Event In Osteoarthritis Research Articles

Antihypertensive drug-associated adverse events in osteoarthritis: a study of a large real-world sample based on the FAERS database.

Hypertension is a common complication in patients with osteoarthritis (OA). There is increasing interest in the relationship between hypertension and OA. However, hypertension has been reported to negatively affect symptoms and quality of life in patients with OA. Therefore, treating hypertension is crucial for patients with OA. However, there is a lack of real-world studies on the effects of medications for treating hypertension on OA. Data from the FAERS database from January 2004 to December 2023 were extracted for disproportionality analyses, and proportional reporting ratios (PRRs) were used to assess the association between medications for hypertension and all types of arthritis. Adverse event signals were identified and determined using reporting odds ratios (RORs) Adverse event signals were considered to have occurred if a drug-induced adverse event was recorded more than or equal to 3 and the lower limit of the ROR confidence interval was more than 1. We selected five classes of drugs including, calcium channel blockers (CCBs), angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), thiazide diuretics and β-blockers and representative drugs were analysed for osteoarthritis-related adverse reactions, and age and gender subgroups were analysed for drugs of significance. We also analysed the occurrence of AEs in relation to time using the Weibull distribution. In terms of overall data, we found significant OA adverse reaction signals only for ARBs among the five drug classes.ARB AEs for spinal osteoarthritis (ROR 4.64, 95% CI 3.62-5.94), osteoarthritis (ROR 3.24 95% CI 2.82-3.72) and gouty arthritis (ROR 3.27 95% CI 1.22-8.75) were the three adverse reactions with the loudest signals. Next, we found that valsartan had strong osteoarthritis adverse reaction signals among the three ARBs, namely, irbesartan, cloxartan, and valsartan. We also analysed age and gender subgroups and found that osteoarthritis signals were strongest in the 18-65 and 65+ population, while females seem to be more prone to valsartan-related OA AEs. ARBs, especially valsartan, have significant positive signals for OA AEs. Therefore, ARB drugs, especially valsartan, should be used with caution when treating patients with OA combined with hypertension.

Syndecans, Exostosins and Sulfotransferases as Potential Synovial Inflammation Moderators in Patients with Hip Osteoarthritis.

The gradual deterioration of articular cartilage was thought to be the central event in osteoarthritis (OA), but recent studies demonstrated the importance of low-grade synovitis in the progression of OA. The Syndecan (SDC) family of membrane proteoglycans is known to be involved in the regulation of inflammation, but there is limited evidence considering the role of syndecans in OA synovitis. Our study aimed to investigate the hip OA synovial membrane expression patterns of SDC1, SDC2 and SDC4, as well as exostosins and sulfotransferases (enzymes involved in the polymerisation and modification of syndecans' heparan sulphate chains). Synovial membrane samples of patients with OA (24) were divided into two groups according to their Krenn synovitis score severity. The immunohistochemical expressions of SDC1, SDC2, SDC4, EXT1, EXT2, NDST1 and NDST2 in synovial intima and subintima were then analysed and compared with the control group (patients with femoral neck fracture). According to our study, the immunoexpression of SDC1, NDST1 and EXT2 is significantly increased in the intimal cells of OA synovial membrane in patients with lower histological synovitis scores and SDC4 in patients with higher synovitis scores, in comparison with non-OA controls. The difference in the expression of SDC2 among the OA and non-OA groups was insignificant. SDC1, SDC4, NDST1 and EXT2 seem to be involved as inflammation moderators in low-grade OA synovitis and, therefore, should be further investigated as potential markers of disease progression and therapeutic goals.

Mathematical model of knee joint degenerative dystrophic changes formation in its flexion contracture at late stages of rheumatoid arthritis

Background. Rheumatoid arthritis (RA) is an immunomodulatory, chronic inflammatory disease accompanied by the proliferation and articular cartilage destruction that cause disability. Biomechanical factors in RA can play an important role in the onset and progress of the joint degenerative processes, secondary to the inflammation process. The biomechanical factors in RA can play an essential role in the start and progress of the degenerative processes within the joint that are secondary to the inflammatory process. Materials and methods. A solid simulation 3D-model of the knee joint was created that contained both tibia and fibula, the femur bone, femoral condyle cartilage and tibial plateau cartilage, menisci. It was done for further analytical calculations and finite element modeling calculations. Analytical calculations are based on the data of previous studies of quantitative evaluation of the knee joint contracture (compliance of contracture to the external corrective action) and on calculations data of the joint forces that manifest in ambulation of the patient with RA. Results. The created simulation computer 3D-model of a knee joint with its flexion contracture at late stages of RA shows that the forced passive flexion in the knee joint to 6°, the load on the condyles of the tibial plateau increased by 12.8 %, and as a result of forced passive flexion in the knee joint to 3°, the load on the condyles of the tibial plateau increased by 95.2 %, which is critical and may cause degradation of the bone tissue in the contact area. Conclusions. Increase of load on the lateral areas of the tibial plateau and, correspondingly, the tensions on the contact areas of the femur bone condyles with the tibial plateau, may contribute to the progress of the clinical picture of RA with the increase of arthrofibrosis and osteoarthritis events, particularly in the lateral areas of the knee joint.

The miR-302c/transforming growth factor-β receptor type-2 axis modulates interleukin-1β-induced degenerative changes in osteoarthritic chondrocytes.

Chondrocyte production of catabolic and inflammatory mediators participating in extracellular matrix degradation has been regarded as a central event in osteoarthritis (OA) development. During OA pathogenesis, interleukin-1β (IL-1β) decreases the mRNA expression and protein levels of transforming growth factor-β receptor type-2 (TGFBR2), thus disrupting transforming growth factor-β signaling and promoting OA development. In the present study, we attempted to identify the differentially expressed genes in OA chondrocytes upon IL-1β treatment, investigate their specific roles in OA development, and reveal the underlying mechanism. As shown by online data analysis and experimental results, TGFBR2 expression was significantly downregulated in IL-1β-treated human primary OA chondrocytes. IL-1β treatment induced degenerative changes in OA chondrocytes, as manifested by increased matrix metalloproteinase 13 and a disintegrin and metalloproteinase with thrombospondin motifs 5 proteins, decreased Aggrecan and Collagen II proteins, and suppressed OA chondrocyte proliferation. These degenerative changes were significantly reversed by TGFBR2 overexpression. miR-302c expression was markedly induced by IL-1β treatment in OA chondrocytes. miR-302c suppressed the expression of TGFBR2 via direct binding to its 3'- untranslated region. Similar to TGFBR2 overexpression, miR-302c inhibition significantly improved IL-1β-induced degenerative changes in OA chondrocytes. Conversely, TGFBR2 silencing enhanced IL-1β-induced degenerative changes and significantly reversed the effects of miR-302c inhibition in response to IL-1β treatment. In conclusion, the miR-302c/TGFBR2 axis could modulate IL-1β-induced degenerative changes in OA chondrocytes and might become a novel target for OA treatment.

Bone marrow lesion in advanced osteoarthritis of the knees. Correlation study between histopathological findings and structural damage

Loss of hyaline articular cartilage is a central pathologic event in osteoarthritis, but the pathogenesis of cartilage loss is poorly understood. Bone marrow lesion (BML) is indicated by focally increased signal in the marrow on fat-suppressed T2-weighted images. To correlate histopathology of a bone marrow lesion (BML) pattern with severity and structural damage in osteoarthritic knees. Twenty consecutive patients (age range, 59–66 years; mean, 65 years) referred for total knee replacements were examined with sagittal short inversion time inversion-recovery (STIR) and T1- and T2-weighted MRI one week prior to surgery before surgery. Different structural abnormalities on MRI were compared with those on histologic maps. The histopathology of BML in cases of OA revealed that 6 biopsies of cases showing bone marrow fibrosis (30%), 4 of them grade 1 (20%) and 2 of them grade 2 (10%). Eighteen biopsies showing cyst (90%), 9 biopsies showing abnormal trabeculae (45%), 2 of them with grade 1 (10%), 4 of them grade 2 (20%) and 3 of them grade 3 (15%). Five biopsies showing lymphocyte (25%), 40% of them had + +CD3, while 60% of them had ++ CD20. Five biopsies showing fatty marrow (25%), 9 biopsies showing haemosidrotic marrow (45%), 6 biopsies showing blood vessels (30%), 5 of them with grade 2 (25%) and 1 with grade 3 (5%). The MRI findings of OA patients had been revealed that there was 6 patients with BML of grade 1 (30%), 10 patients of grade 2 (50%) and 4 patients of grade 3 (20%). BML has a strong correlation with radiographic severity measurements of osteoarthritis of the knee and pain. In patients with knee osteoarthritis, BML in bone underneath cartilage markedly increase risk for structural progression in the knee. Hyperemia and hematopoietic marrow were possible reasons for appearance of BML as high signal intensity on STIR images. BMLs are a cornerstone in progression of osteoarthritis.

Gla-rich protein function as an anti-inflammatory agent in monocytes/macrophages: Implications for calcification-related chronic inflammatory diseases

Calcification-related chronic inflammatory diseases are multifactorial pathological processes, involving a complex interplay between inflammation and calcification events in a positive feed-back loop driving disease progression. Gla-rich protein (GRP) is a vitamin K dependent protein (VKDP) shown to function as a calcification inhibitor in cardiovascular and articular tissues, and proposed as an anti-inflammatory agent in chondrocytes and synoviocytes, acting as a new crosstalk factor between these two interconnected events in osteoarthritis. However, a possible function of GRP in the immune system has never been studied. Here we focused our investigation in the involvement of GRP in the cell inflammatory response mechanisms, using a combination of freshly isolated human leucocytes and undifferentiated/differentiated THP-1 cell line. Our results demonstrate that VKDPs such as GRP and matrix gla protein (MGP) are synthesized and γ-carboxylated in the majority of human immune system cells either involved in innate or adaptive immune responses. Stimulation of THP-1 monocytes/macrophages with LPS or hydroxyapatite (HA) up-regulated GRP expression, and treatments with GRP or GRP-coated basic calcium phosphate crystals resulted in the down-regulation of mediators of inflammation and inflammatory cytokines, independently of the protein γ-carboxylation status. Moreover, overexpression of GRP in THP-1 cells rescued the inflammation induced by LPS and HA, by down-regulation of the proinflammatory cytokines TNFα, IL-1β and NFkB. Interestingly, GRP was detected at protein and mRNA levels in extracellular vesicles released by macrophages, which may act as vehicles for extracellular trafficking and release. Our data indicate GRP as an endogenous mediator of inflammatory responses acting as an anti-inflammatory agent in monocytes/macrophages. We propose that in a context of chronic inflammation and calcification-related pathologies, GRP might act as a novel molecular mediator linking inflammation and calcification events, with potential therapeutic application.

Cytokine-induced MMP13 Expression in Human Chondrocytes Is Dependent on Activating Transcription Factor 3 (ATF3) Regulation

Irreversible breakdown of cartilage extracellular matrix (ECM) by the collagenase matrix metalloproteinase 13 (MMP13) represents a key event in osteoarthritis (OA) progression. Although inflammation is most commonly associated with inflammatory joint diseases, it also occurs in OA and is thus relevant to the prevalent tissue destruction. Here, inflammation generates a cFOS AP-1 early response that indirectly affects MMP13 gene expression. To ascertain a more direct effect on prolonged MMP13 production we examined the potential molecular events occurring between the rapid, transient expression of cFOS and the subsequent MMP13 induction. Importantly, we show MMP13 mRNA expression is mirrored by nascent hnRNA transcription. Employing ChIP assays, cFOS recruitment to the MMP13 promoter occurs at an early stage prior to gene transcription and that recruitment of transcriptional initiation markers also correlated with MMP13 expression. Moreover, protein synthesis inhibition following early FOS expression resulted in a significant decrease in MMP13 expression thus indicating a role for different regulatory factors modulating expression of the gene. Subsequent mRNA transcriptome analyses highlighted several genes induced soon after FOS that could contribute to MMP13 expression. Specific small interfering RNA-mediated silencing highlighted that ATF3 was as highly selective for MMP13 as cFOS. Moreover, ATF3 expression was AP-1(cFOS/cJUN)-dependent and expression levels were maintained after the early transient cFOS response. Furthermore, ATF3 bound the proximal MMP13 AP-1 motif in stimulated chondrocytes at time points that no longer supported binding of FOS Consequently, these findings support roles for both cFOS (indirect) and ATF3 (direct) in effecting MMP13 transcription in human chondrocytes.

Tauroursodeoxycholic acid suppresses endoplasmic reticulum stress in the chondrocytes of patients with osteoarthritis

The main pathogenic events in osteoarthritis (OA) include loss and abnormal remodeling of cartilage extracellular matrix. The present study aimed to evaluate the protective effect of tauroursodeoxycholic acid on chondrocyte apoptosis induced by endoplasmic reticulum (ER) stress. Articular cartilage tissues were collected from 18patients who underwent total knee arthroplasty and were analyzed histologically. Subsequently, chondrocyte apoptosis was assessed by TUNEL. Quantitative polymerase chain reaction and western blot analysis were employed to evaluate gene and protein expression, respectively, of ER stress markers, including glucose‑regulated protein78 (GRP78), growth arrest and DNA‑damage‑inducible gene153 (GADD153) and caspase‑12 along with typeII collagen. Chondrocytes obtained from osteoarthritis patients at different stages were cultured in three conditions including: No treatment (CON group), tunicamycin treatment to induce ER stress (ERS group) and tauroursodeoxycholic acid treatment after 4h of tunicamycin (TDA group); and cell proliferation, apoptosis, function and ER stress level were assessed. Degradation of cartilage resulted in histological damage with more apoptotic cartilage cells observed. Of note, GRP78, GADD153 and caspase‑12 mRNA and protein expression increased gradually from gradeI to III cartilage tissue, while typeII collagen expression decreased. Tunicamycin induced ER stress, as shown by a high expression of ER stress markers, reduced cell proliferation, increased apoptosis and decreased synthesis of typeII collagen. Notably, tauroursodeoxycholic acid treatment resulted in the improvement of tunicamycin‑induced ER stress. These results indicated that ER stress is highly involved in the tunicamycin‑induced apoptosis in chondrocytes, which can be prevented by tauroursodeoxycholic acid.

KPNA2 interacts with P65 to modulate catabolic events in osteoarthritis

ObjectiveKaryopherin alpha 2 (KPNA2) is a member of the importin α family, which acts as an adaptor to deliver P65 to the nucleus by recognizing the classic nuclear localization signal (NLS) of the cargo protein, and which has been reported as being involved in the pathogenesis of many diseases. This study was undertaken to determine the expression and possible functions of KPNA2 in osteoarthritis (OA). MethodsKPNA2 expression in cartilage tissues of OA patients and normal controls was detected by RT-PCR and immunohistochemistry. SW1353 cells were stimulated with IL-1β to establish the chondrocyte injury model in vitro. The expression of KPNA2 and catabolic genes in IL-1β-treated SW1353 cells were determined by Western blot. The interaction between KPNA2 and P65 was analyzed by co-immunoprecipitation, the subcellular distribution and transportation of P65 were detected by the subcellular fractionation followed by immunoblot analysis and immunofluorescence. Furthermore, we used RNA interference to analyze the role of KPNA2 in IL-1β-induced P65 nuclear importation and MMP13, ADAMTS-5 expression in SW1353 cells. ResultsCartilage expression of KPNA2 was higher in patients with OA compared with normal controls and mainly locating in chondrocytes. In IL-1β-treated SW1353 cells, up-regulation of KPNA2 was accompanied by the elevated expression of the catabolic marker protein levels, including MMP13 and ADAMTS-5, and increased NF-κB P65 nuclear importation. Knock-down of KPNA2 resulted in decreased catabolic marker protein levels in IL-1β-treated SW1353 cells. KPNA2 interacted with p65, and loss of KPNA2 caused decreased nuclear translocation of the active p50/p65 NF-κB complex. ConclusionsThese findings suggested that KPNA2 may promote NF-κB activation via facilitating P65 nuclear transportation, and thus subsequently accelerate the catabolic events of osteoarthritis.

Meta-analysis

To compare cyclooxygenase-2 (Cox-2) inhibitors alone with NSAIDs plus proton pump inhibitors (PPIs) in preventing gastrointestinal adverse events: upper gastrointestinal (UGI) adverse events and gastrointestinal symptoms in Osteoarthritis and Rheumatoid arthritis. PubMed, the Cochrane Library, EMBASE, ISI Web of Knowledge, Chinese Biomedical Literature Database, and reference lists of relevant papers for articles published 1990-2010.12 were searched. The related data matching standards set for this study were extracted. Statistical analyses were carried out using RevMan (5.0) software. The meta-analysis of six randomized controlled trials with a total of 6219 patients revealed that there was no difference in the UGI adverse events between Cox-2 inhibitors and nonselective NSAIDs with concurrent use of PPIs [relative risk (RR) 0.61, 95% confidence interval (CI) 0.34-1.09]. There was no significant difference in gastrointestinal symptoms (RR 1.10, 95% CI: 0.88-1.39) and the cardiovascular adverse events (RR 1.67, 95% CI: 0.78-3.59) between the two groups. Cox-2 inhibitors are no better than nonselective NSAIDs with PPIs in regard to UGI adverse events, gastrointestinal symptoms and cardiovascular adverse events in Osteoarthritis and Rheumatoid arthritis. On the basis of the current evidence and the combined wishes of the patient, clinicians should carefully consider and weigh both gastrointestinal and cardiovascular risk before selecting NSAID plus PPIs or Cox-2 inhibitors.

Zerumbone significantly improved immunoreactivity in the synovium compared to Channa striatus extract in monosodium iodoacetate (MIA)-induced knee osteoarthritis in rat

The main aim of this study was to compare the immunoreactivity of some osteoarthritis related neuropeptides following oral administration of two natural remedies that is Channa striatus extract and zerumbone against monosodium iodoacetate induced knee osteoarthritis changes in the rat’s synovial membrane. Assay of PGE2 and PGF2α in the serum were performed to evaluate their role during osteoarthritis events and post oral application of the treatment. Forty rats were divided equally into four groups. Rats in the first and second groups were received channa extract and zerumbone, respectively. Rats in the third group were treated with celecoxib, whereas the fourth group was treated with normal saline. Evaluation of immunoreactivity of the following neuropeptides: Protein gene product 9.5, calcitonin gene related peptide and neuropeptide Y in the synovial membranes was implemented with the aid of both histopathology and immunohistochemistry approaches. Results revealed lower pathology score in both first and second groups accompanied with markedly improved immunoreactivity in zerumbone treated groups compared to channa extract group. Significant different concentrations of PGE2 but not PGF2α were detected within studied groups. Both remedies significantly improved the immunoreactivity which appeared more apparent in the group treated with zerumbone. Prostaglandin E2 has a role in osteoarthritis development and regulation. Key words: Channa striatus, osteoarthritis, neuropeptides, zerumbone, monosodium iodoacetate, rat.

If good things come from above, do bad things come from below?

Factors in the synovial fluid that maintain healthy articular cartilage, such as hyaluronic acid and lubricin, come from above. Is it possible that factors which lead to the destruction of cartilage come from below in the subchondral bone? The recent acquisition of tools to probe early events in osteoarthritis is shedding new light on possible contributions from this compartment on the initiation and progression of the disease. Tanamas and co-workers now provide evidence that bone marrow lesions in the subchondral bone are predictive, both of loss of cartilage and of formation of subchondral cysts. These data provoke questions about the nature and role of bone marrow lesions.

Articular cartilage mineralization in osteoarthritis of the hip

BackgroundThe aim of this study was to examine the frequency of articular cartilage calcification in patients with end-stage hip OA. Further, its impact on the clinical situation and the OA severity are analyzed.MethodsEighty patients with OA of the hip who consecutively underwent total hip replacement were prospectively evaluated, and 10 controls were included. The patients' X-rays were analyzed for the presence of articular cartilage mineralization. A Harris Hip Score (HHS) was preoperatively calculated for every patient.Slab specimens from the femoral head of bone and cartilage and an additional square centimeter of articular cartilage from the main chondral defect were obtained from each patient for analysis of mineralization by digital contact radiography (DCR). Histological grading was also performed. In a subset of 20 patients, minerals were characterized with an electron microscope (FE-SEM).ResultsCalcifications were seen in all OA cartilage and slab specimens using DCR, while preoperative X-rays revealed calcification in only 17.5%. None of the control cartilage specimens showed mineralization. There was a highly significant inverse correlation between articular cartilage calcification and preoperative HHS. Histological OA grade correlated positively with the amount of matrix calcification. FE-SEM analysis revealed basic calcium phosphate (BCP) as the predominant mineral; CPPD crystals were found in only two patients.ConclusionsArticular cartilage calcification is a common event in osteoarthritis of the hip. The amount of calcification correlates with clinical symptoms and histological OA grade.

Proprotein convertase activation of aggrecanases in cartilage in situ

Proteolytic degradation of the major cartilage macromolecules, aggrecan and type II collagen, is a key pathological event in osteoarthritis (OA). ADAMTS-4 and ADAMTS-5, the primary aggrecanases capable of cartilage aggrecan cleavage, are synthesized as latent enzymes and require prodomain removal for activity. The N-termini of the mature proteases suggest that activation involves a proprotein convertase, but the specific family member responsible for aggrecanase activation in cartilage in situ has not been identified. Here we describe purification of a proprotein convertase activity from human OA cartilage. Through biochemical characterization and the use of siRNA, PACE4 was identified as a proprotein convertase responsible for activation of aggrecanases in osteoarthritic and cytokine-stimulated cartilage. Posttranslational activation of ADAMTS-4 and ADAMTS-5 was observed in the extracellular milieu of cartilage, resulting in aggrecan degradation. These findings suggest that PACE4 represents a novel target for the development of OA therapeutics.

The effect of glycosaminoglycan loss on chondrocyte viability: A study on porcine cartilage explants

Loss of glycosaminoglycan (GAG) is an early event in osteoarthritis. Recent findings showed increased cell death in arthritic cartilage and linkage with extracellular matrix degradation. The aim of this study was to analyze the direct effect of GAG loss on chondrocyte survival and cell death following mechanical injury. In full-thickness cartilage explants from porcine knee joints, GAG was depleted by digestion with chondroitinase ABC. Explants were subjected to single-impact mechanical injury. Cell viability and the types of cell death were analyzed by Live/Dead cell assay, staining for active caspase 3, and sensitivity to caspase inhibitor. GAG depletion did not directly lead to increased cell death. In chondroitinase ABC-treated explants, but not in control explants, mechanical injury caused an immediate reduction in cell viability (from 84.6% to 71.0%); the reduction was prominent in the superficial zone. This immediate cell death was not inhibited by the pancaspase inhibitor Z-VAD-FMK, suggesting cell necrosis. During subsequent culture, viability in these explants decreased further, to 50.5% on day 3. The second wave of cell death was reduced by the addition of Z-VAD-FMK in chondroitinase ABC-treated explants and was also associated with activation of caspase 3, suggesting apoptotic mechanisms of cell death. These results indicate that GAG loss alone does not directly lead to chondrocyte death. In response to mechanical injury, there is an immediate induction of necrotic cell death that is seen only in GAG-depleted explants and primarily in the superficial zone. During subsequent culture, cell death spreads via apoptotic mechanisms.

Assessment of glycosaminoglycan concentration in vivo by chemical exchange-dependent saturation transfer (gagCEST).

Glycosaminogycans (GAGs) are involved in numerous vital functions in the human body. Mapping the GAG concentration in vivo is desirable for the diagnosis and monitoring of a number of diseases such as osteoarthritis, which affects millions of individuals. GAG loss in cartilage is typically an initiating event in osteoarthritis. Another widespread pathology related to GAG is intervertebral disk degeneration. Currently existing techniques for GAG monitoring, such as delayed gadolinium-enhanced MRI contrast (dGEMRIC), T(1)(rho), and (23)Na MRI, have some practical limitations. We show that by exploiting the exchangeable protons of GAG one may directly measure the localized GAG concentration in vivo with high sensitivity and therefore obtain a powerful diagnostic MRI method.

Activation of Interleukin-1 Signaling Cascades in Normal and Osteoarthritic Articular Cartilage

Interleukin (IL)-1 is one of the most important catabolic cytokines in rheumatoid arthritis. In this study, we were interested in whether we could identify IL-1 expression and activity within normal and osteoarthritic cartilage. mRNA expression of IL-1beta and of one of its major target genes, IL-6, was observed at very low levels in normal cartilage, whereas only a minor up-regulation of these cytokines was noted in osteoarthritic cartilage, suggesting that IL-1 signaling is not a major event in osteoarthritis. However, immunolocalization of central mediators involved in IL-1 signaling pathways [38-kd protein kinases, phospho (P)-38-kd protein kinases, extracellular signal-regulated kinase 1/2, P-extracellular signal-regulated kinase 1/2, c-Jun NH(2)-terminal kinase 1/2, P-c-Jun NH(2)-terminal kinase 1/2, and nuclear factor kappaB] showed that the four IL-1 signaling cascades are functional in normal and osteoarthritic articular chondrocytes. In vivo, we found that IL-1 expression and signaling mechanisms were detectible in the upper zones of normal cartilage, whereas these observations were more pronounced in the upper portions of osteoarthritic cartilage. Given these expression and distribution patterns, our data support two roles for IL-1 in the pathophysiology of articular cartilage. First, chondrocytes in the upper zone of osteoarthritic articular cartilage seem to activate catabolic signaling pathways that may be in response to diffusion of external IL-1 from the synovial fluid. Second, IL-1 seems to be involved in normal cartilage tissue homeostasis as shown by identification of baseline expression patterns and signaling cascade activation.

Increase in degraded collagen type II in synovial fluid early in the rabbit meniscectomy model of osteoarthritis

The objective of this study was to determine whether collagen type II breakdown products in synovial fluid (SF), detected by an enzyme-linked immunoassay, represent a useful marker for early events in osteoarthritis (OA) in the rabbit medial meniscectomy model. Complete medial meniscectomy was performed on the right knee joints of 32 rabbits. Balanced groups of rabbits were then sacrificed at 2, 4, 8, and 12 weeks post-surgery. An additional 8 unoperated and 11 sham-operated animals served as controls. SF lavages were performed on right and left knee joints of the same animals at sacrifice. The proteolytic epitope of type II collagen was monitored using an enzyme-linked immunoassay. Macroscopically visible surface fibrillation and focal erosions appeared as early as 2 weeks after meniscectomy in the femorotibial joint (P<0.01). OA developed gradually during the later observation period, and then predominantly on the medial tibial plateau and medial femur. Significant histological alterations in cartilage, including a loss of proteoglycans, surface irregularities, and clefts, were detected at 2 weeks after meniscectomy (P<0.01). Collagen type II epitope levels in SF lavage samples were elevated peaking at 2 weeks after meniscectomy (P<0.02). Levels decreased at later time points, but they were still raised at 12 weeks (P< or =0.05). Highly significant correlations were found between the SF collagen type II epitope levels and the macroscopic and microscopic scoring results (Spearman rho correlation coefficient, macroscopy-collagen type II epitope r=0.222, P=0.025; microscopy-collagen type II epitope r=0.436, P< or =0.01). In this rabbit model of medial meniscectomy, levels of type II collagen fragments in SF appear to provide a useful marker of the early degenerative changes.

The volume and morphology of chondrocytes within non-degenerate and degenerate human articular cartilage

Objective: Cartilage swelling is an early event in osteoarthritis (OA). However, the response of chondrocytes to increased tissue hydration is unknown. This work studied the volume and morphology of living in situ human chondrocytes as a function of cartilage degeneration. Methods: The tibial plateaus from knee joints of 40 patients were obtained following above-knee amputations or knee arthroplasty, and degree of cartilage degeneration from 0 (non-eroded) to 3 (extensive fibrillations) was assessed using several criteria. In situ chondrocytes were labeled with fluorescent indicators (calcein for living cells, propidium iodide for dead cells) permitting the quantification of volume and visualisation of morphology of cells within the cartilage zones by confocal scanning laser microscopy (CLSM). Results: Chondrocyte volume within superficial and mid-zones, but not of deep zone cells, increased significantly ( P<0.05 and P<0.02, respectively; one-way analysis of variance), with degree of cartilage hydration and degeneration. The volume increase (∼90% for mid-zone chondrocytes, grade 3 cartilage) was greater than that which might occur following loss/excision of sub-chondral bone (<15% swelling). The CLSM technique utilised here revealed that approximately 40% of chondrocytes within all cartilage grades exhibited at least one cytoplasmic processes of <8 μm. The presence of these processes did not indicate a cell body of larger volume than cells without processes, and did not contribute to cell volume. Conclusions: The volume of in situ chondrocytes within the superficial and mid-zones increased with cartilage degeneration. Cell swelling was greater than that expected from the increased hydration in OA, suggesting that an increase in chondrocyte volume might play a role in the changes to matrix metabolism occurring in OA.

Evaluation of the influence of prostaglandin E2 on recombinant equine interleukin-1beta-stimulated matrix metalloproteinases 1, 3, and 13 and tissue inhibitor of matrix metalloproteinase 1 expression in equine chondrocyte cultures.

To determine the effects of prostaglandin E2 (PGE2) on recombinant equine interleukin (IL)-1beta-stimulated expression of matrix metalloproteinases (MMP 1, MMP 3, MMP 13) and tissue inhibitor of matrix metalloproteinase 1 (TIMP 1) in vitro. Cultured equine chondrocytes. Stationary monolayers of first-passage chondrocytes were exposed to graduated concentrations of PGE2 with or without a subsaturating dose (50 pg/ml) of recombinant equine IL-1beta (reIL-1beta) to induce expression of MMP 1, MMP 3, MMP 13, and TIMP 1, followed by RNA isolation and northern blotting. In subsequent experiments, gene expression was similarly quantified from mRNA isolated from cultures pretreated with phenylbutazone to quench endogenous PGE2 synthesis, followed by exposure to reIL-1beta and exogenous PGE2 (5 mg/ml) with appropriate controls. Exogenous PGE2 (10 mg/ml) significantly reduced reIL-1beta-induced expression of MMP 1, MMP 3, MMP 13, and TIMP 1. Abrogation of cytokine induction with this dose of PGE2 was comparable to that for dexamethasone (10(-5) M) control. Similarly, pretreatment with phenylbutazone, followed by exposure to relL-1beta and PGE2 (5 mg/ml), was associated with a reduced expression of the genes of interest, an effect that was significant for MMP 1, MMP 13, and TIMP 1. The MMP and TIMP 1 are important mediators in the pathophysiologic events in osteoarthritis. The potential for physiologically relevant regulation of expression of these genes by PGE2 is a consideration in the use of drugs that inhibit prostanoid synthesis in the treatment of equine arthropathies.