis of the hip or knee. METHODS: Patients in 12 ambulatory care settings were eligible if they were age >40 years and if they had Kellgren/Lawrence radiographic grade 2-4 osteoarthritis of the knee or hip and a score of > or =30 mm on a 100-mm visual analog pain scale. Patients were randomized to one of two groups, 75 mg diclofenac + 200 microg misoprostol twice daily or 1,000 mg acetaminophen 4 times daily (each for 6 weeks), and were then crossed over to the other treatment for 6 weeks. A placebo was included in each treatment regimen to enable double blinding. The primary outcome measures were the Western Ontario and McMaster Universities Osteoarthritis Index and the visual analog pain scale of the Multidimensional Health Assessment Questionnaire. Safety was assessed using a standard form to review adverse events. RESULTS: We enrolled 227 patients, of whom 218 provided data for the first treatment period and 181 provided data for both treatment periods. Significantly higher levels of improvement in the primary outcomes were seen for diclofenac + misoprostol than for acetaminophen (P < 0.001). Adverse events were more common when patients took diclofenac + misoprostol (P = 0.046). Diclofenac + misoprostol was rated as "better" or "much better" by 57% of the 174 patients who provided such ratings for both treatment periods, while acetaminophen was rated as "better" or "much better" by 20% of these patients, and 22% reported no difference (P < 0.001). Differences favoring diclofenac + misoprostol over acetaminophen were greater in patients with more severe osteoarthritis according to baseline pain scores, radiographs, or number of involved joints. CONCLUSION: Patients with osteoarthritis of the hip or knee had significantly greater improvements in pain scores over 6 weeks with diclofenac + misoprostol than with acetaminophen, although patients with mild osteoarthritis had similar improvements with both drugs. Acetaminophen was associated with fewer adverse events.

Acetaminophen↗
PubMed2001

Nitric oxide and inflammatory mediators in the perpetuation of osteoarthritis.

Articular chondrocyte production of nitric oxide (NO) and other inflammatory mediators, such as eicosanoids and cytokines, are increased in human osteoarthritis. The excessive production of nitric oxide inhibits matrix synthesis and promotes its degradation. Furthermore, by reacting with oxidants such as superoxide anion, nitric oxide promotes cellular injury and renders the chondrocyte susceptible to cytokine-induced apoptosis. PGE(2) exerts anabolic and catabolic effects on chondrocytes, depending on the microenvironment and physiologic condition. The increased expression of inducible NOS (iNOS) and cyclo-oxygenase-2 (COX-2) in OA chondrocytes is largely due to the increased expression of pro-inflammatory cytokines, particularly IL-1, which act in an autocrine/paracrine fashion to perpetuate a catabolic state that leads to progressive destruction of articular cartilage. The initiating factors for the production of inflammatory mediators include altered biomechanical forces; their continued production may be augmented by an increase in extracellular matrix proteins acting through ligation of surface integrins.

Cartilage, Articular↗
PubMed2001

The role of nitric oxide in tissue destruction.

Nitric oxide (NO) is synthesized via the oxidation of arginine by a family of nitric oxide synthases (NOS), which are either constitutive (ie. endothelial (ec)NOS and neuronal (nc)NOS) or inducible (iNOS). The production of nitric oxide plays a vital role in the regulation of physiological processes, host defence, inflammation and immunity. Pro-inflammatory effects include vasodilation, oedema, cytotoxicity and the mediation of cytokine-dependent processes that can lead to tissue destruction. Nitric oxide-dependent tissue injury has been implicated in a variety of rheumatic diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis and osteoarthritis. Conversely, the production of NO by endothelial cell NOS may serve a protective, or anti-inflammatory, function by preventing the adhesion and release of oxidants by activated neutrophils in the microvasculature. In this chapter we describe the multifaceted role of nitric oxide in inflammation and address the potential therapeutic implications of NOS inhibition.

Animals↗
PubMed2001

Activation of stress-activated protein kinase in osteoarthritic cartilage: evidence for nitric oxide dependence.

OBJECTIVE: We have demonstrated in bovine chondrocytes that nitric oxide (NO) mediates IL1 dependent apoptosis under conditions of oxidant stress. This process is accompanied by activation of c-Jun NH2-terminal kinase (JNK; also called stress-activated protein kinase). In these studies we examined activation of JNK in explant cultures of human osteoarthritic cartilage obtained at joint replacement surgery and we characterized the role of peroxynitrite to act as an upstream trigger. DESIGN: A novel technique to isolate chondrocyte proteins (<10% of total cartilage protein) from cartilage specimens was developed. It was used to analyse JNK activation by a western blot technique. To examine the hypothesis that chondrocyte JNK activation is a result of increased peroxynitrite, in vitro experiments were performed in which cultured chondrocytes were incubated with this oxidant. RESULTS: Activated JNK was detected in the cytoplasm of osteoarthritis (OA) affected chondrocytes but not in that of controls. In vitro, chondrocytes produce NO and superoxide anion. IL-1 (48 h), which induces nitric oxide synthase, resulted in an activation of JNK; this effect was reversed by N-monomethylarginine (NMA). TNFalpha treated chondrocytes at 48 h produce superoxide anion (EPR method). Exposure of cells to peroxynitrite led to an accumulation of intracellular oxidants, in association with JNK activation and cell death by apoptosis. CONCLUSION: We suggest that JNK activation is among the IL-1 elicited responses that injure articular chondrocytes and this activation of JNK is dependent on intracellular oxidant formation (including NO peroxynitrite). In addition, the extraction technique here described is a novel method that permits the quantitation and study of proteins such as JNK involved in the signaling pathways of chondrocytes within osteoarthritic cartilage.

Animals↗
PubMed2000

Reversal of autocrine and paracrine effects of interleukin 1 (IL-1) in human arthritis by type II IL-1 decoy receptor. Potential for pharmacological intervention.

Interleukin 1 (IL-1), produced by both synovial cells and chondrocytes, plays a pivotal role in the pathogenesis of cartilage destruction in osteoarthritis (OA). We examined the specific expression and function of IL-1 receptor family-related genes in human joint tissues. Gene array analysis of human normal and OA-affected cartilage showed mRNA expression of IL-1 receptor accessory protein (IL-1RAcp) and IL-1 type I receptor (IL-1RI), but not IL-1 antagonist (IL-1ra) and IL-1 type II decoy receptor (IL-1RII). Similarly, human synovial and epithelial cells showed an absence of IL-1RII mRNA. Functional genomic analyses showed that soluble (s) IL-1RII, at picomolar concentrations, but not soluble TNF receptor:Fc, significantly inhibited IL-1beta-induced nitric oxide (NO) and/or prostaglandin E(2) production in chondrocytes, synovial and epithelial cells. In OA-affected cartilage, the IC(50) for inhibition of NO production by sIL-1RII was 2 log orders lower than that for sIL-1RI. Human chondrocytes that overexpressed IL-1RII were resistant to IL-1-induced IL-1beta mRNA accumulation and inhibition of proteoglycan synthesis. In osteoarthritis, deficient expression by chondrocytes of innate regulators or antagonists of IL-1 such as IL-1ra and IL-1RII (soluble or membrane form) may allow the catabolic effects of IL-1 to proceed unopposed. The sensitivity of IL-1 action to inhibition by sIL-1RII has therapeutic implications that could be directed toward correcting this unfavorable tissue(s) dependent imbalance.

Animals↗
PubMed2000

Nitric oxide synthase/COX cross-talk: nitric oxide activates COX-1 but inhibits COX-2-derived prostaglandin production.

It is recognized that there is molecular cross-talk between the inflammatory mediators NO and PGs that may regulate tissue homeostasis and contribute to pathophysiological processes. However, the literature is divided with respect to whether NO activates or inhibits PG production. In this study, we sought to determine whether conflicting observations could be accounted for by divergent effects of NO on the two cyclooxygenase (COX) isoforms. Exposure of resting macrophages to NO (30 microM) enhanced PGE2 release by 4. 5-fold. This enhancement was inhibited by indomethacin but not by the COX-2 selective inhibitor NS398. To separate the activation of phospholipase A2 and COX, we performed experiments using fibroblasts derived from COX-1-deficient or COX-2-deficient mice. These cells exhibit increased basal PG production, which is due to a constitutively stimulated cytosolic phospholipase A2 and enhanced basal expression of the remaining COX isozyme. The exposure of COX- 2-deficient cells to exogenous NO (10 microM) resulted in a 2.4-fold increase of PGE2 release above controls. Further studies indicated that NO stimulated PGE2 release in COX-2-deficient cells, without altering COX-1 mRNA or protein expression. In contrast, NO inhibited COX-2-derived PGE2 production in both LPS-stimulated macrophages and COX-1 knockout cells. This inhibition was associated with both decreased expression and nitration of COX-2. Thus, these studies demonstrate divergent effects of NO on the COX isoforms. The regulation of PGE production by NO is therefore complex and will depend on the local environment in which these pleiotropic mediators are produced.

Animals↗
PubMed2000

Unresolved issues in the role of cyclooxygenase-2 in normal physiologic processes and disease.

Originally suggested to function mainly in inflammatory situations, recent data have implied important roles for the cyclooxygenase-2 isoenzyme in reproductive biologic processes, renal and neurologic function, and the antithrombotic activities of endothelial cells. As cyclooxygenase-2-specific inhibitors have recently become available as analgesic and anti-inflammatory drugs, a comprehensive view of this rapidly evolving field is necessary to anticipate both the potential therapeutic benefits and toxic effects associated with these agents.

Animals↗
PubMed2000

Functional genomic analysis in arthritis-affected cartilage: yin-yang regulation of inflammatory mediators by alpha 5 beta 1 and alpha V beta 3 integrins.

Osteoarthritis-affected cartilage exhibits enhanced expression of fibronectin (FN) and osteopontin (OPN) mRNA in differential display and bioinformatics screen. Functional genomic analysis shows that the engagement of the integrin receptors alpha 5 beta 1 and alpha v beta 3 of FN and OPN, respectively, have profound effects on chondrocyte functions. Ligation of alpha 5 beta 1 using activating mAb JBS5 (which acts as agonist similar to FN N-terminal fragment) up-regulates the inflammatory mediators such as NO and PGE2 as well as the cytokines, IL-6 and IL-8. Furthermore, up-regulation of these proinflammatory mediators by alpha 5 beta1 integrin ligation is mediated via induction and autocrine production of IL-1 beta, because type II soluble IL-1 decoy receptor inhibits their production. In contrast, alpha v beta 3 complex-specific function-blocking mAb (LM609), which acts as an agonist similar to OPN, attenuates the production of IL-1 beta, NO, and PGE2 (triggered by alpha 5 beta 1, IL-1 beta, IL-18, or IL-1 beta, TNF-alpha, plus LPS) in a dominant negative fashion by osteoarthritis-affected cartilage and activated bovine chondrocytes. These data demonstrate a cross-talk in signaling mechanisms among integrins and show that integrin-mediated "outside in" and "inside out" signaling very likely influences cartilage homeostasis, and its deregulation may play a role in the pathogenesis of osteoarthritis.

Adult↗
PubMed2000

Basic biology and clinical application of specific cyclooxygenase-2 inhibitors.

In summary, COX-2 is a highly regulated gene product that catalyzes the local production of PGs in pathologic and physiologic situations (Figure 1). It is clear that COX-2 is the isoform responsible for production of the PGs that mediate inflammation, pain, and fever. However, the role for COX-2 in normal physiology is still being defined. Specific COX-2 inhibitors represent a significant conceptual advance in therapy for patients with arthritis. Although there is no expectation of superior efficacy, clinical trials suggest that efficacy will be comparable with that of nonselective NSAIDs. Clinical trials demonstrate the potential for clinically meaningful reductions in the incidence of the most serious GI complications found with nonselective NSAIDs, i.e., ulcer, perforation, and GI bleeding. Over the next several years, treatment of large numbers of patients with specific COX-2 inhibitors will help to define the biology of COX-2. The magnitude of this advance in the therapy of rheumatic diseases is yet to be accurately determined, but the development of specific COX-2 inhibitors may afford significant new treatment options for many patients.

Cyclooxygenase 2↗
PubMed2000

Acetylcholine prevents intercellular adhesion molecule 1 (CD54)-induced focal adhesion complex assembly in endothelial cells via a nitric oxide-cGMP-dependent pathway.

OBJECTIVE: Nitric oxide (NO) is induced by exposure of endothelial cells (EC) to acetylcholine, where it acts in a paracrine manner to relax smooth muscle and as a defensive molecule to inhibit the adhesion of leukocytes to EC. The mechanism(s) of the antiadhesive properties of constitutive NO are poorly understood. In these studies, we found that NO induced by acetylcholine exerts autocrine effects, which interfere with normal adhesion mechanisms. METHODS: The function of the adhesion molecule intercellular adhesion molecule 1 (CD54) of EC was measured using latex beads coated with antibody to CD54 as a model for CD54 ligation by the leukocyte beta2 integrin. Recruitment of filamentous actin (F-actin) and of the signaling molecule vasodilator-stimulated phosphoprotein (VASP) was measured by immunofluorescence microscopy. RESULTS: Exposure of EC to anti-CD54 beads induced the subplasmalemmal assembly of F-actin and VASP. Acetylcholine blocked the anti-CD54 bead-induced translocation of F-actin and VASP; this effect was reversed by inhibition of NO production. The NO action did not interfere with binding, but completely inhibited the assembly of the focal activation complex, which we believe is necessary for firm heterotypic adhesion between leukocyte and EC. Further studies indicated that the NO effect was due to its capacity to raise cGMP. Platelet endothelial cell adhesion molecule 1 (CD31, also implicated in leukocyte adhesion) did not mimic CD54 responses. CONCLUSION: These results indicate that the ligation of endothelial cell CD54 induces the assembly of subplasmalemmal F-actin and the recruitment of VASP. NO derived from constitutive nitric oxide synthase acts to disrupt these CD54-elicited endothelial cell responses. This action may protect vascular endothelium from leukocyte-mediated injury.

Acetylcholine↗