Gouty Arthritis: Liu-Bryan R

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

This publication has no abstract.

Masseoud D, Rott K, Liu-Bryan R, Agudelo C. · Division of Rheumatology, Emory University School of Medicine/The Emory Clinic, 1365A Clifton Rd NE, 4th floor, Atlanta, GA 30322, USA. · Curr Pharm Des. · Pubmed #16375732 No free full text.

Abstract: In most mammals purine degradation ultimately leads to the formation of allantoin. Humans lack the enzyme uricase, which catalyzes the conversion of uric acid to allantoin. The resulting higher level of uric acid has been hypothesized to play a role as an antioxidant. Hyperuricaemia is usually an asymptomatic condition which is hypothesized to play a role in cardiovascular disease and hypertension. Some hyperuricaemic individuals develop gout, an inflammatory arthritis caused by the deposition of monosodium urate crystals in joints. Over time, acute intermittent gouty arthritis can develop into a chronic condition with deposits of monosodium urate (MSU) crystals in joints and as tophi. The mechanisms by which MSU crystals lead to an acute inflammatory arthritis are under investigation and current knowledge is reviewed here. Treatment of gout includes management of acute flares with anti-inflammatory medications such as non-steroidal anti-inflammatory drugs or corticosteroids and long term management with urate-lowering therapy when indicated. Future directions in the treatment of gout, in part guided by a better understanding of pathophysiology, are discussed.

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.

Tramontini N, Huber C, Liu-Bryan R, Terkeltaub RA, Kilgore KS. · Pfizer Global Research and Development, Ann Arbor, Michigan, USA. · Arthritis Rheum. · Pubmed #15334478 links to  free full text

Abstract: OBJECTIVE: Monosodium urate monohydrate (MSU) crystals promote gouty inflammation that is critically mediated by neutrophil recruitment and activation. Interleukin-8 (IL-8) and closely related chemokines are major neutrophil chemotaxins in experimental gout. But MSU crystals also activate the classical and alternative pathways of complement, and MSU crystals directly cleave C5 on the crystal surface. Unlike IL-8, the roles in acute gout of individual complement-derived peptides and of the terminal C5b-9 complement components that comprise the membrane attack complex (MAC) are unclear. Hence, we studied rabbits deficient in the MAC component C6 to determine if MAC mediated urate crystal-induced arthritis. METHODS: We injected C6-deficient and C6-sufficient rabbit knee joints with 10 mg of pyrogen-free urate crystals and analyzed IL-8 levels, leukocyte influx, and joint inflammation 24 hours later. RESULTS: There was a significant decrease (>60%) in swelling in MSU crystal-injected knees of C6-deficient animals as compared with C6-sufficient animals (P < 0.05). An attenuated rise in MSU crystal-induced joint effusion levels of IL-8 also was observed, which was concordant with diminished numbers of neutrophils (P < 0.05) but not monocytes in MSU crystal-induced knee synovial fluid from C6-deficient animals. Synovial tissue analysis confirmed mononuclear leukocyte infiltration in response to MSU crystal injection in all animals, but substantial neutrophil infiltration only in C6-sufficient animals. CONCLUSION: MAC activation appears to play a major role in intraarticular IL-8 generation and in neutrophil recruitment in experimental acute gouty arthritis of the rabbit knee. C6 and MAC activation may represent novel therapeutic targets for suppression of neutrophil-mediated joint inflammation in gout.