Pathogenesis Of Joint Diseases Research Articles

Comparative analysis of the expression of the soluble IL-7 receptor in patients with arthropathy

Arthropathy is one of the most prevalent diseases, which are based on the destruction and remodeling of cartilage and bone tissue. The inflammation that precedes destruction can be caused by mechanical stress on the joints, or by autoimmune reactions. Recently, IL-7 is considered as one of the key cytokines that promote the production of matrix metalloproteinases, catabolic enzymes, T cell-mediated activation of monocytes, and maturation of osteoclasts. The soluble form of the IL-7 receptor can help prolong the lifespan of IL-7 and thereby it ensures the bioavailability of the cytokine and mediates effect of IL-7 on cells. The aim of this study was to determine the soluble form of the IL-7 receptor (sIL-7R) in the blood plasma of patients with rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PsA) and psoriasis vulgaris (PS), as well as healthy individuals. The RA patients included in the study had moderate to high disease activity according to the DAS28 index. Patients with PsA predominantly had moderate and low disease activity (DAS28) and were characterized by mild to moderate disease severity (PASI). In accordance with the PASI index, patients with PS with mild and severe severity of the disease were included in the study. All patients with OA had a metabolic phenotype that is accompanied by an elevated body mass index.sIL-7R was determined in blood plasma by enzyme-linked immunosorbent assay. It was found that in patients with arthropathy, the level of soluble form of IL-7 was increased relative to healthy individuals, with the exception of the group of patients with PsA. Also, a high concentration of sIL-7R was observed in patients with PS. Analyzing the clinical characteristics of the patients, we found that sIL-7R levels were elevated in RA and PsA patients with high disease activity by DAS28. In addition, positive correlations were found between the concentration of sIL-7R and DAS28 in RA and PsA. In patients with PsA with moderate severity of the disease (PASI), the concentration of sIL-7R was also increased relative to donor's values. On the contrary, in patients with PS, a high level of sIL-7R was noted regardless of the severity of the disease. In patients with OA, no relationship was found between sIL-7R levels and clinical parameters.Thus, an elevated level of sIL-7R in patients with arthropathy may indicate the involvement of IL-7 and its receptor system in the pathogenesis of joint diseases. The IL-7 receptor may become a promising target both in the treatment of joint diseases and other autoimmune diseases, including psoriasis.

Semaphorin 4D induces articular cartilage destruction and inflammation in joints by transcriptionally reprogramming chondrocytes.

Proinflammatory cytokines play critical roles in the pathogenesis of joint diseases. Using a mass spectrometry-based cloning approach, we identified Semaphorin 4D (Sema4D) as an inflammatory cytokine that directly promoted cartilage destruction. Sema4d-deficient mice showed less cartilage destruction than wild-type mice in a model of rheumatoid arthritis. Sema4D induced a proinflammatory response in mouse articular chondrocytes characterized by the induction of proteolytic enzymes that degrade cartilage, such as matrix metalloproteinases (MMPs) and aggrecanases. The activation of Mmp13 and Mmp3 expression in articular chondrocytes by Sema4D did not depend on RhoA, a GTPase that mediates Sema4D-induced cytoskeletal rearrangements. Instead, it required NF-κB signaling and Ras-MEK-Erk1/2 signaling downstream of the receptors Plexin-B2 and c-Met and depended on the transcription factors IκBζ and C/EBPδ. Genetic and pharmacological blockade of these Sema4D signaling pathways inhibited MMP induction in chondrocytes and cartilage destruction in femoral head organ culture. Our results reveal a mechanism by which Sema4D signaling promotes cartilage destruction.

The effect of long non-coding RNAs in joint destruction of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease accompanied with joint destruction. Serious joint destruction will eventually lead to disability and the decline of life quality in RA patients. At present, the therapeutic effect of drugs to alleviate joint destruction in RA is limited. Recently, accumulating evidences have shown that long non-coding RNAs (lncRNAs) play an important role in the pathogenesis of joint diseases. Therefore, this paper reviews the expression change and the action mechanism of lncRNAs in joint destruction of RA in recent years. A more comprehensive understanding of the role of lncRNAs in joint destruction will help the treatment of RA.

Эффективность и безопасность левилимаба, блокирующего рецепторы интерлейкина-6, в лечении ревматоидного артрита

Interleukin (IL)-6 is a proinlammatory cytokine contributing significantly to the pathogenesis of joint disease and systemic manifestations of rheumatoid arthritis (RA). Levilimab is a new original monoclonal antibody that blocks both soluble and membrane-bound IL-6 receptors. Efficacy and favorable safety profile of levilimab in combination with methotrexate were shown in two randomized double-blind placebo-controlled trials (AURORA and SOLAR) that included patients with active RA despite treatment with methotrexate alone. Both primary and multiple secondary efficacy endpoints including ACR response, low disease activity or remission rates, changes in RA activity scores, etc, confirmed a higher efficacy of levilimab compared to placebo. Profile of adverse events was typical for IL-inhibitors. Several observational studies suggested that unlike rituximab or medium or high dose glucocorticoids IL-6 receptors inhibitors do not worsen outcomes of COVID19 and do not impair immunogenicity of vaccines against COVID-19. Therefore, patients treated with levilimab should not delay vaccination or modify the dosing regimen prior to vaccination.

The non-coding RNA interactome in joint health and disease.

Non-coding RNAs have distinct regulatory roles in the pathogenesis of joint diseases including osteoarthritis (OA) and rheumatoid arthritis (RA). As the amount of high-throughput profiling studies and mechanistic investigations of microRNAs, long non-coding RNAs and circular RNAs in joint tissues and biofluids has increased, data have emerged that suggest complex interactions among non-coding RNAs that are often overlooked as critical regulators of gene expression. Identifying these non-coding RNAs and their interactions is useful for understanding both joint health and disease. Non-coding RNAs regulate signalling pathways and biological processes that are important for normal joint development but, when dysregulated, can contribute to disease. The specific expression profiles of non-coding RNAs in various disease states support their roles as promising candidate biomarkers, mediators of pathogenic mechanisms and potential therapeutic targets. This Review synthesizes literature published in the past 2 years on the role of non-coding RNAs in OA and RA with a focus on inflammation, cell death, cell proliferation and extracellular matrix dysregulation. Research to date makes it apparent that 'non-coding' does not mean 'non-essential' and that non-coding RNAs are important parts of a complex interactome that underlies OA and RA.

The Crucial Questions on Synovial Biopsy: When, Why, Who, What, Where, and How?

In the majority of joint diseases, changes in the organization of the synovial architecture appear early. Synovial tissue analysis might provide useful information for the diagnosis, especially in atypical and rare joint disorders, and might have a value in case of undifferentiated inflammatory arthritis, by improving disease classification. After patient selection, it is crucial to address the dialogue between the clinician and the pathologist for adequately handling the sample, allowing identifying histological patterns depending on the clinical suspicion. Moreover, synovial tissue analysis gives insight into disease progression helping patient stratification, by working as an actionable and mechanistic biomarker. Finally, it contributes to an understanding of joint disease pathogenesis holding promise for identifying new synovial biomarkers and developing new therapeutic strategies. All of the indications mentioned above are not so far from being investigated in everyday clinical practice in tertiary referral hospitals, thanks to the great feasibility and safety of old and more recent techniques such as ultrasound-guided needle biopsy and needle arthroscopy. Thus, even in rheumatology clinical practice, pathobiology might be a key component in the management and treatment decision-making process. This review aims to examine some essential and crucial points regarding why, when, where, and how to perform a synovial biopsy in clinical practice and research settings and what information you might expect after a proper patient selection.

Total Antioxidant Capacity, Catalase Activity and Salivary Oxidative Parameters in Patients with Temporomandibular Disorders.

Objectives:Temporomandibular disorders (TMD) are characterized by pain or discomfort in the temporomandibular joint, periauricular region, masticatory muscles, and neck on one or both sides. It may also be associated with joint sounds, restricted mandibular movements and mandibular deviation. Oxidative agents may have a deleterious role in the pathogenesis of joint diseases, and oxidative stress can lead to TMD. The aim of this study was to assess the oxidative stress biomarkers in the saliva of TMD patients and healthy controls.Materials and Methods:This case-control study was conducted on 30 patients with TMDs (5 males and 25 females) with a mean age of 30.7±13.2 years, and 30 healthy controls (5 males and 25 females) with a mean age of 29.16±11.2 years. Saliva samples were collected according to the standard protocol and the total antioxidant capacity of the saliva (non-enzymatic), catalase activity, and malondialdehyde (MDA) levels were measured using the ferric reducing ability of plasma, Aebi’s method, and high-performance liquid chromatography, respectively. Finally, The MDA levels were analyzed by the Mann-Whitney test. Other quantitative parameters were analyzed by independent t-test.Results:TMD patients had significantly higher salivary levels of MDA compared to the control group (P=0.001). But there were no significant differences in catalase (P=0.49) and total antioxidant capacity (P=0.22) of TMD patients and healthy controls.Conclusion:It seems that oxidative stress may be involved in the pathogenesis of TMDs.

Catalpol promotes mitochondrial biogenesis in chondrocytes

The chondrocyte mitochondrial dysfunction has been considered to be associated with the pathogenesis of joint diseases. Catalpol is an active traditional Chinese medicine ingredient named Di-Huang, which is used widely to treat different diseases. In this study, we found the addition of catalpol in chondrocytes induced the expression of crucial mitochondrial regulators, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), nuclear respiratory factor-1 (NRF1), and mitochondrial transcription factor A (TFAM). Catalpol promoted mitochondrial biogenesis, as revealed by the induction on the mitochondrial DNA/nuclear DNA (mtDNA/nDNA) and the expression of several mitochondrial genes including translocase of outer mitochondrial membrane 22 (Tomm22), translocase of outer mitochondrial membrane 70 (Tomm70), mitochondrial import inner membrane translocase subunit 50 (Timm50), NADH dehydrogenase [ubiquinone] iron-sulphur protein 3 (NDUFS3), adenosine triphosphate (ATP) synthase subunit D (ATP5d), and cytochrome B. Consequently, catalpol increased cytochrome c oxidase activity, the mitochondrial respiratory rate, and the extracellular ATP production, indicating that catalpol boosted mitochondrial function. Mechanistically, catalpol increased the activation of the cAMP-responsive element-binding protein (CREB), and the inhibition of CREB abolished catalpol-mediated promotion on mitochondrial biogenesis. In summary, this study demonstrated that catalpol has the potential to be used in the treatment of joint diseases.

Changes in concentrations of haemostatic and inflammatory biomarkers in synovial fluid after intra-articular injection of lipopolysaccharide in horses

BackgroundSeptic arthritis is a common and potentially devastating disease characterized by severe intra-articular (IA) inflammation and fibrin deposition. Research into equine joint pathologies has focused on inflammation, but recent research in humans suggests that both haemostatic and inflammatory pathways are activated in the joint compartment in arthritic conditions. The aim of this study was to characterize the IA haemostatic and inflammatory responses in horses with experimental lipopolysaccharide (LPS)-induced joint inflammation. Inflammation was induced by IA injection of LPS into one antebrachiocarpal joint of six horses. Horses were evaluated clinically with subjective grading of lameness, and blood and synovial fluid (SF) samples were collected at post injection hours (PIH) -120, −96, −24, 0, 2, 4, 8, 16, 24, 36, 48, 72 and 144. Total protein (TP), white blood cell counts (WBC), serum amyloid A (SAA), haptoglobin, iron, fibrinogen, thrombin-antithrombin (TAT) and d-dimer concentrations were assessed in blood and SF.ResultsIntra-articular injection of LPS caused local and systemic signs of inflammation including increased rectal temperature, lameness and increased joint circumference and skin temperature. Most of the biomarkers (TP, WBC, haptoglobin, fibrinogen and TAT) measured in SF increased quickly after LPS injection (at PIH 2–4), whereas SAA and d-dimer levels increased more slowly (at PIH 16 and 144, respectively). SF iron concentrations did not change statistically significantly. Blood WBC, SAA, haptoglobin and fibrinogen increased and iron decreased significantly in response to the IA LPS injection, while TAT and d-dimer concentrations did not change. Repeated pre-injection arthrocenteses caused significant changes in SF concentrations of TP, WBC and haptoglobin.ConclusionSimilar to inflammatory joint disease in humans, joint inflammation in horses was accompanied by an IA haemostatic response with changes in fibrinogen, TAT and d-dimer concentrations. Inflammatory and haemostatic responses were induced simultaneously and may likely interact. Further studies of interactions between the two responses are needed for a better understanding of pathogenesis of joint disease in horses. Knowledge of effects of repeated arthrocenteses on levels of SF biomarkers may be of value when markers are used for diagnostic purposes.

Changes in the salivary oxidative status in individuals with temporomandibular disorders and pain

Temporomandibular joint disorders are quite common among the general public. Free radicals may play a role in the pathogenesis of joint diseases, and the oxidative stress is an important aspect in the mechanism of TMDs. The use of new biotechnologies has enabled the use of saliva as a diagnostic method. This is the first paper that aims to investigate changes in the oxidative status, through saliva analysis, in individuals who suffer from temporomandibular disorder and pain. Sixty individuals, 54 women and 06 men, aged between 10 and 60, participated in this research. The questionnaire ‘Research Diagnostic Criteria for Temporomandibular Disorders’ (RDC/TMD) was filled out in order to determine the presence and the type of TMD, and the Visual Analogue Scale (VAS) was conducted in order to measure the pain perception caused by TMD. In addition, the total oxidant status (TOS), and the total antioxidant capacity (TAC) were measured, and the oxidative stress index (OSI) was calculated. The t-test and the Pearson Correlation Test were used with the significance level of p<0.05. The TAC in individuals with TMD and pain was significantly reduced (p<0.001). There was no difference regarding the levels of TOS (p=0.765) between both groups. As a result, the OSI was significantly higher in the group TMD and pain (p=0.011). There was no correlation between VAS, TAC, and TOS values. Within the limits of this study, oxidative changes seem to influence the pathogenesis of pain in TMDs.

Upregulation of Matrix Degrading Enzymes and Lubricin in the Pathogenesis of Joint Disease Requiring Arthroplasty

IntroductionThe prevalence of total knee and hip arthroplasty (TKA and THA) has been increasing; it is projected that TKA and THA procedures will increase to over 4 million procedures by 2030. Since TKA and THA are performed on individuals who experience joint degeneration, it is of interest to study the matrix degrading enzymes (MDE) such as elastase, collagenase‐1, and heparanase. Lubricin is a synovial/joint glycoprotein‐detectable in circulation‐ that plays a vital role in joint mobility by reducing friction in the joint and may have matrix‐stabilizing properties. Previous studies have investigated MDEs in TKA and THA patients, particularly involving prosthesis loosening, yet the role of lubricin is unclear. Simultaneous MDE and lubricin measurement may provide insight on the role of lubricin and these MDEs in the pathogenesis of joint diseases.MethodsBlood samples were obtained from patients undergoing THA or TKA procedures as de‐identified samples day one pre‐op and day one post‐op. Patient blood samples were collected in 3.2% sodium citrate to obtain plasma. Patient and control plasma samples were stored at −80°C. Plasma samples were analyzed utilizing commercially available ELISA kits for elastase, collagenase‐1, heparanase, and lubricin.ResultsIn comparison to normal samples, collagenase and elastase levels were significantly higher in the pre‐op samples (p&lt;0.0001). However heparanase levels were not significantly different between the normal and patient group (p&lt;0.748). On post‐op day 1, a further increase in the collagenase and elastase levels were noted again (p&lt;0.0001). No further increase was evident in the heparanase level. Lubricin levels were markedly higher in the patient groups in comparison to the normal (p&lt;0.0001). On post‐op day 1 marked enhancement of circulating lubricin was noted.DiscussionThe increased levels of lubricin suggest that, joint matrix deteriorates during joint degeneration damaging the capsule allows the joint fluid into systemic circulation. This may be the primary cause of the increased level of lubricin in circulation. Since DJD is a systemic disease with multiple pathogenic factors, it may result in the upregulation of collagenase and elastase. The role of heparanase remains unclear and requires further exploration. It is likely that lubricin may regulate the functional behavior of matrix degrading proteins. These studies also suggest that beside matrix degrading proteins, lubricin may also have a prognostic role in DJD.

How the Mediterranean diet and some of its components modulate inflammatory pathways in arthritis.

Arthritis encompasses a heterogeneous group of diseases characterised by inflammation that leads not only to joint damage, bone erosion, severe pain and disability, but also affects other organs of the body, resulting in increased morbidity and mortality. Although the mechanisms underlying the pathogenesis of joint diseases are for the most part unknown, a number of nutrient and non-nutrient components of food have been shown to affect the inflammatory process and, in particular, to influence clinical disease progression. The Mediterranean diet model has already been linked to a number of beneficial health effects: both fat and non-fat components of the Mediterranean dietary pattern have been shown to exert important anti-inflammatory activities by affecting the arachidonic acid cascade, the expression of some proinflammatory genes, and the activity of immune cells. N-3 polyunsaturated fatty acids, in particular, have been shown to affect lymphocyte and monocyte functions, crucially involved in adaptive and innate immunity. Although some aspects concerning the mechanisms of action through which the Mediterranean diet pattern exerts its beneficial effects remain to be elucidated, arthritis patients may potentially benefit from it in view of their increased cardiovascular risk and the treatment they require which may have side effects.

MRNA expression of genes involved in inflammation and haemostasis in equine fibroblast-like synoviocytes following exposure to lipopolysaccharide, fibrinogen and thrombin

BackgroundStudies in humans have shown that haemostatic and inflammatory pathways both play important roles in the pathogenesis of joint disease. The aim of this study was to assess mRNA expression of haemostatic and inflammatory factors in cultured equine fibroblast-like synoviocytes exposed to lipopolysaccharide (LPS), fibrinogen and thrombin. Synovial membranes were collected from metacarpo-phalangeal joints of 6 skeletally mature horses euthanized for non-orthopaedic reasons. Passage 4 fibroblast-like synoviocytes were left non-treated or treated with either 0.1 μg/ml LPS, 5 mg/ml fibrinogen or 5 U/ml thrombin and harvested at time points 0, 6, 24 and 48 h. mRNA expression of serum amyloid A (SAA), interleukin-6 (IL-6), monocyte chemotactic protein 1 (MCP-1), tissue factor (TF), plasminogen activator inhibitor 1 (PAI-1), urokinase plasminogen activator (uPA), vascular endothelial growth factor (VEGF) and protease activator receptor 1 (PAR-1) was assessed using quantitative real time reverse transcriptase PCR.ResultsLPS caused a significant increase in mRNA expression of SAA, IL-6, MCP-1 and uPA, and a decrease in TF, PAI-1 and PAR-1 when compared to non-treated cells. Treatment with thrombin resulted in increased mRNA expression of SAA, IL-6, MCP-1 and PAI-1, and a decreased PAR-1 expression compared to non-treated cells. The fibrinogen-treated synoviocytes showed significantly increased mRNA expression of IL-6, MCP-1, TF and PAI-1, and decreased PAR-1 expression compared to non-treated cells.ConclusionLPS, fibrinogen and thrombin induced an increased gene expression of inflammatory markers in isolated equine fibroblast-like synoviocytes. LPS caused changes in gene expression promoting increased fibrinolysis, while fibrinogen and thrombin changed the gene expression resulting potentially in reduced fibrinolysis. Overall, it appeared that both inflammatory and haemostatic stimuli affected expression of genes involved in inflammatory and haemostatic pathways, supporting their importance in equine joint diseases.

Mice Deficient in Urokinase-Type Plasminogen Activator (uPA) or uPA Receptor Develop Significantly Diminished Collagen-Induced Arthritis

Rheumatoid arthritis (RA) is a common and debilitating autoimmune disease characterized by chronic inflammation, synovial hyperplasia, edema, cartilage and bone erosion and loss of joint function. Increasing evidence suggests that the plasminogen activation (PA) system plays a fundamental role in the mechanisms mediating inflammatory joint disease pathogenesis. However, analysis of the precise contribution of PA system components to arthritis pathogenesis has been complicated by the use of gene-targeted mice on non-susceptible genetic backgrounds or experimental models that simultaneously induce wound trauma in conjunction with arthritis induction. To rigorously define the contribution of the urokinase-type plasminogen activator system to arthritis pathogenesis, previously generated genetic deficiencies in both uPA and uPA receptor (uPAR) were inbred for 7 generations (99% inbred) to the well-characterized, collagen-induced arthritis (CIA)-susceptible strain, DBA/1J. Our results indicate a near complete amelioration of joint disease in uPA-deficient mice that was also observed in uPAR-deficient mice. Limited disease development in both uPA- and uPAR-deficient mice correlated with significantly reduced local mRNA levels of key inflammatory mediators (e.g., TNFα, IL-1β, and IL-6) in these animals. To determine if development of inflammatory joint disease in CIA-challenged mice was dependent on the expression of uPAR by non-hematopoietic- or hematopoietic-derived cells, reciprocal bone marrow transplant studies were performed. Mice in which uPAR deficiency was limited to the bone marrow compartment elicited significantly reduced macroscopic and histopathological disease in the paws and knees compared to wild-type mice or mice in which only hematopoietic-derived cells express uPAR. Our results are the first to report in the context of the highly CIA susceptible DBA/1 background that both uPA and uPAR are key determinants of inflammatory joint disease pathogenesis. Furthermore, our findings indicate a fundamental role for uPAR expression by hematopoietic cells in driving arthritis incidence and progression. Thus, these findings suggest that cell-surface associated uPA/uPAR-mediated proteolysis and/or uPAR-mediated signaling events from bone-marrow derived cells are important in promoting inflammatory joint disease, and that disrupting this key proteolytic/signaling system may provide a novel therapeutic strategy to limit clinical arthritis. DisclosuresNo relevant conflicts of interest to declare.

Comprehensive Protein Profiling of Synovial Fluid in Osteoarthritis

Reasons for performing studySynovial fluid (SF) is located in joint cavities, tendon sheaths and bursae. In joints it comprises a serum filtrate with additional contributions from articular cartilage, synovium and bone. It represents a potential source of disease specific proteins that could aid in the understanding of the pathogenesis of joint disease and be used in the early diagnosis of disease.ObjectivesTo comprehensively profile the protein complement of SF in health and osteoarthritis (OA) using liquid chromatography mass spectrometry (LC‐MS/MS) and identify potential OA biomarkers.Study designSF was used from the metacarpophalangeal joints of 9 normal and 9 OA Thoroughbred horses following macroscopic, microscopic and synovitis scoring.MethodsSamples were analysed with LC‐MS/MS using a NanoAcquity LC coupled to a LTQ Orbitrap Velos. ProgenesisTM LC‐MS software was used for label‐free quantification with data searched using Mascot in the Ensembl database for horse. Adjusted ANOVA values of P&lt;0.05 and regulation of &gt;2‐fold were regarded as significant.Results754 proteins were identified in SF. Thus ProteominerTM beads concentrated the lower abundance proteins enabling the most comprehensive SF proteome to date. Proteins identified included those relating to matrix proteins, inflammatory factors, complement activation proteins and proteases. A subset of 10 proteins was identified which were differentially expressed in OA SF.ConclusionsA number of proteins were identified for the first time in SF which may be involved in the pathogenesis of OA. We identified a distinct set of proteins that may act as potential biomarkers to distinguish between normal and OA joints. S100‐A10, a calcium binding protein has upregulated in OA. This may have a role in the synthesis and activation of matrix degrading proteases. CD109 is a TGF‐β co‐receptor, released from the chondrocyte cell surface that inhibits TGF‐β signalling. Its contribution to the disregulation of TGF‐β is unknown.Ethical animal research: Ethical committee oversight not currently required by this congress: the study was performed on material collected during post mortem examination. Explicit owner informed consent for participation in this study was not stated. Sources of funding: Horserace Betting Levy Board, Wellcome Trust. Competing interests: None.

RBP‐Jκ–Dependent Notch Signaling Is Required for Murine Articular Cartilage and Joint Maintenance

Osteoarthritis (OA) is a degenerative disease resulting in severe joint cartilage destruction and disability. While the mechanisms underlying the development and progression of OA are poorly understood, gene mutations have been identified within cartilage-related signaling molecules, implicating impaired cell signaling in OA and joint disease. The Notch pathway has recently been identified as a crucial regulator of growth plate cartilage development, and components are expressed in joint tissue. This study was undertaken to investigate a novel role for Notch signaling in joint cartilage development, maintenance, and the pathogenesis of joint disease in a mouse model. We performed the first mouse gene study in which the core Notch signaling component, RBP-Jκ, was tissue specifically deleted within joints. The Prx1Cre transgene removed Rbpjk loxP-flanked alleles in mesenchymal joint precursor cells, while the Col2Cre(ERT2) transgene specifically deleted Rbpjk in postnatal chondrocytes. Murine articular chondrocyte cultures were also used to examine Notch regulation of gene expression. Loss of Notch signaling in mesenchymal joint precursor cells did not affect embryonic joint development in mice, but rather, resulted in an early, progressive OA-like pathology. Additionally, partial loss of Notch signaling in murine postnatal cartilage resulted in progressive joint cartilage degeneration and an age-related OA-like pathology. Inhibition of Notch signaling altered the expression of the extracellular matrix (ECM)-related factors type II collagen (COL2A1), proteoglycan 4, COL10A1, matrix metalloproteinase 13, and ADAMTS. Our findings indicate that the RBP-Jκ-dependent Notch pathway is a novel pathway involved in joint maintenance and articular cartilage homeostasis, a critical regulator of articular cartilage ECM-related molecules, and a potentially important therapeutic target for OA-like joint disease.

C-Fos Regulation by the MAPK and PKC Pathways in Intervertebral Disc Cells

BackgroundThe gene encoding c-fos is an important factor in the pathogenesis of joint disease in patients with osteoarthritis. However, it is unknown whether the signal mechanism of c-fos acts in intervertebral disc (IVD) cells. We investigated whether c-fos is activated in relation to mitogen-activated protein kinases (MAPKs) and the protein kinase C (PKC) pathway in nucleus pulposus (NP) cells.Methodology/ResultsReverse transcription-polymerase chain reaction and western blotting analyses were used to measure the expression of c-fos in rat IVD cells. Transfections were performed to determine the effects of c-fos on target gene activity. The effect of c-fos protein expression was examined in transfection experiments and in a 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide cell viability assay. Phorbol 12-myristate 13-acetate (PMA), the most commonly used phorbol ester, binds to and activates protein kinase C (PKC), causing a wide range of effects in cells and tissues. PMA induced the expression of c-fos gene transcription and protein expression, and led to activation of the MAPK pathways in NP cells. The c-fos promoter was suppressed completely in the presence of the MAPK inhibitor PD98059, an inhibitor of the MEK/ERK kinase cascade, but not in the presence of SKF86002, SB202190, or SP600125. The effects of the PKC pathway on the transcriptional activity of the c-fos were evaluated. PKCγ and PKCδ suppressed the promoter activity of c-fos. Treatment with c-fos inhibited aggrecan and Col2 promoter activities and the expression of these genes in NP cells.ConclusionsThis study demonstrated, for the first time, that the MAPK and PKC pathways had opposing effects on the regulation of c-fos in NP cells. Thus, the expression of c-fos can be suppressed in the extracellular matrix of NP cells.

Antibodies to citrullinated α-enolase peptide 1 and clinical and radiological outcomes in rheumatoid arthritis

IntroductionThe anticyclic citrullinated peptide 2 (anti-CCP2) assay is a generic test for antibodies to citrullinated proteins, among which there is a subset of about 50% with antibodies to citrullinated enolase...

High‐resolution interleaved water‐fat MR imaging of finger joints with chemical‐shift elimination

To study the use of an interleaved water-fat (IWF) sequence with a custom-made radiofrequency (RF) coil for high-resolution imaging of arthritic finger joints. High-resolution finger magnetic resonance imaging (MRI) was performed using a custom-made dedicated RF receiver coil and an IWF sequence. A phantom, a cadaver finger specimen, and the fingers of two normal controls and six arthritic subjects were imaged with a resolution of 156 × 156 × 600 μm. The appearance of anatomic structures on the IWF images were compared with images acquired with a regular sequence. The images were reviewed by two musculoskeletal radiologists for the depiction of anatomical structures and for the presence of abnormalities. The high-resolution images revealed detailed structures of the finger joints not detectable using typical clinical resolution. The IWF sequence gave more realistic depiction of subchondral bone thickness, and avoided false bone erosions displayed in the regular sequence. It also allowed better visualization of ligaments and tendons. This pilot study shows the feasibility and the potential usefulness of high-resolution IWF imaging for finger joint evaluation. This technique may be useful for the diagnosis and treatment assessment of arthritis, and for the study of joint disease pathogenesis.

The role of chloroquine phosphate on tumor necrosis factor - alpha and interleukin-one in knee osteoarthritic patients

Osteoarthritis (OA) is a condition characterized by a series of inflammatory processes. Various pro inflammatory cytokines like interleukin– one (IL-1) and tumor necrosis factor–alpha (TNF-α) are present in synovium and tissue of rheumatic patients, so these agents play an essential role in pathogenesis of joint diseases. Chloroquine phosphate (CQP) interferes the cellular function of acid microenvironments such as lysosome, endosome and Golgi's complex, as well as affects pathways of inflammation, immune cascade and enzyme activity which ultimately resulted in cartilage destruction in knee joint with OA.