Faculty Bibliography

Annexins are intracellular molecules implicated in the down-regulation of inflammation. Recently, annexin-1 has also been identified as a secreted molecule, suggesting it may have more complex effects on inflammation than previously appreciated. We studied the role of annexin-1 in mediating MMP-1 secretion from rheumatoid arthritis (RA) synovial fibroblasts (SF) stimulated with TNF-alpha. TNF-alpha induced a biphasic secretion of annexin-1 from RA SF. Early (< or = 60 min), cycloheximide-independent secretion from preformed intracellular pools was followed by late (24 h) cycloheximide-inhibitable secretion requiring new protein synthesis. Exogenous annexin-1 N-terminal peptide Ac2-26 stimulated MMP-1 secretion in a dose- (EC(50) approximately 25 microM) and time- (8-24 h) dependent manner; full-length annexin-1 had a similar effect. Down-regulation of annexin-1 using small interfering RNA resulted in decreased secretion of both annexin-1 and MMP-1, confirming that annexin-1 mediates TNF-alpha-stimulated MMP-1 secretion. Erk, Jnk, and NF-kappaB have been implicated in MMP-1 secretion. Erk, Jnk, and NF-kappaB inhibitors had no effect on annexin-1 secretion stimulated by TNF-alpha but inhibited MMP-1 secretion in response to Ac2-26, indicating that these molecules signal downstream of annexin-1. Annexin-1 stimulation of MMP-1 secretion was inhibited by both a formyl peptide receptor antagonist and pertussis toxin, suggesting that secreted annexin-1 acts via formyl peptide family receptors, most likely FPLR-1. In contrast to its commonly appreciated anti-inflammatory roles, our data indicate that annexin-1 is secreted by RA SF in response to TNF-alpha and acts in an autacoid manner to engage FPRL-1, activate Erk, Jnk, and NF-kappaB, and stimulate MMP-1 secretion

OBJECTIVE: Recommendations for screening for latent Mycobacterium tuberculosis (MTB) infection have been proposed but are not well studied in patients with rheumatoid arthritis (RA). We estimated the prevalence of anergy in RA and evaluated different methods to detect MTB exposure. METHODS: This was a prospective pilot study of 61 patients with RA and 42 healthy controls. Tuberculin skin test (TST) antigen, Candida, and tetanus toxoid were injected intradermally using the Mantoux method. Subjects negative for TST returned for a second-step test. Whole-blood interferon-gamma (IFN-gamma) release to mycobacterial antigens was evaluated with the first-generation QuantiFeron test (QIFN). RESULTS: Cutaneous anergy in patients with RA was not significantly different than healthy controls (p = 0.154), and was not affected by disease modifying antirheumatic drugs (p = 0.270). In patients with RA, 16.4% had positive TST with 10 mm cutoff vs 11.9% of controls. Using a 5 mm cutoff, 21.3% of patients with RA were positive, and this increased to 29.5% with a second-step TST. QIFN detected MTB exposure in 18% of patients with RA and 19% of controls (p = 0.897). However, indeterminate QIFN tests were higher in RA patients (11.5%) compared to controls (2.4%), demonstrating a lower sensitivity to detect latent MTB. CONCLUSION: Cutaneous anergy may be less common than previously reported in patients with RA. patients. However, the single-step TST and 10 mm cutoff may fail to detect all cases of latent exposure in RA patients. High rates of indeterminate results in QIFN testing suggest that QIFN should not be employed as an alternative, single-screening test in patients with RA. These pilot results require confirmation in larger studies to determine the optimal screening strategy in RA

Scott et al. conducted a systematic review to evaluate the risk of myocardial infarction (MI) associated with cyclo-oxygenase-2 (COX2) inhibitors and traditional NSAIDs. The review found a small increased risk of MI associated with COX2 inhibitors, particularly rofecoxib. Although a fixed-effects model of 14 case-control studies suggested a slightly increased risk of MI with NSAID use, a random-effects model of the same data and analysis of 6 cohort studies found no such link. An increased risk of MI was found in four RCTs of NSAID use in colonic adenoma. In an analysis of 14 RCTs that compared COX2 inhibitors with traditional NSAIDs in patients with arthritis, the odds ratio for MI with COX2 inhibitors was 1.6 (95% CI 1.1-2.4), although most of this risk was accounted for by rofecoxib. COX2 inhibitors were, however, associated with a reduced risk of serious gastrointestinal events. An analysis of previous systematic reviews showed increased risks of MI associated with rofecoxib and celecoxib

While research in osteoarthritis has focused on the events that lead to the destruction of articular cartilage, recent evidence suggests that two other components of the joints-bone and synovium-also play key roles in pathogenesis. All three tissues undergo alterations in concert at the structural levels in response to mechanical stress and joint malalignment. Advanced imaging studies such as MRI support this interdependence, revealing the classical changes of joint space narrowing and cartilage degeneration as well as the more recently appreciated bone marrow lesions and synovitis that may correlate with clinical symptoms. Molecular evidence also points to a coordinated release of cytokines and other inflammatory mediators from each of the three tissues together in progression of disease, although we are still in search of biochemical signatures that will predict the subset of patients who progress more quickly-and who will provide key clues to successful molecular targets in future therapies. At this time we lack definitive evidence pointing to which, if any, of the three tissues should serve as the main target for disease modification or structure protection, although most efforts have focused on cartilage. Thus current therapies focus on controlling symptoms, while research efforts search for reliable imaging and molecular biomarkers to help guide future trials of potential disease-modifying agents

Osteoarthritis (OA) is a degenerative disease involving chondrocytes, cartilage and other joint tissues, and has a number of underlying causes, including both biochemical and mechanical factors. Although proinflammatory factors including nitric oxide (NO) are associated with OA, there is recent evidence suggesting that NO and its redox derivatives may also play protective roles in the joint. However, the mechanisms that underlie the development and progression of OA are not completely understood. Experiments have demonstrated that NO plays a catabolic role in the development of OA and mediates the inflammatory response, is involved in the degradation of matrix metalloproteinases, inhibits the synthesis of both collagen and proteoglycans, and helps to mediate apoptosis. However, there is also evidence that in cultured chondrocytes the addition of exogenous NO may inhibit proinflammatory activation by preventing the nuclear localization of the transcription factor nuclear factor-kappaB, whereas the presence of peroxynitrite--a redox derivative of NO--appears to enhance the inflammatory response by sustaining the nuclear localization of nuclear factor-kappaB. In addition, under some conditions exogenous NO can stimulate collagen synthesis in cultured rat fibroblasts and human tendon cells. The protective roles of NO in multiple cell types, along with the opposing activities in cultured chondrocytes, suggest that NO may play additional protective roles in chondrocyte function. NO and its derivatives have a similarly complicated involvement in nociception and pain, which may contribute to the functional disability of OA. Further research may help to elucidate a potential role for NO-donating agents in the management of OA

Osteoarthritis (OA) is caused by both biochemical and mechanical factors. While the mechanisms that underlie the disease are not completely understood, investigators have characterized a number of catabolic and protective factors that have a role in the disease process. Nitric oxide (NO) and its redox derivatives appear to have a number of different functions in both normal and pathophysiological joint conditions. Until recently, NO was considered a catabolic factor that was responsible for perpetuating the OA disease process by mediating the expression of proinflammatory cytokines, inhibiting the synthesis of collagen and proteoglycans and inducing apoptosis. However, recent studies suggest that NO and its redox derivatives may also have protective effects on cartilage. This review will summarize the literature on the effects of NO on cartilage and chondrocytes as well as discuss some evidence that suggests potential protective effects of NO and/or its derivatives on other cell types. More research is needed to elucidate the role of NO and its derivatives on both normal and osteoarthritis cartilage