Search

Background We examined effects of single-nucleotide variants (SNVs) of IL1RN , the gene encoding the anti-inflammatory interleukin 1 receptor antagonist (IL-1Ra), on the cytokine release syndrome (CRS) and mortality in patients with acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Methods IL1RN CTA haplotypes formed from 3 SNVs (rs419598, rs315952, rs9005) and the individual SNVs were assessed for association with laboratory markers of inflammation and mortality. We studied 2589 patients hospitalized with SARS-CoV-2 between March 2020 and March 2021. Results Mortality was 15.3% and lower in women than men (13.1% vs 17.3%, P =.0003). Carriers of the CTA-1/2 IL1RN haplotypes exhibited decreased inflammatory markers and increased plasma IL-1Ra. Evaluation of the individual SNVs of the IL1RN, carriers of the rs419598 C/C SNV exhibited significantly reduced inflammatory biomarker levels and numerically lower mortality compared to the C/T-T/T genotype (10.0% vs 17.8%, P =.052) in men, with the most pronounced association observed in male patients ≤74 years old, whose mortality was reduced by 80% (3.1% vs 14.0%, P =.030). Conclusions The IL1RN haplotype CTA and C/C variant of rs419598 are associated with attenuation of the CRS and decreased mortality in men with acute SARS-CoV-2 infection. The data suggest that the IL1RN pathway modulates the severity of coronavirus disease 2019 (COVID-19) via endogenous anti-inflammatory mechanisms. [ABSTRACT FROM AUTHOR]

Objective Degeneration of articular cartilage is central to the pathology of osteoarthritis (OA). However, the molecular mechanisms leading to these irreversible changes are still poorly understood. This study was undertaken to investigate how changes in the chondrocyte translational apparatus may contribute to the development and progression of knee OA. Methods Articular cartilage from the knees of normal healthy subjects and patients with OA was used to analyze the activity of different components of the translational machinery. Chondrocytes isolated from lesional and nonlesional areas of the human OA cartilage were used to estimate the relative rate of protein synthesis by metabolic labeling. Experimental OA was induced by transection of the anterior cruciate ligament of rats to investigate changes in the translational apparatus associated with OA. The role of interleukin-1β (IL-1β) signaling was assessed in vitro using rat articular chondrocytes. In human or rodent knee cartilage, messenger RNA expression was analyzed by quantitative polymerase chain reaction, and protein levels were determined by immunohistochemistry and Western blotting. Results Several novel traits of OA chondrocytes were identified, including up-regulation of the serine/threonine kinases Akt-2 and Akt-3 at the posttranscriptional level and an increased rate of total protein synthesis, likely attributable to inactivation of eukaryotic initiation factor 4E binding protein 1 (4E-BP1), a known repressor of cap-dependent translation. Inactivation of 4E-BP1 was dependent on the activity of mechanistic target of rapamycin and was crucial for the up-regulation of protein synthesis in general and expression of matrix metalloproteinase 13 and ADAMTS-5 in particular. In addition, treatment of articular chondrocytes with IL-1β led to inactivation of 4E-BP1 and up-regulation of protein synthesis. Conclusion Precise control of protein synthesis is vital for cartilage homeostasis, and its dysregulation contributes to the molecular pathology of OA. The results of this study therefore identify a novel set of potential therapeutic targets to ameliorate the effects of knee OA. [ABSTRACT FROM AUTHOR]

Objective Inflammatory mediators, such as prostaglandin E2 (PGE2) and interleukin-1β (IL-1β), are produced by osteoarthritic (OA) joint tissue, where they may contribute to disease pathogenesis. We undertook the present study to examine whether inflammation, evidenced in plasma and peripheral blood leukocytes (PBLs), reflects the presence, progression, or specific symptoms of symptomatic knee OA. Methods Patients with symptomatic knee OA were enrolled in a 24-month prospective study of radiographic progression. Standardized knee radiographs were obtained at baseline and 24 months. At baseline, levels of the plasma lipids PGE2 and 15-hydroxyeicosatetraenoic acid (15-HETE) were measured, and transcriptome analysis of PBLs was performed by microarray and quantitative polymerase chain reaction. Results Baseline PGE2 synthase (PGES) levels determined by PBL microarray gene expression and plasma PGE2 levels distinguished patients with symptomatic knee OA from non-OA controls (area under the receiver operating characteristic curve [AUC] 0.87 and 0.89, respectively, P < 0.0001). Baseline plasma 15-HETE levels were significantly elevated in patients with symptomatic knee OA versus non-OA controls ( P < 0.0195). In the 146 patients who completed the 24-month study, elevated baseline expression of IL-1β, tumor necrosis factor α, and cyclooxygenase 2 (COX-2) messenger RNA in PBLs predicted higher risk of radiographic progression as evidenced by joint space narrowing (JSN). In a multivariate model, AUC point estimates of models containing COX-2 in combination with demographic traits overlapped the confidence interval of the base model in 2 of the 3 JSN outcome measures (JSN >0.0 mm, JSN >0.2 mm, and JSN >0.5 mm; AUC 0.62-0.67). Conclusion The inflammatory plasma lipid biomarkers PGE2 and 15-HETE identify patients with symptomatic knee OA, and the PBL inflammatory transcriptome identifies a subset of patients with symptomatic knee OA who are at increased risk of radiographic progression. These findings may reflect low-grade inflammation in OA and may be useful as diagnostic and prognostic biomarkers in clinical development of disease-modifying OA drugs. [ABSTRACT FROM AUTHOR]

We investigated the role of periostin, an extracellular matrix protein, in the pathophysiology of osteoarthritis (OA). In OA, dysregulated gene expression and phenotypic changes in articular chondrocytes culminate in progressive loss of cartilage from the joint surface. The molecular mechanisms underlying this process are poorly understood. We examined periostin expression by immunohistochemical analysis of lesional and nonlesional cartilage from human and rodent OA knee cartilage. In addition, we used small interfering (si)RNA and adenovirus transduction of chondrocytes to knock down and up-regulate periostin levels, respectively, and analyzed its effect on matrix metalloproteinase (MMP)-13, a disintegrin and MMP with thrombospondin motifs (ADAMTS)-4, and type II collagen expression. We found high periostin levels in human and rodent OA cartilage. Periostin increased MMP-13 expression dose [1-10 µg/ml (EC50 0.5-1 μg/ml)] and time (24-72 h) dependently, significantly enhanced expression of ADAMTS4 mRNA, and promoted cartilage degeneration through collagen and proteoglycan degradation. Periostin induction of MMP-13 expression was inhibited by CCT031374 hydrobromide, an inhibitor of the canonical Wnt/β-catenin signaling pathway. In addition, siRNA-mediated knockdown of endogenous periostin blocked constitutive MMP-13 expression. These findings implicate periostin as a catabolic protein that promotes cartilage degeneration in OA by up-regulating MMP-13 through canonical Wnt signaling. [ABSTRACT FROM AUTHOR]

The aims of this study are to compare plasma levels of IL17A, A/F, and F biomarkers in RA patients versus controls, and to determine responsiveness to methotrexate (MTX), anti-TNFs, and abatacept. We selected plasma samples from RA cohorts consisting of a cross-sectional RA cohort ( N = 78) not receiving DMARDs at the time of sampling, as well as from longitudinal drug start cohorts ( N = 71 patients) with pre/post samples including anti-TNF, abatacept, and MTX-treated patients. We assayed IL-17A, IL-17F, and IL17-A/F using a highly sensitive immunoassay system. Plasma levels of IL-17A, IL-17A/F, and IL-17F were all significantly increased in RA versus controls. The difference was largest in IL-17F, with median IL-17F levels in RA patients being approximately 18-fold higher than controls (81 pg/mL in RA vs. 4.4 pg/mL in controls, p < 0.001). Among the forms of IL-17, only IL-17F was decreased after therapy in the MTX cohort ( p = 0.006), abatacept cohort ( p < 0.001), and anti-TNF cohorts ( p = 0.02), whereas IL-17A and IL-17A/F were not significantly decreased for any of the three drug cohorts. Synovial fluid analysis demonstrated higher IL-17F levels in RA ( p = 0.016) than healthy controls. These results suggest a specific role for IL-17F in human RA pathogenesis and as a therapeutic target. [ABSTRACT FROM AUTHOR]

F-spondin is a pericellular matrix protein upregulated in developing growth plate cartilage and articular cartilage during osteoarthritis. To address its function in bone and cartilage in vivo, we generated mice that were deficient for the F-spondin gene, Spon1. Spon1−/− mice were viable and developed normally to adulthood with no major skeletal abnormalities. At 6 months, femurs and tibiae of Spon1−/− mice exhibited increased bone mass, evidenced by histological staining and micro CT analyses, which persisted up to 12 months. In contrast, no major abnormalities were observed in articular cartilage at any age group. Immunohistochemical staining of femurs and tibiae revealed increased levels of periostin, alkaline phosphate and tartrate resistant acid phosphatase (TRAP) activity in the growth plate region of Spon1−/− mice, suggesting elevated bone synthesis and turnover. However, there were no differences in serum levels of TRAP, the bone resorption marker, CTX-1, or osteoclast differentiation potential between genotypes. Knockout mice also exhibited reduced levels of TGF-β1 in serum and cultured costal chondrocytes relative to wild type. This was accompanied by increased levels of the BMP-regulatory SMADs, P-SMAD1/5 in tibiae and chondrocytes. Our findings indicate a previously unrecognized role for Spon1 as a negative regulator of bone mass. We speculate that Spon1 deletion leads to a local and systemic reduction of TGF-β levels resulting in increased BMP signaling and increased bone deposition in adult mice. [ABSTRACT FROM AUTHOR]

Background Age, gender and genetic predisposition are major intrinsic risk factors for osteoarthritis (OA). Iron increases are associated with age and gene mutation. In the present study, we examined whether serum ferritin, an indicator of total body iron stores, correlates with clinical features in patients with OA, and whether the hemochromatosis Fe (HFE) gene mutation plays a role. Methods In a 2-year longitudinal observational study, 127 patients with knee OA and 20 healthy individuals (controls) were enrolled. All patients underwent standardized weight-bearing fixed-flexion posteroanterior knee radiographs. Peripheral blood samples were analyzed for serum ferritin, and genotyped for HFE using allelic discrimination methods. Results Higher levels of serum ferritin were found in patients older than 56 years (P =0.0186) and males (P =0.0006), with a trend toward higher ferritin in patients with OA. HFE gene mutation carriers were more prevalent among patients with OA than among healthy controls. When stratified further by gender, we found that male patients with OA had higher levels of serum ferritin than male control subjects [odds ratio = 4.18 (limits of 95% confidence interval: 0.86–27.69, P = 0.048)]. Analyses of radiographic data indicated that higher ferritin was associated with narrower joint space width at baseline (P = 0.032) in male patients. Additionally, among men, risk prediction of radiographic severity [Kellgren-Lawrence (KL) grade >2)] in the higher ferritin group was almost five times that of the lower ferritin group (odds ratio = 4.74, P = 0.023). Conclusion Our data suggest that increased ferritin levels are associated with symptomatic knee OA in males. This finding needs to be validated in a larger cohort of patients. [ABSTRACT FROM AUTHOR]

Objective Mutations in LMNA encoding the A-type lamins cause several diseases, including those with features of premature aging and skeletal abnormalities. The aim of this study was to examine the expression of lamin A in cartilage from patients with osteoarthritis (OA) and the effects of its overexpression on chondrocyte senescence and apoptosis. Methods Human chondrocyte-like cells (SW-1353) were used. RNA isolated from human OA and non-OA cartilage was used for profiling messenger RNA expression, using Affymetrix microarray analysis. The effects of lamin A overexpression on mitochondrial function and apoptosis were examined by assessing mitochondrial membrane potential, ATP levels, and cytochrome c release, and with a TUNEL assay. Western blotting was performed to determine protein expression. Results Lamin A expression was markedly elevated in OA cartilage samples compared with non-OA control samples. Western blot analysis confirmed increased expression of lamin A in OA compared with non-OA cartilage. Interleukin-1β treatment inhibited lamin A accumulation, whereas treatment with prostaglandin E2 (PGE2) caused a marked increase in lamin A accumulation. These effects of exogenous PGE2 on lamin A expression were mediated via the EP2/EP4 receptors. Transfected chondrocytes that expressed lamin A displayed markers of early senescence/apoptosis. Conclusion The results of this study suggest that lamin A is up-regulated in OA chondrocytes, and that increased nuclear accumulation of lamin A in response to catabolic stress may account for the premature aging phenotype and apoptosis of OA chondrocytes. [ABSTRACT FROM AUTHOR]

Objective To evaluate whether gene expression profiles could serve as biomarkers of symptomatic knee osteoarthritis (OA) by examining gene expression profiles in peripheral blood leukocytes (PBLs) from patients with OA compared with those from non-OA controls, and to determine whether candidate genomic biomarkers (PBL expression of inflammatory genes) predict an increased risk of disease progression in patients with symptomatic radiographic knee OA. Methods Three independent cohorts of patients with knee OA and non-OA control subjects were studied. Two cohorts (a learning cohort and a validation cohort) were recruited at New York University Hospital for Joint Diseases (NYUHJD), and 1 cohort (a validation cohort) was recruited at Duke University Medical Center. PBL gene expression was assessed using Affymetrix microarray and was confirmed by quantitative polymerase chain reaction (qPCR). Radiographic progression at 2 years was assessed in 86 patients. Results We identified 173 genes that were significantly up-regulated or down-regulated (≥1.5-fold change) in OA PBLs, at a false discovery rate of 5%. Cluster analysis revealed 2 distinct subgroups among the patients with OA: those in whom the expression of interleukin-1β (IL-1β) was increased ≥2-fold compared with controls, and those in whom the expression of IL-1β was comparable with that in controls. Overexpression of IL-1β in these OA subclasses was validated using qPCR in all 3 cohorts. Patients with the inflammatory 'IL-1β signature' had higher pain scores and decreased function and were at higher risk of radiographic progression of OA. Conclusion PBLs from patients with symptomatic knee OA display a characteristic transcriptome profile. Moreover, increased expression of IL-1β identifies a subset of patients with OA who have increased pain and are at higher risk of radiographic progression of OA. [ABSTRACT FROM AUTHOR]

Objective To evaluate whether gene expression profiles could serve as biomarkers of symptomatic knee osteoarthritis (OA) by examining gene expression profiles in peripheral blood leukocytes (PBLs) from patients with OA compared with those from non-OA controls, and to determine whether candidate genomic biomarkers (PBL expression of inflammatory genes) predict an increased risk of disease progression in patients with symptomatic radiographic knee OA. Methods Three independent cohorts of patients with knee OA and non-OA control subjects were studied. Two cohorts (a learning cohort and a validation cohort) were recruited at New York University Hospital for Joint Diseases (NYUHJD), and 1 cohort (a validation cohort) was recruited at Duke University Medical Center. PBL gene expression was assessed using Affymetrix microarray and was confirmed by quantitative polymerase chain reaction (qPCR). Radiographic progression at 2 years was assessed in 86 patients. Results We identified 173 genes that were significantly up-regulated or down-regulated (≥1.5-fold change) in OA PBLs, at a false discovery rate of 5%. Cluster analysis revealed 2 distinct subgroups among the patients with OA: those in whom the expression of interleukin-1β (IL-1β) was increased ≥2-fold compared with controls, and those in whom the expression of IL-1β was comparable with that in controls. Overexpression of IL-1β in these OA subclasses was validated using qPCR in all 3 cohorts. Patients with the inflammatory 'IL-1β signature' had higher pain scores and decreased function and were at higher risk of radiographic progression of OA. Conclusion PBLs from patients with symptomatic knee OA display a characteristic transcriptome profile. Moreover, increased expression of IL-1β identifies a subset of patients with OA who have increased pain and are at higher risk of radiographic progression of OA. [ABSTRACT FROM AUTHOR]

In osteoarthritis (OA) articular chondrocytes undergo phenotypic changes culminating in the progressive loss of cartilage from the joint surface. The molecular mechanisms underlying these changes are poorly understood. Here we report enhanced (~7-fold) expression of F-spondin, a neuronal extracellular matrix glycoprotein, in human OA cartilage (P<0.005). OA-specific up-regulation of F-spondin was also demonstrated in rat knee cartilage following surgical menisectomy. F-spondin treatment of OA cartilage explants caused a 2-fold increase in levels of the active form of TGF-β1 (P<0.01) and a 10-fold induction of PGE2 (P<0.005) in culture supernatants. PGE2 induction was found to be dependent on TGF-β and the thrombospondin domain of the F-spondin molecule. F-spondin addition to cartilage explant cultures also caused a 4-fold increase in collagen degradation (P<0.05) and a modest reduction in proteoglycan synthesis (~20%; P<0.05), which were both TGF-β and PGE2 dependent. F-spondin treatment also led to increased secretion and activation of MMP-13 (P<0.05). Together these studies identify F-spondin as a novel protein in OA carthage, where it may act in situ at lesional areas to activate latent TGF-β and induce carthage degradation via pathways that involve production of PGE2. [ABSTRACT FROM AUTHOR]

The article presents a study that aims to determine the effects of the antioxidant resveratrol regarding the functions of human chondrocytes in osteoarthritis (OA). The study shows that resveratrol protects against induced catabolic effects and prevents the chondrocyte apoptosis through its inhibition of mitochondrial membrane depolarization adenosine triphosphate (ATP) depletion. It concludes that resveratrol may protect against oxidant injury and apoptosis.

The NR4A orphan receptors (Nur77, NURR1, and NOR-1) are emerging as key regulators of cytokine and growth factor action in chronic inflammatory diseases. In this study, we address the role of these receptors in cartilage homeostasis during inflammatory joint disease. We document for the first time expression of the NR4A receptors in osteoarthritic cartilage. Relative to Nut77 and NOR-1, NURR1 is expressed at the highest level and correlates with cyclooxygenase-2 levels in cartilage. Consistent with this observation, cyclooxygenase-2-derived prostaglandin E2 (PGE2) rapidly and potently induces NURR1 expression in chondrocytes, suggesting that this receptor may regulate PGE2-mediated processes in cartilage. We demonstrate that PGE2 represses interleukin-1β-induced matrix metalloproteinase (MMP)-1 and that transient over-expression of NURR1 is sufficient to antagonize expression of this gene. Furthermore, MMP-1 promoter activity is potently suppressed by NURR1, resulting in a significant reduction in endogenous MMP-1 mRNA and secreted pro-MMP-1 protein. In addition, NURR1 selectively antagonizes cytoldne-induced MMP-3 and -9 expression with minimal effects on MMP-2 and -13 and tissue inhibitor of matrix metalloproteinases-1 and -2. To explore the molecular mechanisms of NURR1 transrepression, we reveal that this receptor targets a critical region of the MMP-1 promoter (-1772 to -1546 bp) and that repression does not require consensus binding sites for NURR1. We confirm that NURR1 targets a 40-bp promoter sequence that is also positively regulated by ETS transcription factors. Finally, functional studies indicate that transcriptional antagonism exists between NURR1 and ETS1 on the MMP-1 promoter. We propose a protective function for NURR1 in cartilage homeostasis by selectively repressing MMP gene expression during inflammation. [ABSTRACT FROM AUTHOR]

Evaluates the effect of tetracyclines on the expression and function of human osteoarthritis (OA)-affected nitric oxide synthase (OA-NOS) and rodent inducible NOS. Cell lines and reagents; Effect of doxycycline and minocycline on inducible OA-NOS activity in human OA-affected cartilage; Effects of doxycycline and minocycline on iNOS in murine macrophages.

Background: Age, gender and genetic predisposition are major intrinsic risk factors for osteoarthritis (OA). Iron increases are associated with age and gene mutation. In the present study, we examined whether serum ferritin, an indicator of total body iron stores, correlates with clinical features in patients with OA, and whether the hemochromatosis Fe (HFE) gene mutation plays a role.Methods: In a 2-year longitudinal observational study, 127 patients with knee OA and 20 healthy individuals (controls) were enrolled. All patients underwent standardized weight-bearing fixed-flexion posteroanterior knee radiographs. Peripheral blood samples were analyzed for serum ferritin, and genotyped for HFE using allelic discrimination methods.Results: Higher levels of serum ferritin were found in patients older than 56 years (P =0.0186) and males (P =0.0006), with a trend toward higher ferritin in patients with OA. HFE gene mutation carriers were more prevalent among patients with OA than among healthy controls. When stratified further by gender, we found that male patients with OA had higher levels of serum ferritin than male control subjects [odds ratio = 4.18 (limits of 95% confidence interval: 0.86-27.69, P = 0.048)]. Analyses of radiographic data indicated that higher ferritin was associated with narrower joint space width at baseline (P = 0.032) in male patients. Additionally, among men, risk prediction of radiographic severity [Kellgren-Lawrence (KL) grade >2)] in the higher ferritin group was almost five times that of the lower ferritin group (odds ratio = 4.74, P = 0.023).Conclusion: Our data suggest that increased ferritin levels are associated with symptomatic knee OA in males. This finding needs to be validated in a larger cohort of patients. [ABSTRACT FROM AUTHOR]

Objective The pathogenesis of osteoarthritis (OA) includes both mechanical and inflammatory features. Studies have implicated synovial fluid uric acid (UA) as a potential OA biomarker, possibly reflecting chondrocyte damage. Whether serum UA levels reflect/contribute to OA is unknown. We investigated whether serum UA levels predict OA progression in a non-gout knee OA population. Methods Eighty-eight patients with medial knee OA (body mass index [BMI] <33 kg/m2) but without gout were studied. Baseline serum UA levels were measured in previously banked serum samples. At 0 and 24 months, patients underwent standardized weight-bearing fixed-flexion posteroanterior knee radiography to determine joint space width (JSW) and Kellgren/Lawrence grades. Joint space narrowing (JSN) was calculated as the change in JSW from 0 to 24 months. Twenty-seven patients underwent baseline contrast-enhanced 3T knee magnetic resonance imaging for assessment of synovial volume. Results Serum UA levels correlated with JSN values in both univariate (r = 0.40, P < 0.01) and multivariate (r = 0.28, P = 0.01) analyses. There was a significant difference in mean JSN after dichotomization at a serum UA cut point of 6.8 mg/dl, the solubility point for serum urate, even after adjustment (JSN of 0.90 mm for a serum UA ≥6.8 mg/dl and 0.31 mm for a serum UA <6.8 mg/dl; P < 0.01). Baseline serum UA levels distinguished progressors (JSN >0.2 mm) and fast progressors (JSN >0.5 mm) from nonprogressors (JSN ≤0.0 mm) in multivariate analyses (area under the receiver operating characteristic curve 0.63 [ P = 0.03] and 0.62 [ P = 0.05], respectively). Serum UA levels correlated with the synovial volume (r = 0.44, P < 0.01), a possible marker of JSN, although this correlation did not persist after controlling for age, sex, and BMI (r = 0.13, P = 0.56). Conclusion In non-gout patients with knee OA, the serum UA level predicted future JSN and may serve as a biomarker for OA progression. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis is a chronic systemic immune-mediated disease caused by genetic and environmental factors. It is often characterized by the generation of autoantibodies that lead to synovial inflammation and eventual multi-joint destruction. A growing number of studies have shown significant differences in the gut microbiota composition of rheumatoid arthritis (RA) patients compared to healthy controls. Environmental factors, and changes in diet and nutrition are thought to play a role in developing this dysbiosis. This review aims to summarize the current knowledge of intestinal dysbiosis, the role of nutritional factors, and its implications in the pathogenesis of rheumatoid arthritis and autoimmunity. The future direction focuses on developing microbiome manipulation therapeutics for RA disease management. [ABSTRACT FROM AUTHOR]

Abstract: MicroRNAs (miRNAs) represent a class of non-coding RNA molecules playing pivotal roles in cellular and developmental processes. miRNAs modulate the expression of multiple target genes at the post-transcriptional level and are predicted to affect up to one-third of all human protein-encoding genes. Recently, miRNA involvement in the adaptive and innate immune systems has been recognized. Rheumatoid arthritis serves an example of a chronic inflammatory disorder in which miRNAs modulate the inflammatory process in the joints, with the potential to serve as biomarkers for both the inflammatory process and the potential for therapeutic response. This review discusses the investigations that led to miRNA discovery, miRNA biogenesis and mode of action, and the diverse roles of miRNAs in modulating the immune and inflammatory responses. We conclude with a discussion of the implications of miRNA biology in rheumatoid arthritis and other autoimmune disorders. [Copyright &y& Elsevier]

Background: Osteoarthritis (OA) is a disease with multiple endotypes. A hallmark of OA is loss of cartilage; however, it is evident that the rate of cartilage loss differs among patients, which may partly be attributed to differential capacity for cartilage repair. We hypothesize that a low cartilage repair endotype exists and that such endotypes are more likely to progress radiographically. The aim of this study is to examine the associations of level of cartilage formation with OA severity and radiographic OA progression. We used the blood-based marker PRO-C2, reflecting type II collagen formation, to assess levels of cartilage formation.Materials and Methods: The type II collagen propeptide PRO-C2 was measured in the serum/plasma of knee OA subjects from New York University (NYU, n = 106) and a subcohort of the phase III oral salmon calcitonin (sCT) trial SMC021-2301 (SMC, n = 147). Risk of radiographic medial joint space narrowing (JSN) over 24 months was compared between quartiles (very low, low, moderate, and high) of PRO-C2. Associations were adjusted for age, gender, BMI, race, baseline pain levels, and baseline joint space width.Results: In both the NYU and SMC cohorts, subjects with low PRO-C2 levels had greater JSN compared with subjects with high PRO-C2. Mean difference in JSN between subjects with very low and high levels of PRO-C2 was 0.65 mm (p = 0.002), corresponding to a 3.4 (1.4-8.6)-fold higher risk of progression. There was no significant effect of sCT treatment, compared with placebo, on JSN over 2 years before stratification based on baseline PRO-C2. However, there were proportionately fewer progressors in the sCT arm of the very low/low PRO-C2 group compared with the moderate/high group (Chi squared = 6.5, p = 0.011).Conclusion: Serum/plasma level of type II collagen formation, PRO-C2, may be an objective indicator of a low cartilage repair endotype, displaying radiographic progression and superior response to a proanabolic drug.Level Of Evidence: Level III post hoc exploratory analysis of one longitudinal cohort and a sub-study from one phase III clinical trial. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is characterized by progressive loss of articular cartilage accompanied by the new bone formation and, often, a synovial proliferation that culminates in pain, loss of joint function, and disability. However, the cellular and molecular mechanisms of OA progression and the relative contributions of cartilage, bone, and synovium remain unclear. We recently found that the extracellular matrix (ECM) protein periostin (Postn, or osteoblast-specific factor, OSF-2) is expressed at high levels in human OA cartilage. Multiple groups have also reported elevated expression of Postn in several rodent models of OA. We have previously reported that in vitro Postn promotes collagen and proteoglycan degradation in human chondrocytes through AKT/β-catenin signaling and downstream activation of MMP-13 and ADAMTS4 expression. Here we show that Postn induces collagen and proteoglycan degradation in cartilage by signaling through discoidin domain receptor-1 (DDR1), a receptor tyrosine kinase. The genetic deficiency or pharmacological inhibition of DDR1 in mouse chondrocytes blocks Postn-induced MMP-13 expression. These data show that Postn is signaling though DDR1 is mechanistically involved in OA pathophysiology. Specific inhibitors of DDR1 may provide therapeutic opportunities to treat OA. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a highly prevalent, disabling joint disease with no existing therapies to slow or halt its progression. Cartilage degeneration hallmarks OA pathogenesis, and pannexin 3 (Panx3), a member of a novel family of channel proteins, is upregulated during this process. The function of Panx3 remains poorly understood, but we consistently observed a strong increase in Panx3 immunostaining in OA lesions in both mice and humans. Here, we developed and characterized the first global and conditional Panx3 knockout mice to investigate the role of Panx3 in OA. Interestingly, global Panx3 deletion produced no overt phenotype and had no obvious effect on early skeletal development. Mice lacking Panx3 specifically in the cartilage and global Panx3 knockout mice were markedly resistant to the development of OA following destabilization of medial meniscus surgery. These data indicate a specific catabolic role of Panx3 in articular cartilage and identify Panx3 as a potential therapeutic target for OA. Lastly, while Panx1 has been linked to over a dozen human pathologies, this is the first in vivo evidence for a role of Panx3 in disease. Key message: [ABSTRACT FROM AUTHOR]

Objective To characterize the diversity and taxonomic relative abundance of the gut microbiota in patients with never-treated, recent-onset psoriatic arthritis (PsA). Methods High-throughput 16S ribosomal RNA pyrosequencing was utilized to compare the community composition of gut microbiota in patients with PsA (n = 16), patients with psoriasis of the skin (n = 15), and healthy, matched control subjects (n = 17). Samples were further assessed for the presence and levels of fecal and serum secretory IgA (sIgA), proinflammatory proteins, and fatty acids. Results The gut microbiota observed in patients with PsA and patients with skin psoriasis was less diverse when compared to that in healthy controls. This could be attributed to the reduced presence of several taxa. Samples from both patient groups showed a relative decrease in abundance of Coprococcus species, while samples from PsA patients were also characterized by a significant reduction in Akkermansia, Ruminococcus, and Pseudobutyrivibrio. Supernatants of fecal samples from PsA patients revealed an increase in sIgA levels and decrease in RANKL levels. Analysis of fatty acids revealed low fecal quantities of hexanoate and heptanoate in both patients with PsA and patients with psoriasis. Conclusion Patients with PsA and patients with skin psoriasis had a lower relative abundance of multiple intestinal bacteria. Although some genera were concomitantly decreased in both conditions, PsA samples had a lower abundance of reportedly beneficial taxa. This gut microbiota profile in PsA was similar to that previously described in patients with inflammatory bowel disease and was associated with changes in specific inflammatory proteins unique to this group, and distinct from that in patients with skin psoriasis and healthy controls. Thus, the role of the gut microbiome in the continuum of psoriasis-PsA pathogenesis and the associated immune response merits further study. [ABSTRACT FROM AUTHOR]

Objective To profile the abundance and diversity of subgingival oral microbiota in patients with never-treated, new-onset rheumatoid arthritis (RA). Methods Periodontal disease (PD) status, clinical activity, and sociodemographic factors were determined in patients with new-onset RA, patients with chronic RA, and healthy subjects. Multiplexed-454 pyrosequencing was used to compare the composition of subgingival microbiota and establish correlations between the presence/abundance of bacteria and disease phenotypes. Anti- Porphyromonas gingivalis antibody testing was performed to assess prior exposure to the bacterial pathogen P gingivalis. Results The more advanced forms of periodontitis were already present at disease onset in patients with new-onset RA. The subgingival microbiota observed in patients with new-onset RA was distinct from that found in healthy controls. In most cases, however, these microbial differences could be attributed to the severity of PD and were not inherent to RA. The presence and abundance of P gingivalis were also directly associated with the severity of PD and were not unique to RA. The presence of P gingivalis was not correlated with anti-citrullinated protein antibody (ACPA) titers. Overall exposure to P gingivalis was similar between patients with new-onset RA and controls, observed in 78% of patients and 83% of controls. The presence and abundance of Anaeroglobus geminatus correlated with the presence of ACPAs/rheumatoid factor. Prevotella and Leptotrichia species were the only characteristic taxa observed in patients with new-onset RA irrespective of PD status. Conclusion Patients with new-onset RA exhibited a high prevalence of PD at disease onset, despite their young age and paucity of smoking history. The subgingival microbiota profile in patients with new-onset RA was similar to that in patients with chronic RA and healthy subjects whose PD was of comparable severity. Although colonization with P gingivalis correlated with the severity of PD, overall exposure to P gingivalis was similar among the groups. The role of A geminatus and Prevotella/Leptotrichia species in this process merits further study. [ABSTRACT FROM AUTHOR]

Objective To address the role of the nuclear receptor 4A (NR4A) family of orphan nuclear receptors in synoviocyte transformation, hyperplasia, and regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in models of inflammatory arthritis. Methods NR4A messenger RNA levels in synovial tissue and primary synoviocytes were measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR). NR4A2 was stably overexpressed in normal synoviocytes, and cell proliferation, survival, anchorage-independent growth, migration, and invasion were monitored in vitro. MMP and TIMP expression levels were analyzed by quantitative RT-PCR, and MMP-13 promoter activity was measured using reporter assays. Stable depletion of endogenous NR4A levels was achieved by lentiviral transduction of NR4A short hairpin RNA (shRNA), and the effects on proliferation, migration, and MMP-13 expression were analyzed. Results NR4A2 was expressed at elevated levels in normal, OA, and RA synovial tissue and in primary RA synoviocytes. Tumor necrosis factor α (TNFα) rapidly and selectively induced expression of NR4A2 in synoviocytes. Ectopic expression of NR4A2 in normal synoviocytes significantly increased proliferation and survival, promoted anchorage-independent growth, and induced migration and invasion. MMP-13 gene expression was synergistically induced by NR4A2 and TNFα, while expression of TIMP-2 was antagonized. NR4A2 directly transactivated the proximal MMP-13 promoter, and a point mutation in the DNA binding domain of NR4A2 abolished transcriptional activation. Depletion of endogenous NR4A receptors with shRNA reduced synoviocyte proliferation, migration, and MMP-13 expression. Conclusion The orphan nuclear receptor NR4A2 is a downstream mediator of TNFα signaling in synovial tissue. NR4A2 transcriptional activity contributes to the hyperplastic and invasive phenotype of synoviocytes that leads to cartilage destruction, suggesting that this receptor may show promise as a therapeutic target in inflammatory arthritis. [ABSTRACT FROM AUTHOR]

Objective To evaluate the relationships between both quantitative and semiquantitative assessments of the degree of knee synovitis on 3T magnetic resonance imaging (MRI) and the severity of knee osteoarthritis (OA) on radiography. Methods Fifty-eight patients with knee OA underwent nonfluoroscopic fixed-flexion knee radiography. In addition, dynamic contrast-enhanced 3T MRI of the knees was performed, before and after gadolinium administration, to quantify synovial membrane volume (SV) as a measure of synovial proliferation (expressed as the quantitative SV), and semiquantitative measures of synovitis were also applied using both contrast-enhanced and unenhanced images. Two radiologists scored the knee radiographs using the Osteoarthritis Research Society International atlas; interreader agreement was assessed using kappa statistics and concordance correlation coefficients. Multiple linear and logistic regression analyses were used to assess associations among variables, while controlling for the effects of age, body mass index, sex, and meniscal extrusion. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for measures of disease activity. Results The Kellgren/Lawrence (K/L) grade of radiographic knee OA severity (β = 0.78), the diseased compartment joint space width (dcJSW) (β = −0.22), and the diseased compartment joint space narrowing (dcJSN) score (β = 0.53) were each significantly associated with the quantitative SV ( P = 0.0001, P = 0.0003, and P = 0.0001, respectively). Furthermore, the quantitative SV strongly correlated with the total volume of subchondral bone marrow lesions (BMLs) (β = 0.22, P = 0.0003). The K/L grade, dcJSW, and dcJSN score were each significantly associated with the semiquantitative Boston Leeds Osteoarthritis Knee Score (BLOKS) for the extent of infrapatellar synovitis (OR 9.05 [95% CI 1.94, 42.3] for K/L grade; OR 0.75 [95% CI 0.54, 1.03] for dcJSW; and OR 2.22 [95% CI 1.15, 4.31] for dcJSN score) and extent of joint effusion (OR 5.75 [95% CI 1.23, 26.8] for K/L grade; OR 0.70 [95% CI 0.50, 0.98] for dcJSW; and OR 1.96 [95% CI 1.02, 3.74] for dcJSN score). In addition, the semiquantitative synovitis grade on contrast-enhanced MRI was significantly associated with the K/L grade (β = 0.036, P = 0.0040) and dcJSN score (β = 0.015, P = 0.0266), and also significantly associated with the BLOKS synovitis score. Conclusion Synovitis is a characteristic feature of advancing knee OA and is significantly associated with the K/L grade, JSW, JSN score, and total volume of BMLs on radiographs. Furthermore, BLOKS scoring of synovitis on unenhanced MRI is associated with measurements of synovitis on contrast-enhanced MRI. [ABSTRACT FROM AUTHOR]

This study examines the role of F-spondin, an extracellular matrix protein of osteoarthritic cartilage, during chondrocyte maturation in embryonic growth plate cartilage. In chick tibia, F-spondin expression localized to the hypertrophic and calcified zones of the growth plate. Functional studies using tibial organ cultures indicated that F-spondin inhibited (∼35%, p = 0.02), and antibodies to F-spondin increased (∼30%, p < 0.1) longitudinal limb growth relative to untreated controls. In cell cultures, induction of chondrocyte maturation, by retinoic acid (RA) or transforming growth factor (TGF)-β treatment led to a significant upregulation of F-spondin ( p < 0.05). F-spondin transfection increased mineral deposition, alkaline phosphatase (AP) and matrix metalloproteinase (MMP)-13 mRNA levels ( p < 0.05), and AP activity following RA stimulation, compared to mock transfected controls. Using AP as a differentiation marker we then investigated the mechanism of F-spondin promaturation effects. Blocking endogenous F-spondin via its thrombospondin (TSR) domain inhibited RA induced AP activity 40% compared to controls ( p < 0.05). The stimulatory effect of F-spondin on AP expression was also inhibited following depletion of TGF-β from culture supernatants. Our findings indicate that F-spondin is expressed in embryonic cartilage, where it has the capacity to enhance chondrocyte terminal differentiation and mineralization via interactions in its TSR domain and TGF-β dependent pathways. Published by Wiley Periodicals, Inc. J Orthop Res 28:1323-1329, 2010 [ABSTRACT FROM AUTHOR]

T cell receptor (TCR)-dependent regulatory T cell (Treg) activity controls effector T cell (Teff) function and is inhibited by the inflammatory cytokine tumor necrosis factor-α (TNF-α). Protein kinase C-ϑ (PKC-ϑ) recruitment to the immunological synapse is required for full Teff activation. In contrast, PKC-ϑ was sequestered away from the Treg immunological synapse. Furthermore, PKC-ϑ blockade enhanced Treg function, demonstrating PKC-ϑ inhibits Treg- -mediated suppression. Inhibition of PKC-ϑ protected Treg from inactivation by TNF-α, restored activity of defective Treg from rheumatoid arthritis patients, and enhanced protection of mice from inflammatory colitis. Treg freed of PKC-ϑ-mediated inhibition can function in the presence of inflammatory cytokines and thus have therapeutic potential in control of inflammatory diseases. [ABSTRACT FROM AUTHOR]

The article details a study which examined whether protein prenylation regulates the matrix metalloproteinase (MMP) secretion from rheumatoid arthritis synovial fibroblasts (RASFs). The study authors determined whether MMP-1 secretion can be regulated by statins or prenyltransferase inhibitors via effects mediated by ERK, JNK and NF-κB. They conclude that protein farnesylation is required for expression and secretion of MMP-1 from RASFs via effects on JNK and NF-κB.

Background: To investigate the expression of vascular adhesion protein-1 (VAP-1) in joint tissues and serum in symptomatic knee osteoarthritis (SKOA) patients and examine whether VAP-1 levels predict increased risk of disease severity in a cross-sectional study. Methods: Baseline VAP-1 expression and soluble VAP-1 (sVAP-1) levels were assessed in the synovium synovial fluid and in the serum in cohorts of patients with tibiofemoral medial knee OA and healthy subjects. Standardized fixed-flexion poster anterior knee radiographs scored for Kellgren–Lawrence (KL) grade (0–4) and medial joint space width (JSW). KL1/2 vs. KL3/4 scores defined early and advanced radiographic severity, respectively. Biochemical markers assessed in serum or synovial fluids (SF) comprised sVAP-1, interleukin 1 receptor antagonist (IL-1Ra), interleukin 6 (IL-6), soluble receptor for advanced glycation end-products (sRAGE), C-C motif chemokine ligand 2 (CCL2), C-C motif chemokine ligand 4 (CCL4), cluster of differentiation 163 (CD163), high sensitivity C-reactive protein (hsCRP), and matrix metalloproteinases (MMPs)-1,-3,-9. Associations between biomarkers and radiographic severity KL1/2 vs. KL3/4 (logistic regression controlling for covariates) and pain (Spearman correlation) were evaluated. Results: Elevated levels of sVAP-1 observed in OA synovial fluid and VAP-1 expression in synovium based on immunohistochemical, microarray, and real-time quantitative polymerase chain reaction (qRT-PCR) analyses. However, serum sVAP-1 levels in OA patients were lower than in controls and inversely correlated with pain and inflammation markers (hsCRP and soluble RAGE). Soluble VAP-1 levels in serum were also lower in radiographically advanced (KL3/4) compared with early KL1/2 knee SKOA patients. Conclusion: Local (synovial fluid) semicarbazide-sensitive amine oxidase (SSAO)/sVAP-1 levels were elevated in OA and correlated with radiographic severity. However, systemic (serum) sVAP-1 levels were lower in SKOA patients than normal and inversely correlated with pain and inflammation markers. Serum sVAP-1 levels were higher in early (KL1/2) compared with advanced (KL3/4) SKOA patients. [ABSTRACT FROM AUTHOR]