Gout: So A

So A. · No affiliation provided · Arthritis Res Ther. · Pubmed #18564404 links to  free full text

Abstract: Understanding how uric acid crystals provoke inflammation is crucial to improving our management of acute gout. It is well known that urate crystals stimulate monocytes and macrophages to elaborate inflammatory cytokines, but the tissue response of the synovium is less well understood. Microarray analysis of mRNA expression by these lining cells may help to delineate the genes that are modulated. Employing a murine air-pouch model, a number of genes expressed by innate immune cells were found to be rapidly upregulated by monosodium urate crystals. These findings provide new research avenues to investigate the physiopathology of gouty inflammation, and may eventually lead to new therapeutic targets in acute gout.

So A. · Service de Rhumatologie, Departement de Médecine, CHU Vaudois, University of Lausanne, Ave Pierre Decker, 1011 Lausanne, Switzerland. · Arthritis Res Ther. · Pubmed #18947374 links to  free full text

Abstract: Gout is the most common form of inflammatory arthritis in the elderly. In the last two decades, both hyperuricemia and gout have increased markedly and similar trends in the epidemiology of the metabolic syndrome have been observed. Recent studies provide new insights into the transporters that handle uric acid in the kidney as well as possible links between these transporters, hyperuricemia, and hypertension. The treatment of established hyperuricemia has also seen new developments. Febuxostat and PEG-uricase are two novel treatments that have been evaluated and shown to be highly effective in the management of hyperuricemia, thus enlarging the therapeutic options available to lower uric acid levels. Monosodium urate (MSU) crystals are potent inducers of inflammation. Within the joint, they trigger a local inflammatory reaction, neutrophil recruitment, and the production of pro-inflammatory cytokines as well as other inflammatory mediators. Experimentally, the uptake of MSU crystals by monocytes involves interactions with components of the innate immune system, namely Toll-like receptor (TLR)-2, TLR-4, and CD14. Intracellularly, MSU crystals activate multiple processes that lead to the formation of the NALP-3 (NACHT, LRR, and pyrin domain-containing-3) inflammasome complex that in turn processes pro-interleukin (IL)-1 to yield mature IL-1 beta, which is then secreted. The inflammatory effects of MSU are IL-1-dependent and can be blocked by IL-1 inhibitors. These advances in the understanding of hyperuricemia and gout provide new therapeutic targets for the future.

So A. · Service de Rhumatologie, Departement de Médicine, CHU Vaudois, University of Lausanne, 1011, Lausanne, Schweiz. · Z Rheumatol. · Pubmed #17924125 No free full text.

Abstract: Gout is caused by the deposition of monosodium urate crystals (MSU) in tissue and provokes a local inflammatory reaction. It is the most common form of inflammatory arthritis in the elderly. The formation of MSU crystals is facilitated by hyperuricemia. In the last two decades, both hyperuricemia and gout have increased markedly and similar trends in the epidemiology of the metabolic syndrome have been observed. Recent studies provide new insights into uric acid metabolism in the kidneys as well as possible links between hyperuricemia and hypertension. MSU crystals provoke inflammation by activating leukocytes to produce inflammatory cytokines and other inflammatory mediators. The uptake of MSU crystals by monocytes involves interactions with Toll-like receptors (TLR-2 and TLR-4) and CD14, components of the innate immune system. Intracellularly, MSU crystals activate inflammasomes to activate pro-IL-1 (interleukin 1) processing to yield mature IL-1beta. The inflammatory effects of MSU are IL-1-dependent and can be blocked by IL-1 inhibitors. These advances provide new therapeutic targets to treat hyperuricemia and gout.

So A. · Service de rhumatologie, médecine physique et rééducation, Département de médecine CHUV, 1011 Lausanne. · Rev Med Suisse. · Pubmed #17458149 No free full text.

Abstract: Gout is due to the formation and tissue deposition of MSU crystals. Hyperuricemia promotes crystal formation and results from the disequilibrium between the synthetic and elimination rates of uric acid. Recent studies have elucidated the mechanisms of renal handling of uric acid by specific transporters (URATI and OAT) which play a role in uric acid excretion. MSU crystals provoke inflammation by activating leukocytes to produce inflammatory cytokines. One mechanism is through the TLR2 and TLR4 receptors, which form part of the innate immune system. MSU crystals can also activate a protein complex called the inflammasome, which in turn activates IL-1 processing to yield the secreted mature form of IL- 1beta. The inflammatory effects of MSU can be blocked by IL-1 inhibitors. These advances could provide new targetted therapeutic approaches to treat hyperuricemia and gout.

So A, De Smedt T, Revaz S, Tschopp J. · Service of Rhumatologie, Department of Medicine, Centre Hospitalier Universtaire Vaudois and University of Lausanne, 1011 Lausanne, Switzerland. · Arthritis Res Ther. · Pubmed #17352828 links to  free full text

Abstract: Monosodium urate crystals stimulate monocytes and macrophages to release IL-1beta through the NALP3 component of the inflammasome. The effectiveness of IL-1 inhibition in hereditary autoinflammatory syndromes with mutations in the NALP3 protein suggested that IL-1 inhibition might also be effective in relieving the inflammatory manifestations of acute gout. The effectiveness of IL-1 inhibition was first evaluated in a mouse model of monosodium urate crystal-induced inflammation. IL-1 inhibition prevented peritoneal neutrophil accumulation but TNF blockade had no effect. Based on these findings, we performed a pilot, open-labeled study (trial registration number ISRCTN10862635) in 10 patients with gout who could not tolerate or had failed standard antiinflammatory therapies. All patients received 100 mg anakinra daily for 3 days. All 10 patients with acute gout responded rapidly to anakinra. No adverse effects were observed. IL-1 blockade appears to be an effective therapy for acute gouty arthritis. The clinical findings need to be confirmed in a controlled study.

Lin D, Watahiki A, Bayani J, Zhang F, Liu L, Ling V, Sadar MD, English J, Fazli L, So A, Gout PW, Gleave M, Squire JA, Wang YZ. · Department of Cancer Endocrinology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. · Cancer Res. · Pubmed #18519696 links to  free full text

Abstract: Metastatic prostate cancer is a terminal disease, and the development of reliable prognostic tools and more effective therapy is critically important for improved disease survival and management. This study was aimed at identifying genes that are differentially expressed in metastatic and nonmetastatic prostate cancer cells and, as such, could be critical in the development of metastasis. Long-SAGE analysis was used to compare a transplantable human metastatic prostate cancer subline, PCa1-met, with a nonmetastatic counterpart, PCa2. Both sublines were developed from a patient's prostate cancer specimen via subrenal capsule grafting and subsequent orthotopic implantation into SCID mice. Among various differentially expressed genes identified, ASAP1, an 8q24 gene encoding an ADP-ribosylation factor GTPase-activating protein not previously associated with prostate cancer, was up-regulated in the metastatic subline as confirmed by quantitative real-time PCR. Immunohistochemistry of xenograft sections showed that cytoplasmic ASAP1 protein staining was absent or weak in benign tissue, significantly stronger in nonmetastatic PCa2 tissue, and strongest in PCa1-met tissue. In clinical specimens, ASAP1 protein staining was elevated in 80% of primary prostate cancers and substantially higher in metastatic lesions compared with benign prostate tissue. Moreover, additional ASAP1 gene copies were detected in 58% of the primary prostate cancer specimens. Small interfering RNA-induced reduction of ASAP1 protein expression markedly suppressed in vitro PC-3 cell migration (approximately 50%) and Matrigel invasion (approximately 67%). This study suggests that the ASAP1 gene plays a role in prostate cancer metastasis and may represent a therapeutic target and/or biomarker for metastatic disease.