PubMed Health⌕ Search

Biomedical subjects

Francis Berenbaum

Publications and source records attributed to Francis Berenbaum.

At least 19 recordsLinked to original sources
PubMed2006

The role of IL-1 and IL-1Ra in joint inflammation and cartilage degradation.

Interleukin (IL)-1 is a cytokine that plays a major role in inflammatory responses in the context of infections and immune-mediated diseases. IL-1 refers to two different cytokines, termed IL-1alpha and IL-1beta, produced from two genes. IL-1alpha and IL-1beta are produced by different cell types following stimulation by bacterial products, cytokines, and immune complexes. Monocytes/macrophages are the primary source of IL-1beta. Both cytokines do not possess leader peptide sequences and do not follow a classical secretory pathway. IL-1alpha is mainly cell associated, whereas IL-1beta can be released from activated cells after cleavage of its amino-terminal region by caspase-1. IL-1 is present in the synovial tissue and fluids of patients with rheumatoid arthritis. Several in vitro studies have shown that IL-1 stimulates the production of mediators such as prostaglandin E(2), nitric oxide, cytokines, chemokines, and adhesion molecules that are involved in articular inflammation. Furthermore, IL-1 stimulates the synthesis and activity of matrix metalloproteinases and other enzymes involved in cartilage destruction in rheumatoid arthritis and osteoarthritis. The effects of IL-1 are inhibited in vitro and in vivo by natural inhibitors such as IL-1 receptor antagonist and soluble receptors. IL-1 receptor antagonist belongs to the IL-1 family of cytokines and binds to IL-1 receptors but does not induce any intracellular response. IL-1 receptor antagonist inhibits the effect of IL-1 by blocking its interaction with cell surface receptors. The use of IL-1 inhibitors in experimental models of inflammatory arthritis and osteoarthritis has provided a strong support for the role of IL-1 in the pathogeny of these diseases. Most importantly, these findings have been confirmed in clinical trials in patients with rheumatic diseases. Additional strategies aimed to block the effect of IL-1 are tested in clinical trials.

Animals↗
PubMed2006

Inhibition of anti-tuberculosis T-lymphocyte function with tumour necrosis factor antagonists.

Reactivation of latent Mycobacterium tuberculosis (Mtb) infection is a major complication of anti-tumour necrosis factor (TNF)-alpha treatment, but its mechanism is not fully understood. We evaluated the effect of the TNF antagonists infliximab (Ifx), adalimumab (Ada) and etanercept (Eta) on anti-mycobacterial immune responses in two conditions: with ex vivo studies from patients treated with TNF antagonists and with the in vitro addition of TNF antagonists to cells stimulated with mycobacterial antigens. In both cases, we analysed the response of CD4+ T lymphocytes to purified protein derivative (PPD) and to culture filtrate protein (CFP)-10, an antigen restricted to Mtb. The tests performed were lymphoproliferation and immediate production of interferon (IFN)-gamma. In the 68 patients with inflammatory diseases (rheumatoid arthritis, spondylarthropathy or Crohn's disease), including 31 patients with a previous or latent tuberculosis (TB), 14 weeks of anti-TNF-alpha treatment had no effect on the proliferation of CD4+ T lymphocytes. In contrast, the number of IFN-gamma-releasing CD4+ T lymphocytes decreased for PPD (p < 0.005) and CFP-10 (p < 0.01) in patients with previous TB and for PPD (p < 0.05) in other patients (all vaccinated with Bacille Calmette-Guérin). Treatments with Ifx and with Eta affected IFN-gamma release to a similar extent. In vitro addition of TNF antagonists to CD4+ T lymphocytes stimulated with mycobacterial antigens inhibited their proliferation and their expression of membrane-bound TNF (mTNF). These effects occurred late in cultures, suggesting a direct effect of TNF antagonists on activated mTNF+ CD4+ T lymphocytes, and Ifx and Ada were more efficient than Eta. Therefore, TNF antagonists have a dual action on anti-mycobacterial CD4+ T lymphocytes. Administered in vivo, they decrease the frequency of the subpopulation of memory CD4+ T lymphocytes rapidly releasing IFN-gamma upon challenge with mycobacterial antigens. Added in vitro, they inhibit the activation of CD4+ T lymphocytes by mycobacterial antigens. Such a dual effect may explain the increased incidence of TB in patients treated with TNF antagonists as well as possible differences between TNF antagonists for the incidence and the clinical presentation of TB reactivation.

Adalimumab↗
PubMed2006

Prostaglandin E2 synthesis in cartilage explants under compression: mPGES-1 is a mechanosensitive gene.

Knee osteoarthritis (OA) results, at least in part, from overloading and inflammation leading to cartilage degradation. Prostaglandin E2 (PGE2) is one of the main catabolic factors involved in OA. Its synthesis is the result of cyclooxygenase (COX) and prostaglandin E synthase (PGES) activities whereas NAD+-dependent 15 hydroxy prostaglandin dehydrogenase (15-PGDH) is the key enzyme implicated in the catabolism of PGE2. For both COX and PGES, three isoforms have been described: in cartilage, COX-1 and cytosolic PGES are constitutively expressed whereas COX-2 and microsomal PGES type 1 (mPGES-1) are inducible in an inflammatory context. COX-3 (a variant of COX-1) and mPGES-2 have been recently cloned but little is known about their expression and regulation in cartilage, as is also the case for 15-PGDH. We investigated the regulation of the genes encoding COX and PGES isoforms during mechanical stress applied to cartilage explants. Mouse cartilage explants were subjected to compression (0.5 Hz, 1 MPa) for 2 to 24 hours. After determination of the amount of PGE2 released in the media (enzyme immunoassay), mRNA and proteins were extracted directly from the cartilage explants and analyzed by real-time RT-PCR and western blotting respectively. Mechanical compression of cartilage explants significantly increased PGE2 production in a time-dependent manner. This was not due to the synthesis of IL-1, since pretreatment with interleukin 1 receptor antagonist (IL1-Ra) did not alter the PGE2 synthesis. Interestingly, COX-2 and mPGES-1 mRNA expression significantly increased after 2 hours, in parallel with protein expression, whereas COX-3 and mPGES-2 mRNA expression was not modified. Moreover, we observed a delayed overexpression of 15-PGDH just before the decline of PGE2 synthesis after 18 hours, suggesting that PGE2 synthesis could be altered by the induction of 15-PGDH expression. We conclude that, along with COX-2, dynamic compression induces mPGES-1 mRNA and protein expression in cartilage explants. Thus, the mechanosensitive mPGES-1 enzyme represents a potential therapeutic target in osteoarthritis.

Animals↗
PubMed2006

Muscle involvement in sarcoidosis: a retrospective and followup studies.

OBJECTIVE: Muscle involvement is a frequent histopathologic feature of sarcoidosis, but its clinical presentation has been rarely reported and its longterm outcome is unclear. We describe the features and outcome of 5 patients with muscle sarcoidosis. METHODS: A retrospective study from hospital charts over the period 1985-2001 in 2 academic rheumatology centers. RESULTS: Muscle involvement was identified in 5 patients (3 women, 2 men) aged 37 to 61 years, out of a cohort of 45 patients with sarcoidosis. No symptomatic muscle involvement was observed in the 20 patients with Lofgren syndrome of our series. Muscle involvement was the initial feature of the disease in 2 patients. Three patients had nodular type and the 2 others the myositic type. Chronic myopathy was not observed. Followup of patients with muscle disease ranged from 30 to 144 months (mean 72.6). Prednisone was used at a starting dose from about 0.33 to 1 mg/kg/day in all patients, then progressively tapered, and was associated with use of hydroxychloroquine (HCQ) in 2 cases. One poorly compliant patient was persistently prescribed 40 mg/day prednisone and HCQ by his general practitioner and was still complaining of diffuse myalgia at the last 30-month followup visit. One patient also receiving HCQ experienced cardiac and renal relapse, leading to transient increase in steroid dosage, but remained symptom-free 3 years after steroid discontinuation. Muscle relapses occurred in the 3 other patients. Muscle symptoms disappeared after readministration of corticosteroids or increase of prednisone dosage. The first patient was symptom-free without any treatment at the last followup visit. The second was still taking 10 mg/day 144 months after disease onset because of steroid-dependent myalgia. The last patient was asymptomatic with 10 mg/day prednisone at the last evaluation. CONCLUSION: Symptomatic muscle involvement may be an initial feature of chronic, and usually the systemic form of, sarcoidosis. It responds to corticosteroid therapy, but relapse seems to be frequent.

Adult↗
PubMed2005

New target genes for NOV/CCN3 in chondrocytes: TGF-beta2 and type X collagen.

UNLABELLED: We studied the involvement of NOV/CCN3, whose function is poorly understood, in chondrocyte differentiation. NOV was found to upregulate TGF-beta2 and type X collagen and to act as a downstream effector of TGF-beta1 in ATDC5 and primary chondrocytes. Thus, NOV is a positive modulator of chondrogenesis. INTRODUCTION: NOV/CCN3 is a matricellular protein that belongs to the CCN family. A growing body of evidence indicates that NOV could play a role in cell differentiation, particularly in chondrogenesis. During chick embryo development, NOV expression is tightly regulated in cartilage, and a high expression of NOV has been associated with cartilage differentiation in Wilms' tumors. However, a precise role for NOV and potential target genes of NOV in chondrogenesis are unknown. MATERIALS AND METHODS: ATDC5 cells and primary chondrocytes were either treated with NOV recombinant protein or transfected with a NOV-specific siRNA to determine, using quantitative RT-PCR, the effect of NOV on the expression of several molecules involved in chondrocyte differentiation. Stable ATDC5 clones expressing NOV were also established to show that NOV was a downstream effector of TGF-beta1. RESULTS: We established that NOV/CCN3 expression increases in ATDC5 cells at early stages of chondrogenic differentiation and precedes the appearance of TGF-beta2 and of several chondrocytic markers such as SOX9 or type X collagen. When exogenously administered, NOV recombinant protein up-regulates TGF-beta2 and type X collagen mRNA levels both in ATDC5 cells and in primary mouse chondrocytes but does not influence SOX9 expression. This regulation also occurs at the endogenous level because downregulation of NOV expression is correlated with an inhibition of TGF-beta2 and type X collagen in primary chondrocytes. Furthermore, we found that NOV expression is downregulated when chondrocytes are exposed to TGF-beta1-dedifferentiating treatment in chondrocytes, further providing evidence that NOV may counteract TGF-beta1 effects on chondrocytes. CONCLUSIONS: This study provides the first characterization of two new targets of NOV involved in chondrocyte differentiation, shows that NOV acts with TGF-beta1 in a cascade of gene regulation, and indicates that NOV is a positive modulator of chondrogenesis.

Animals↗
PubMed2005

Cartilage breakdown in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a connective tissue disease characterized by destruction of the joint cartilage and subsequently of the underlying bone. Cartilage destruction is due to proteolysis by enzymes called metalloproteinases (MMPs), whose production and expression are regulated by numerous local mediators such as cytokines, growth factors, prostaglandins, oxygen species, and neuropeptides. MMP activation is largely due to a stimulatory effect of cytokines including IL-1beta and TNFalpha. When these cytokines bind to their membrane receptor, they set off signaling cascades, with activation of TGFbeta-activating kinase (TAK-1), of NF-kappaB by Ikappa-B kinase, of mitogen-activated protein kinases (MAP kinases), and finally of activator protein-1 (AP-1). Tissue inhibitors of MMPs (TIMPs) specifically inhibit MMPs. The interrelations between joint inflammation and joint destruction remain poorly understood. Experimental data suggest that IL-1 may be involved chiefly in joint destruction and TNF in joint inflammation. However, TNF antagonists are potent inhibitors of joint destruction in clinical practice. These results suggest that the mediators function as a network and that inhibition of a single mediator can affect the entire web. Insights gained into the innermost mechanisms of cartilage breakdown in patients with RA have led to major therapeutic breakthroughs. Thus, TNF antagonists have proved highly effective in RA. Future progress will no doubt stem from new knowledge about the extracellular mediators and intracellular signaling pathways that lead to the production and activation of enzymes responsible for cartilage degradation.

Animals↗
PubMed2005

Immature murine articular chondrocytes in primary culture: a new tool for investigating cartilage.

OBJECTIVE: Many genetically modified animal models are providing new keys for unlocking the pathophysiology of cartilage degradation. To produce a tool for cellular and molecular studies in genetically engineered murine models, we defined the optimal culture conditions for primary cultures of articular chondrocytes from newborn mice (C57Bl/6). METHODS: To determine whether the cultured cells exhibited the typical articular chondrocyte phenotype, we examined several morphological, biochemical, and functional features. RESULTS: The cells had the typical chondrocyte morphology, with a rounded or polygonal shape. Immunolocalization studies showed high levels of type II collagen and aggrecan expression, together with sulfated glycosaminoglycan accumulation. Type II collagen and aggrecan expression decreased with passaging. In contrast, type I collagen expression was low in primary cultures and high after four passages, indicating a fibroblast phenotype. To evaluate the functional integrity of our cultured cells, we evaluated their ability to produce prostaglandin E2 (PGE2) and nitric oxide (NO) in response to the catabolic cytokine interleukin (IL)-1beta (10 ng/ml). Production of both PGE2 and NO increased significantly as compared to untreated controls. In addition, IL-1beta induced COX-2 expression by the cultured cells, as shown by Western blotting. CONCLUSIONS: Since functional and molecular parameters can be measured readily in mice, the immature murine articular chondrocyte (iMAC) model described here should prove a powerful tool for research, particularly as many transgenic and knockout mouse strains are available, even if iMACs are not optimal substitutes for human chondrocytes.

Aggrecans↗
PubMed2005

Clinical pharmacology of lumiracoxib, a second-generation cyclooxygenase 2 selective inhibitor.

Although highly selective cyclooxygenase (COX)-2 inhibitors have been shown to be less toxic to the gastrointestinal tract than conventional non-steroidal anti-inflammatory drugs (NSAIDs), their overall safety profile is questioned. Since different selective COX-2 inhibitors were found to be associated with increased cardiovascular thrombotic events, the thrombotic hazard may be a class effect. Furthermore, warnings have been issued regarding serious skin and hypersensitivity reactions associated with valdecoxib. Lumiracoxib is a novel COX-2 selective inhibitor (coxib) with improved biochemical selectivity over that of currently available coxibs. It is structurally distinct from other drugs in the class and has weakly acidic properties. Clinical studies support a once-daily dosing regimen, despite its relatively short plasma elimination half-life (3 - 6 h). In randomised, controlled clinical trials, lumiracoxib 100 - 200 mg/day has been shown to be superior to placebo in patients with symptomatic osteoarthritis, with clinical efficacy similar to diclofenac 150 mg/day, celecoxib 200 mg/day or rofecoxib 25 mg/day. Furthermore, lumiracoxib 200 - 400 mg/day appeared to be effective in patients with rheumatoid arthritis. In patients with acute pain related to primary dysmenorrhoea, dental or orthopaedic surgery, lumiracoxib 400 mg/day was found to be at least as effective as standard doses of traditional NSAIDs and other coxibs. Endoscopic studies have indicated that lumiracoxib is associated with a rate of gastroduodenal ulcer formation that is significantly lower than with ibuprofen and does not differ from celecoxib. In the Therapeutic Arthritis Research and Gastrointestinal Trial, which enrolled 18,325 patients with osteoarthritis, the cumulative 1-year incidence of ulcer complications (primary end point) was significantly reduced by approximately threefold on lumiracoxib 400 mg/day compared with naproxen 1000 mg/day or ibuprofen 2400 mg/day (0.32 versus 0.91%). Reduction in ulcer complications was more pronounced in the population not taking low-dose aspirin (0.2 versus 0.92%, respectively). Conversely, the gastrointestinal advantage of lumiracoxib was abrogated in patients receiving low-dose aspirin (0.69 versus 0.88%, respectively, p = 0.49). Regarding cardiovascular events contributing to the trialists' composite end point (myocardial infarction, stroke or cardiovascular death), there was no significant difference between lumiracoxib (0.65%) versus combined comparator NSAIDs (0.55%). Similarly, no significant difference was recorded in rates of myocardial infarction (clinical and silent) between the lumiracoxib (0.25%) and the combined NSAID (0.19%) treatment groups. Liver function test abnormalities were more frequent with lumiracoxib (2.57%) than with the comparator NSAIDs (0.63%). Whether or not this would result in an increased risk of clinical hepatitis in the real world setting is unforeseeable.

Animals↗
PubMed2004

Up-regulation of microsomal prostaglandin E synthase 1 in osteoarthritic human cartilage: critical roles of the ERK-1/2 and p38 signaling pathways.

OBJECTIVE: Microsomal prostaglandin E synthase 1 (mPGES-1) is the final enzyme of the cascade that produces prostaglandin E(2) (PGE(2)), a key actor in arthritis. To study mPGES-1 synthesis in human cartilage and its regulation by interleukin-1beta (IL-1beta), we used human cartilage and an immortalized human chondrocyte cell line. Furthermore, we investigated the signaling pathways involved in mPGES-1 expression. METHODS: We used real-time quantitative reverse transcription-polymerase chain reaction, Northern blotting, and Western blotting to measure mPGES-1 messenger RNA (mRNA) and protein expression in human chondrocytes. PGE(2) production was measured by enzyme-linked immunosorbent assay. RESULTS: Cartilage specimens from osteoarthritis (OA) patients contained far greater amounts of mPGES-1 and cyclooxygenase 2 (COX-2) mRNA than did normal cartilage. Incubation with IL-1beta markedly increased mPGES-1 mRNA and protein in a dose-dependent and time-dependent manner, in parallel with an increase in PGE(2) levels. Both PD98059, an ERK pathway inhibitor, and SB203580, a p38alpha/beta MAPK inhibitor, abolished the increases in mPGES-1 mRNA and protein in response to IL-1beta. The specific p38alpha MAPK inhibitor SC906 suppressed IL-1beta-induced COX-2 expression but not IL-1beta-induced mPGES-1 expression, suggesting preferential involvement of p38beta MAPK in IL-1beta-induced mPGES-1 expression. CONCLUSION: This study is the first to show that mPGES-1 is stimulated in human chondrocytes by the proinflammatory cytokine IL-1beta via activation of both ERK-1/2 and p38 MAPK in an isoform-specific manner. We postulate that mPGES-1 may be a novel target for OA therapy.

Cartilage, Articular↗
PubMed2004

Signal transduction pathways: new targets for treating rheumatoid arthritis.

Biotherapies and other new treatments introduced over the last few years have considerably enriched the therapeutic armamentarium for rheumatoid arthritis. Nevertheless, primary refractoriness or secondary escape phenomenon may occur, indicating a need for identifying new treatment targets. Promising candidates can be found among compounds involved in signal transduction pathways, most notably protein kinases (mitogen-activated protein kinase, MAPK and phosphatidylinositol-3 protein kinase, PI3) and transcription factors (nuclear factor kappa B, NF-kappaB; activating protein 1, AP-1; CCAAT/enhancer-binding protein, C/EBP and signal transducer and activator of transcription, STAT). Inhibition of signal transduction pathways may be achievable via three main strategies: pharmacological inhibitors, anti-sense or more specific inhibitors such as oligionucleotides or interfering mRNA, and induced overexpression of naturally occurring inhibitors. Clinical trials are under way to evaluate pharmacological inhibitors such as p38 MAPK. Although the preliminary results are promising, proof of safety has not yet been obtained. Signal transduction pathways are involved in normal processes, whose inhibition might produce untoward effects.

Arthritis, Rheumatoid↗
PubMed2004

The regulation of chondrocyte function by proinflammatory mediators: prostaglandins and nitric oxide.

Within the mature articular cartilage matrix, which has no blood or nerve supply, chondrocytes show little metabolic activity with low turnover of matrix components. Under conditions of stress because of biomechanical factors, however, chondrocytes are capable of producing mediators that are associated with inflammation, including cytokines such as interleukin-1 and tumor necrosis factor-alpha, which in turn stimulate the production of prostaglandins and nitric oxide. Chondrocytes also express receptors for these mediators, which accumulate at high local concentrations and can act in an autocrine-paracrine fashion to feedback-regulate chondrocyte responses. Prostaglandin E2 can exert catabolic or anabolic effects depending on the microenvironment. Nitric oxide can promote cellular injury and increase chondrocyte susceptibility to cytokine-induced apoptosis. Because cross-talk between these mediators produces complex modulation of catabolic and anabolic pathways, further studies in vitro and in vivo are required to elucidate their precise roles in osteoarthritis.

Animals↗
PubMed2004

Signaling transduction: target in osteoarthritis.

PURPOSE OF REVIEW: The pathophysiology of osteoarthritis is the result of an imbalance between anabolic and catabolic pathways. This imbalance is the result of the activation of joint cells by inflammatory mediators, matrix components, and mechanical stress. All these mediators act through specific receptors that transmit the signals to the nucleus to activate the transcription of matrix metalloproteinases and inflammatory genes. Targeting these signaling pathways in osteoarthritis is considered a novel approach to modulate this imbalance. RECENT FINDINGS: Although many signaling pathways are necessary for physiologic cell life, it is now well established that a few are more specifically induced in an inflammatory environment. In osteoarthritis, the nuclear factor-kappaB and mitogen-activated protein kinase pathways have been shown to play a predominant role in the expression of metalloproteinases and inflammatory genes and proteins. Also involved in the activation of osteoarthritic cells are other molecules interacting with one or several signaling pathways, such as nitric oxide, peroxisome proliferator-activated receptor-gamma ligands, or C/EBP transcriptional factors. Based on this knowledge, specific inhibitors for some of these signaling pathways have been designed and include p38 mitogen-activated protein kinase or nuclear factor-kappaB inhibitors. Experimental studies evaluating cartilage degradation in arthritis models are promising, although fewer have been done specifically in osteoarthritis models. SUMMARY: Targeting signaling pathways in osteoarthritis did not seem feasible a few years ago because of the complexity of the multiple intracellular pathways, mainly physiologic, defined by a high degree of redundancy and cross-talk. However, important advances in the knowledge of chondrocyte and synoviocyte signaling in osteoarthritis have been achieved in recent years and suggest that inhibitors of specific signaling pathways could shortly provide effective treatments for this disease.

Chondrocytes↗
PubMed2004

Culture and phenotyping of chondrocytes in primary culture.

The culture of chondrocytes is one of the most powerful tool for exploring the intracellular and molecular features of chondrocyte differentiation and activation. However, chondrocytes tend to dedifferentiate to fibroblasts when they are subcultured, which is a major problem. This chapter describes several protocols for culturing chondrocytes of different anatomical origins (articular and costal chondrocytes) from various species (humans, mice, rabbits, and cattle). All these protocols involve primary cultures in order to limit dedifferentiation. This chapter also describes a new protocol for culturing mouse articular chondrocytes.

Animals↗
PubMed2003

[Non-steroidal anti-inflammatory agents].

Non steroidal anti-inflammatory drugs have the highest rate of prescription in the world due to their efficacy in counteracting inflammation, pain, fever and blood clot (with low-dose aspirin). This therapeutic class has been recently widen by a new family of NSAID, namely COX-2 selective inhibitors or coxibs. A 50%-reduction in the rate of gastric ulcers and bleeding has been achieved with coxibs. However, some questions remain unanswered yet, such as the cardiovascular issue with coxibs. Although the tolerability of NSAIDs is generally good, some well-established good clinical practices avoid the rare unexpected events which could sparsely occurred.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2003

Concomitant recruitment of ERK1/2 and p38 MAPK signalling pathway is required for activation of cytoplasmic phospholipase A2 via ATP in articular chondrocytes.

Extracellular ATP is a pro-inflammatory mediator involved in the release of prostaglandin from articular chondrocytes, but little is known about its effects on intracellular signaling. ATP triggered the rapid release of prostaglandin E(2) (PGE(2)) by acting on P2Y(2) receptors in rabbit articular chondrocytes. We have explored the signaling events involved in this synthesis. ATP significantly increased arachidonic acid production, which involved the activation of the 85-kDa cytosolic phospholipase A(2) (cPLA(2)) but not a secreted form of PLA(2), as demonstrated by various PLA(2) inhibitors and translocation experiments. We also showed that ATP induced the phosphorylation of p38 and ERK1/2 mitogen-activated-protein kinases (MAPKs). Both PD98059, an inhibitor of the ERK pathway, and SB203580, an inhibitor of p38 MAPK, completely inhibited the ATP-induced release of PGE(2). Finally, dominant-negative plasmids encoding p38 and ERK transfected alone into the cells impaired the ATP-induced release of PGE(2) to about the same extent as both plasmids transfected together. These results suggest that PGE(2) production induced by ATP requires the activation of both ERK1/2 and p38 MAPKs. Thus, ATP acts via P2Y(2)-purine receptors to recruit cPLA(2) by activating both ERK1/2 and p38 MAPKs and stimulates the release of PGE(2) from articular chondrocytes.

Adenosine Triphosphate↗