Genetics and experimental models of crystal-induced arthritis. Lessons learned from mice and men: is it crystal clear?
OBJECTIVE
We examine the major genes in mice and humans involved in the pathogenesis of monosodium urate, calcium pyrophosphate dihydrate and hydroxyapatite crystal-induced arthritis.


RESULTS
Several genetic causes of renal disease associated with hyperuricemia and gout provide insight into genes involved in renal urate handling. Mutations or polymorphisms in exons 4 and 5 and intron 4 of urate transporter 1 may be independent genetic markers of hyperuricemia and gout. Genetic analysis supports the role of ANKH mutations in calcium pyrophosphate dihydrate-induced arthritis. ANKH gain-of-function mutations were confirmed by functional studies; however, the crystals formed in ATD5 cells were basic calcium phosphate, not calcium pyrophosphate dihydrate, underlying the significance of chondrocyte differentiation state and the factors regulating normal and pathological mineralization. Animal models have implicated a general model of crystal-induced inflammation involving innate immunity through the NALP3 (Natch domain, leucine-rich repeat, and PYD-containing protein 3) inflammasome signaling through the interleukin-1 receptor and its signaling protein myeloid differentiation primary response protein 88.


CONCLUSIONS
Genetic analysis has elucidated genes responsible for crystal formation and animal models have unveiled mechanisms in the development of crystal-induced arthritis. Future studies will hasten understanding of the pathology of crystal-induced arthritis and provide new therapies.
Reginato
Anthony M
AM
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA. areginato@partners.org
Olsen
Bjorn R
BR
D000818:Animals; D015210:Arthritis, Gouty / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D002805:Chondrocalcinosis / Q000235:genetics* / Q000276:immunology; D003460:Crystallization; D004195:Disease Models, Animal; D006801:Humans; D006882:Hydroxyapatites / Q000276:immunology; D033461:Hyperuricemia / Q000235:genetics*; D007249:Inflammation / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology; D051379:Mice; D051437:Renal Insufficiency / Q000235:genetics
D006882:Hydroxyapatites