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ID PMID Title PublicationDate abstract
19689372 Successful structure-based design of recent p38 MAP kinase inhibitors. 2009 Inflammation is a complex immune response to cellular and tissue damage caused by physical, chemical, immunological, or microbial stimuli [1]. Prior to the successful launch of the anti-cytokine biologics [2-4], therapeutic approaches for the treatment of chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease were associated with severe side effects. Although biological agents have revolutionized the treatment of inflammatory disorders, the high costs and inconvenient dosing regimens would greatly benefit from novel safe and effective orally active inhibitors of tumor necrosis factor (TNF) alpha and interleukin (IL) 1beta. The clinical benefit of anti-cytokine therapy [5] and the central role of the p38 mitogen-activated protein (MAP) kinase in up-regulation of pro-inflammatory cytokines such as IL-1beta and TNF-alpha [6] suggest that p38 MAP kinase is a promising target for anti-inflammatory therapy [7-14]. Since 1993 an immense number of inhibitors of p38 MAP kinase have been characterized. To date, aside from the well known pyridinylimidazoles, multiple novel scaffolds have been identified, but only a small number have advanced into clinical phase II studies [15], probably due to high toxicity and poor selectivity [16]. To gain safe drug profiles, high potency, marginal CYP450 (cytochrome P450) interaction and toxicity, as well as high levels of selectivity would be desirable. This review will summarize current knowledge on p38 MAP kinase inhibitors and will critically discuss proceedings and strategies toward achieving selectivity and potency.
19669924 Pharmacophore generation and atom-based 3D-QSAR of novel 2-(4-methylsulfonylphenyl)pyrimid 2010 Aug Cyclooxygenase-2 (COX-2) inhibitors are widely used for the treatment of pain and inflammatory disorders such as rheumatoid arthritis and osteoarthritis. A series of novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives has been reported as COX-2 inhibitors. In order to understand the structural requirement of these COX-2 inhibitors, a ligand-based pharmacophore and atom-based 3D-QSAR model have been developed. A five-point pharmacophore with four hydrogen bond acceptors (A) and one hydrogen bond donor (D) was obtained. The pharmacophore hypothesis yielded a 3D-QSAR model with good partial least-square (PLS) statistics results. The training set correlation is characterized by PLS factors (r (2) = 0.642, SD = 0.65, F = 82.7, P = 7.617 e - 12). The test set correlation is characterized by PLS factors (Q (2) (ext) = 0.841, RMSE = 0.24,Pearson-R = 0.91). A docking study revealed the binding orientations of these inhibitors at active site amino acid residues (Arg513, Val523, Phe518, Ser530, Tyr355, His90) of COX-2 enzyme. The results of ligand-based pharmacophore hypothesis and atom-based 3D-QSAR give detailed structural insights as well as highlights important binding features of novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives as COX-2 inhibitors which can provide guidance for the rational design of novel potent COX-2 inhibitors.
19647202 Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients trea 2009 Aug Progressive multifocal leucoencephalopathy (PML) is a serious and usually fatal CNS infection caused by JC polyoma virus. CD4+ and CD8+ T lymphopenia, resulting from HIV infection, chemotherapy, or immunosuppressive therapy, are the primary risk factors. The immune modulatory monoclonal antibodies rituximab, natalizumab, and efalizumab have received regulatory approval in the USA and Europe for treatment of non-Hodgkin lymphoma, rheumatoid arthritis, and chronic lymphocytic leukaemia (Europe only); multiple sclerosis and Crohn's disease; and psoriasis, respectively. Efalizumab and natalizumab administration is associated with CD4+ T lymphopenia and altered trafficking of T lymphocytes into the CNS, and rituximab leads to prolonged B-lymphocyte depletion. Unexpected cases of PML developing in people who receive these drugs have been reported, with many of the affected individuals dying from this disease. Herein, we review clinical findings, pathology, epidemiology, basic science, and risk-management issues associated with PML infection developing after treatment with these monoclonal antibodies.
19608087 Systemic CD5+ MALT lymphoma: presentation with Waldenstrom syndrome. 2009 Aug We report a case of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) in a 75-year-old woman with a neuropathy related to high levels of serum immunoglobulin M and a history of rheumatoid arthritis and polymyositis. The patient developed a mass in the right submandibular salivary gland, and this mass demonstrated histopathologic features that are typical of MALT lymphoma, including infiltrates of small monocytoid B cells in the epithelium (forming "lymphoepithelial lesions"), a reactive background of florid germinal center hyperplasia, and follicular colonization by the monocytoid B cells. Many plasma cells in the background expressed cytoplasmic immunoglobulin M lambda, matching the serum spike. Flow cytometric analysis confirmed the presence of clonal mature B cells; however, unlike most MALT lymphomas, these cells coexpressed dim CD5. Clinical staging revealed evidence of systemic distribution with documented disease involving the bone marrow, the lung, and a paratracheal lymph node. Analysis of this unusual systemic MALT lymphoma, and a comparison with similar examples from the literature, illuminates relationships among MALT lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and Waldenstrom macroglobulinemia.
19569123 Feasibility of electrodialysis as a fast and selective sample preparation method for the p 2009 Jul Considerable interest exists in endogenous peptides as potential biomarkers, since they act as signaling molecules and are formed by degradation of proteins. A crucial step in the profiling of these peptides is the sample preparation, which aims to enrich the low-abundant peptides, while removing interfering matrix compounds. In a feasibility study we examined the suitability of electrodialysis (ED) for this purpose. A custom-made device was developed from the low-binding material Kel-F. It consisted of two compartments separated by a dialysis membrane, over which a voltage was applied. One compartment served as donor (containing the sample), while the smaller acceptor compartment collected the peptides. The procedure was optimized by investigating the effect of the applied voltage, ammonium acetate buffer concentration, and ED duration using model peptides. Optimum conditions were found at 300 V (150 V/cm), 25 mM ammonium acetate buffer (pH 3.8) containing 20% v/v DMSO, and 10 min, respectively. With these optimized parameters, recoveries for the model peptides were found to be 35-85% (average 64%). Additionally, ED was successfully applied to the challenging synovial fluid biological sample (due to its high viscosity). In a synovial fluid sample from a rheumatoid arthritis patient, 27 peptides originating from 12 proteins were identified, of which a considerable fraction was not identified before with other methods. This demonstrates the usefulness and complementary nature of combining ED with nanoLC-MS for biomarker discovery. These results indicate that ED is promising as a fast and selective sample preparation method for the profiling of endogenous peptides.
19514471 [Modified Swanson's hip replacement--intraoperative complications and learning curve of th 2009 Jan Our study aimed at analysis and presentation of intraoperative complications during total hip replacements with the use of limited posterior approach according to T.V. Swanson. Consecutive 210 hip arthroplasies (79 males, 131 females, aged 20-87 years, mean age 61 +/- 12,) were analyzed according to intraoperative complications. Left hip was operated in 117 cases, right in 93, bilateral procedure was performed in 27 cases (9 men, 18 women). Idiopathic disease occurred in 196 hips, 8 were result of rheumatoid arthritis, in 5 was of dysplastic origin and one occurred due to idiopathic necrosis of femoral head. In 120 cases concomitant arthrosis of the lumbosacral spine and the other joints of the lower limbs was recorded. Preoperative Harris Hip Score (HSS) was 30 +/- 5 points and Body Mass Index (BMI) ranged from 23 to 36. Our clinical material was divided into three equeal series of consecutive hip replacements (n = 70). Each of the series represented different intraoperative complications. In the first series five intraoperative notorious bleedings, four transient sciatic nerve palsies, two injuries to piriforimis muscle and one spiral fracture of the proximal femur were noted. In the second series no important adverse intraoperative findings occurred. In the third series two perforations of the acetabulum and one fracture of the femur were observed. Differences of frequencies of vascular and neural complications between these three series appeared statistically significant. The authors suggested that these observations represent the "learning curve" of the new surgical procedure--the first phase reflects difficulties and technical errors, the second without complications--maturity of the procedure and the third one carelessness due to having false sense of "perfection" by the operators.
19384549 [B-cell-targeted therapy in the treatment of autoimmune diseases]. 2009 May In recent years a growing body of evidence suggests a more central role for B-cells in the pathogenesis of several autoimmune diseases, apart from being the precursors of autoantibody-producing plasma cells. B-lymphocytes play an important role in the pathogenesis of various autoimmune diseases. In particular, the introduction of rituximab, a depleting antibody targeting CD20+ B cells and its clinical efficacy in rheumatoid arthritis, systemic lupus erythematosus, vasculitis and multiple sclerosis has stimulated further B-cell-targeted therapies. Other biologicals targeting CD20 are under clinical investigation. New strategies include targeting further B-cell surface markers such as CD22, as well as blocking B-cell-activating factors or their receptors.
19275551 Role of NF-kappaB in the regulation of cytochrome P450 enzymes. 2009 Feb Nuclear factor kappa B (NF-kappaB) is an important transcription factor that regulates a wide spectrum of genes including cytochrome P450 (CYP), the most important family of drug metabolizing enzymes. Therefore, in this review, we addressed the potential role of NF-kappaB in CYP regulation. We proposed three mechanisms by which NF-kappaB can regulate CYP expression and activity. First, NF-kappaB can directly regulate the expression of CYP1A1, CYP2B1/2, CYP2C11, CYP2D5, CYP2E1, CYP3A7, and CYP27B1 through binding to the promoter region of these genes. Second, NF-kappaB indirectly regulates the transcription of CYP genes through mutual repression with some nuclear receptors that are involved in CYP regulation such as AhR, CAR, GR, PXR, RXR, PPAR, FXR, and LXR. Finally, NF-kappaB can regulate CYP activity at post-transcriptional level by inducing heme oxygenase or by affecting the CYP protein stability. In addition, increased inflammatory mediators, oxidative stress, and subsequent NF-kappaB activation have been demonstrated in many conditions such as inflammatory bowel diseases, rheumatoid arthritis, psychological stress, diabetes, aging, cancer, renal diseases, and congestive heart failure. Meanwhile, there is a significant alteration of CYP expression and activity in these diseases. Therefore, we propose that NF-kappaB could be one of the links between inflammation, oxidative stress, and CYP regulation in these diseases. In conclusion, NF-kappaB plays a crucial role in the regulation of CYP through several mechanisms and this role can explain the altered CYP regulation in many conditions.
19236867 Suppression of Tie-1 in endothelial cells in vitro induces a change in the genome-wide exp 2009 Mar 18 Tie-1 is an endothelial specific receptor tyrosine kinase that is upregulated in diseases such as atherosclerosis and rheumatoid arthritis. We recently demonstrated that Tie-1 induced a proinflammatory response when overexpressed in endothelial cells. Here, we used a complementary approach and suppressed endogenous Tie-1 expression in endothelial cells to examine its function by microarray analysis. Tie-1 appeared to govern expression of many genes involved in inflammation. Expression knockdown of Tie-1 significantly reduced endothelial conditioned medium ability to stimulate MCP-1 production in U937 cells. Collectively, our results support the notion that Tie-1 has an inflammatory function in endothelial cells.
19220017 Nuclear factor-kappaB mediated inhibition of cytokine production by imidazoline scaffolds. 2009 Mar 12 The mammalian nuclear transcription factor NF-kappaB is responsible for the transcription of multiple cytokines, including the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). Elevated levels of pro-inflammatory cytokines play an important role in the pathogenesis of inflammatory disorders such as rheumatoid arthritis (RA). Inhibition of the pro-inflammatory transcription factor NF-kappaB has therefore been identified as a possible therapeutic treatment for RA. We describe herein the synthesis and biological activity of a series of imidazoline-based scaffolds as potent inhibitors of NF-kappaB mediated gene transcription in cell culture as well as inhibitors of TNF-alpha and IL-6 production in interleukin 1 beta (IL-1beta) stimulated human blood.
19089894 Goal achievement provides new insights into interstitial cystitis/painful bladder syndrome 2009 AIMS: Goal Assessment Scaling (GAS), wherein patients specify goals then evaluate treatments with regard to goal achievement, has proven utility in assessing treatment of complex conditions such as chronic pain, rheumatoid arthritis, and incontinence. We used surveys and focus groups to characterize the goals of patients with interstitial cystitis/painful bladder syndrome (IC/PBS) in order to create a pilot GAS. METHODS: 37 patients with IC/PBS recorded and ranked their treatment goals which were pooled and analyzed for emergent domains and priority rankings. 15 patients participated in 3 separate focus groups. Focus group audiotapes were transcribed and reviewed to identify major themes and goals domains. RESULTS: 140 separate goals were collected. Mean number of goals 4+/-2.73% had pain goals and 56% had frequency and/or nocturia goals. Focus groups revealed that urgency is a separate entity from pain or frequency and any of these may take priority. The groups defined urgency for IC/PBS patient as "the need to urinate due to an unpleasant sensation that prevents attention to any other task." Additional goal domains of control, predictability, and information were explored. Unsatisfactory aspects of common urological surveys were discussed as well as positive and negative aspects of GAS. CONCLUSIONS: Patients have individualized treatment goals. GAS holds promise for addressing individuality in a standardized format. A new instrument developed from this work is being piloted in a multicenter RCT. We also suggest that questionnaires investigating urgency in IC/PBS clarify the definition in a way more applicable to the specific condition.
18962898 Short leucine-rich glycoproteins of the extracellular matrix display diverse patterns of c 2009 Feb The extracellular matrix consists of structural macromolecules and other proteins with regulatory functions. An important family of the latter class of molecules found in most tissues is the small leucine-rich repeat proteins (SLRPs). We have previously shown that the SLRP fibromodulin binds directly to C1q and activates the classical pathway of complement. In the present study we further examine the interactions between SLRPs and complement. Osteoadherin, like fibromodulin, binds C1q and activates the classical pathway strongly while moderate activation is seen in the terminal pathway. This can be explained by the interaction of fibromodulin and osteoadherin with factor H, a major soluble inhibitor of complement. Also, chondroadherin was found to bind C1q and activate complement, albeit to a lesser extent. Chondroadherin also binds factor H. We confirm published data showing that biglycan and decorin bind C1q but do not activate complement. In this study a similar pattern is seen for lumican although its affinity for C1q is lower than for biglycan and decorin. Furthermore, using electron microscopy and radiolabeled SLRPs, we demonstrate two different classes of SLRP binding sites on C1q, to head and stalk respectively, where only binding to the head appears to be activating. We propose a role for SLRPs in the regulation of complement activation in diseases involving the extracellular matrix, particularly those characterized by chronic inflammation such as rheumatoid arthritis, atherosclerosis, osteoarthritis and chronic obstructive lung disease.
21221071 The role of radiolabelled anti-TNFa monoclonal antibodies for diagnostic purposes and ther 2010 Dec Radiolabelled cytokines and monoclonal antibodies are an emerging class of radiopharmaceuticals for imaging inflammation. These radiopharmaceuticals bind to their targets with high affinity and specificity and therefore have excellent diagnostic potential for imaging of patients with chronic inflammatory diseases. One of the key cytokines involved in the process of inflammation is tumor necrosis factor alpha (TNFα). With the introduction of anti-TNFα monoclonal antibodies over the past decade, treatment of inflammatory diseases has evolved, which allowed remarkable advances in controlling signs and symptoms of inflammation and in slowing destruction. However, drugs may lose efficacy over time in patients or induce adverse events. Using immediately the right medication tailored to the patient's molecular status avoids unnecessary costs and side effects. Significant differences in mechanisms of action and in therapy outcome, depending on the disease to be treated, exist among the different TNFα antagonists. Labelling these agents may help to find out if TNFα is present in the inflammatory process and will therefore help in therapy prediction and stratification in the individual patient. This review describes the role of cytokines and in particular of TNFα in the process of inflammation as well as the influence of TNFα in some well-known and common inflammatory diseases, such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel diseases, psoriasis and sarcoidosis. The main focus of this article is to review the role of molecular imaging with radiolabelled anti-TNFα monoclonal antibodies for diagnostic purposes, and in therapy precision, decision-making and evaluation.
21145999 Denosumab and bisphosphonates: different mechanisms of action and effects. 2011 Apr 1 To treat systemic bone loss as in osteoporosis and/or focal osteolysis as in rheumatoid arthritis or periodontal disease, most approaches target the osteoclasts, the cells that resorb bone. Bisphosphonates are currently the most widely used antiresorptive therapies. They act by binding the mineral component of bone and interfere with the action of osteoclasts. The nitrogen-containing bisphosphonates, such as alendronate, act as inhibitors of farnesyl-pyrophosphate synthase, which leads to inhibition of the prenylation of many intracellular signaling proteins. The discovery of RANKL and the essential role of RANK signaling in osteoclast differentiation, activity and survival have led to the development of denosumab, a fully human monoclonal antibody. Denosumab acts by binding to and inhibiting RANKL, leading to the loss of osteoclasts from bone surfaces. In phase 3 clinical studies, denosumab was shown to significantly reduce vertebral, nonvertebral and hip fractures compared with placebo and increase areal BMD compared with alendronate. In this review, we suggest that the key pharmacological differences between denosumab and the bisphosphonates reside in the distribution of the drugs within bone and their effects on precursors and mature osteoclasts. This may explain differences in the degree and rapidity of reduction of bone resorption, their potential differential effects on trabecular and cortical bone, and the reversibility of their actions.
21059888 Pharmacokinetic-pharmacodynamic modeling of apratastat: a population-based approach. 2011 Apr Apratastat is an orally active, potent, and reversible dual inhibitor of tumor necrosis factor-α converting enzyme (TACE) and matrix metalloproteinases (MMPs). This study characterizes the pharmacodynamic (PD) effect of apratastat following oral administration on tumor necrosis factor-alpha (TNF-α) release. Data were obtained from 3 clinical studies carried out in healthy subjects. Apratastat was administered orally in these studies as single doses or multiple doses (twice daily). The inhibition of TNF-α release by apratastat was investigated in studies of in vitro, ex vivo, and in vivo. Inhibitory E(max) models were used to characterize the inhibition of TNF-α release in both in vitro and ex vivo studies. Apratastat inhibited TNF-α release with a population mean IC(50) of 144 ng/mL in vitro and of 81.7 ng/mL ex vivo, respectively. The relationship between TNF-α and apratastat plasma concentration in the endotoxin-challenged study in healthy subjects was well characterized by a mechanism-based PD population model with IC(50) of 126 ng/mL. Apratastat can potently inhibit the release of TNF-α in vitro, ex vivo, and in vivo. Even though the dosage provided adequate exposure to inhibit TNF-α release, apratastat was not efficacious in rheumatoid arthritis (RA). This inconsistency between TNF-α inhibition and the clinical response requires further investigation.
20953224 Outcome of patients on azathioprine: a need for a better pre-treatment assessment and dosi 2010 Oct 15 BACKGROUND: Azathioprine (AZA) is a commonly used drug for the management of various rheumatologic disorders. Due to individual variation of the metabolism of AZA, related to genetic polymorphism of the thiopurine methyl transferase (TPMT), serious toxic effects can result if inappropriate dose is administered. AZA dosing according to patients TPMT status can reduce drug-induced morbidity and can be cost effective. AIM: To determine the current local practice of AZA dosing, identify AZA-related toxicity and to compare the local practice with the British Society of Rheumatology (BSR) recommendations. METHODS: Retrospective review of patients on AZA for various rheumatologic conditions from inpatient (n=22) and outpatient (n=38) database at Middlemore Hospital, from January 2003 to January 2007. Data were collected on patient's demographics, treatment history including AZA dosing regimen, TPMT testing, drug-related toxicities and their management. RESULTS: The mean age was 53 years; 73% were females. 43% of European ethnicity; mean weight of patient was 75±25 kg. 42% had SLE, 22% had rheumatoid arthritis, and 13% had systemic vasculitis. Average initial dose of AZA prescribed was 100±37 mg. 45% developed AZA related toxicity. AZA was withdrawn in 35 % of patients due to drug-related side-effects and inefficacy.15% of the patients required dose reduction. TPMT status was tested in 6 (10%) patients; three had low TMPT level, needing dose reduction. BSR recommendation for AZA dosing was followed in 15% cases. CONCLUSION: A significant proportion of the studied cohort of rheumatologic patients on AZA had drug-related toxicity resulting in discontinuation of AZA. Our data suggests that better pre-treatment assessment including TPMT testing and the practice of guideline based dosing regimen would reduce the incidence of undue side-effects and discontinuation of such treatment.
20943397 Molecular modeling study on potent and selective adenosine A(3) receptor agonists. 2010 Nov 15 Adenosine A(3) receptor (A(3)AR) is involved in a variety of key physio-pathological processes and its agonists are potential therapeutic agents for the treatment of rheumatoid arthritis, dry eye disorders, asthma, as anti-inflammatory agents, and in cancer therapy. Recently reported MECA (5'-N-methylcarboxamidoadenosine) derivatives bearing a methyl group in N(6)-position and an arylethynyl substituent in 2-position demonstrated to possess sub-nanomolar affinity and remarkable selectivity for the human A(3)AR, behaving as full agonists of this receptor. In this study, we made an attempt to get a rationalization of the high affinities and selectivities of these molecules for the human A(3)AR, by using adenosine receptor (AR) structural models based on the A(2A)AR crystal structure and molecular docking analysis. Post-docking analysis allowed to evaluate the ability of modeling tools in predicting AA(3)R affinity and in providing interpretation of compound substituents effect on the A(3)AR affinity and selectivity.
20621167 Comparative study on the anti-inflammatory and immune suppressive effect of Wilforlide A. 2010 Dec Tripterygium Glycosides (TG) is effective in the treatment of patients with a variety of inflammatory and autoimmune diseases, especially rheumatoid arthritis (RA) in clinical. Wilforlide A (T(1)) serves as a quality control standard of TG that be listed in Drug Standard of Ministry of Public Health of the People's Republic of China. The pharmacologic actions of T(1) remain to be unidentified. In this paper, we studied the anti-inflammatory and immune suppressive effect of T(1), and compared it with Triptolide (TP), which believed to be the major active component of TG. Carrageenan-induced rat pedal swelling, tampon-induced rat granulation, and mice ear inhibition rate of swelling trail results show that high-dose T(1) has obvious anti-inflammatory effect. Colorimetric detection contents of hemolysin, carbon elimination from plasma of mice, mice delayed hypersensitivity immune, and organ index were measured. The results show that T(1) has no significant immune suppressive activity, and there has a significant difference with TP and TG. Therefore, we think the content of TP also should be controlled as a supplement standard in order to ensure safe and effective medication.
20641204 Gd-DOTA-G-NH(CH(2))(11)CO-RSPAYYTAA-(CH(2)CH(2)O)(8)-R. 2004 Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases localized at the cell surface or in extracellular compartments (1). MMPs degrade all components of the extracellular matrix (ECM) and are associated with a variety of pathological conditions such as wound healing, tissue remodeling, tumor angiogenesis, and embryo development. The active site of MMPs contains a catalytic domain coordinated by zinc to recognize motifs with a consensus sequence of PXX↓X(Hy), where ↓ represents the cleavage point and X(Hy) represents a large hydrophobic residue (2). Excess MMP activity has been observed in conjunction with many diseases, including rheumatoid arthritis, osteoarthritis, autoimmune diseases, cardiovascular diseases, and cancer (3). For example, an overexpression of MMP subtype-2 (MMP-2 or gelatinase A), an enzyme that degrades type IV collagen and gelatin, is present in many human tumors (4). Thus, MMP has been an important therapeutic target for many years (5). Gadolinium (Gd)-labeled DOTA-G-NH(CH(2))(11)CO-RSPAYYTAA-(CH(2)CH(2)O)(8)-R (GdPCA2) is a proteinase-modulated contrast agent (PCA) for in vivo imaging of MMP-2 with magnetic resonance imaging (MRI) (6). GdPCA2 consists of four components: a peptide substrate (RSPAY↓YTAA) specific for MMP-2, a Gd-DOTA complex as an MRI probe, an alkyl chain of 12-carbon as a hydrophilic linker between the N-terminus of the peptide and the MRI probe, and an eight-unit polyethylene glycol (PEG(8)) chain linked to the C-terminus of the peptide to enhance the solubility of GdPCA2. The cleavage of GdPCA2 by MMP-2 produces a less soluble Gd(3+)-labeled fragment. Thus, the Gd species acts as a solubility switch specific for the enzyme MMP-2. GdPCA2 may have different pharmacokinetics than its cleaved product, which can be used to evaluate MMP-2 activity via dynamic MRI measurement.
20112365 Effect of interleukin-32gamma on differentiation of osteoclasts from CD14+ monocytes. 2010 Feb OBJECTIVE: Interleukin-32 (IL-32) induces various inflammatory molecules in human monocytes and differentiation of monocytes into macrophage-like cells. This study was undertaken to evaluate the effects of IL-32gamma, the most biologically active isoform, on the differentiation and activation of osteoclasts. METHODS: CD14+ monocytes were obtained from healthy volunteers, and samples of synovial tissue and synovial fluid were obtained from patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA). The concentration and expression levels of IL-32gamma in RA and OA samples were evaluated by enzyme-linked immunosorbent assay and immunoblotting, respectively. To examine the osteoclastogenic effects and functional activities, isolated monocytes were treated with either IL-32gamma or IL-17 in the presence or absence of soluble RANKL (sRANKL) on a culture system and on Osteologic disks. The expression of RANKL and osteoprotegerin (OPG) messenger RNA (mRNA) in RA fibroblast-like synoviocytes (FLS) was measured using reverse transcription-polymerase chain reaction (PCR) and real-time PCR. RESULTS: The concentration and expression levels of IL-32gamma were higher in the RA samples than in the OA samples. Upon costimulation with sRANKL, the osteoclast count and resorbed area increased more significantly in the IL-32gamma-stimulated cultures than in those stimulated with IL-17. In the IL-32gamma-treated group without sRANKL stimulation, osteoclasts were differentiated, but the cells displayed low resorption activity. In RA FLS, RANKL mRNA expression increased in the presence of both IL-32gamma and IL-17. However, transcription of OPG decreased following IL-32gamma stimulation, resulting in a significant increase in the RANKL:OPG ratio. CONCLUSION: Our results suggest that IL-32gamma is a potent mediator of active osteoclast generation in the presence of sRANKL. Moreover, this novel cytokine creates more favorable conditions for osteoclastogenesis in the RA joint by increasing the RANKL:OPG ratio in FLS.