Gouty Arthritis: Terkeltaub R

Liu-Bryan R, Terkeltaub R. · No affiliation provided · Arthritis Rheum. · Pubmed #16447213 links to  free full text

This publication has no abstract.

Cronstein BN, Terkeltaub R. · Department of Medicine and Division of Clinical Pharmacology, New York University School of Medicine, New York, New York, USA. · Arthritis Res Ther. · Pubmed #16820042 No free full text.

Abstract: Gouty arthritis is a characteristically intense acute inflammatory reaction that erupts in response to articular deposits of monosodium urate (MSU) crystals. Important recent molecular biologic advances in this field have given us a clear picture of the mechanistic basis of gouty inflammation. The innate immune inflammatory response is critically involved in the pathology of gout. Specifically, MSU crystals promote inflammation directly by stimulating cells via Toll-like receptor signaling and by providing a surface for cleavage of C5 and formation of complement membrane attack complex (C5b-9), culminating in secretion of cytokines, chemokines, and other inflammatory mediators with a dramatic influx of neutrophils into the joint. Despite the detailed mechanistic picture for gouty inflammation, there are no placebo-controlled, randomized clinical studies for any of the therapies commonly used, although comparative studies have demonstrated that many nonsteroidal anti-inflammatory drugs are equivalent to indomethacin with respect to controlling acute gouty attacks. In general, the first line of anti-inflammatory therapy for acute gout is nonsteroidal anti-inflammatory drugs, and the selective cyclo-oxygenase-2 inhibitor celecoxib can be used where appropriate. The second line of treatment is glucocorticosteroids, given systemically (oral, intravenous, or intramuscular) or intra-articularly. Alternatively, synthetic adrenocorticotropic hormone is effective, partly via induction of adrenal glucocorticosteroids and partly via rapid peripheral suppression of leukocyte activation by melatonin receptor 3 signaling. The third line of treatment is oral colchicine, which is highly effective when given early in an acute gouty attack, but it is poorly tolerated because of predictable gastrointestinal side effects.

Liu-Bryan R, Scott P, Sydlaske A, Rose DM, Terkeltaub R. · VA Medical Center, University of California, San Diego 92161, USA. · Arthritis Rheum. · Pubmed #16142712 links to  free full text

Abstract: OBJECTIVE: In gout, incompletely defined molecular factors alter recognition of dormant articular and bursal monosodium urate monohydrate (MSU) crystal deposits, thereby inducing self-limiting bouts of characteristically severe neutrophilic inflammation. To define primary determinants of cellular recognition, uptake, and inflammatory responses to MSU crystals, we conducted a study to test the role of Toll-like receptor 2 (TLR-2), TLR-4, and the cytosolic TLR adapter protein myeloid differentiation factor 88 (MyD88), which are centrally involved in innate immune recognition of microbial pathogens. METHODS: We isolated bone marrow-derived macrophages (BMDMs) in TLR-2-/-, TLR-4-/-, MyD88-/-, and congenic wild-type mice, and assessed phagocytosis and cytokine expression in response to endotoxin-free MSU crystals under serum-free conditions. MSU crystals also were injected into mouse synovium-like subcutaneous air pouches. RESULTS: TLR-2-/-, TLR-4-/-, and MyD88-/- BMDMs demonstrated impaired uptake of MSU crystals in vitro. MSU crystal-induced production of interleukin-1beta (IL-1beta), tumor necrosis factor alpha, keratinocyte-derived cytokine/growth-related oncogene alpha, and transforming growth factor beta1 also were significantly suppressed in TLR-2-/- and TLR-4-/- BMDMs and were blunted in MyD88-/- BMDMs in vitro. Neutrophil influx and local induction of IL-1beta in subcutaneous air pouches were suppressed 6 hours after injection of MSU crystals in TLR-2-/- and TLR-4-/- mice and were attenuated in MyD88-/- mice. CONCLUSION: The murine host requires TLR-2, TLR-4, and MyD88 for macrophage activation and development of full-blown neutrophilic, air pouch inflammation in response to MSU crystals. Our findings implicate innate immune cellular recognition of naked MSU crystals by specific TLRs as a major factor in determining the inflammatory potential of MSU crystal deposits and the course of gouty arthritis.