Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation.
Uric acid (UA) is known to activate the NLRP3 (Nacht, leucine-rich repeat and pyrin domain containing protein 3) inflammasome. When activated, the NLRP3 (also known as NALP3) inflammasome leads to the production of IL-18 and IL-1β. In this cohort of subjects with knee osteoarthritis (OA), synovial fluid uric acid was strongly correlated with synovial fluid IL-18 and IL-1β. Synovial fluid uric acid and IL-18 were strongly and positively associated with OA severity as measured by both radiograph and bone scintigraphy, and synovial fluid IL-1β was associated with OA severity but only by radiograph. Furthermore, synovial fluid IL-18 was associated with a 3-y change in OA severity, on the basis of the radiograph. We conclude that synovial fluid uric acid is a marker of knee OA severity. The correlation of synovial fluid uric acid with the two cytokines (IL-18 and IL-1β) known to be produced by uric acid-activated inflammasomes and the association of synovial fluid IL-18 with OA progression, lend strong support to the potential involvement of the innate immune system in OA pathology and OA progression.
Departments of Medicine and Radiology Duke University Medical Center, Durham, NC 27710, USA.
Anna E
AE
Denoble
Kim M
KM
Huffman
Thomas V
TV
Stabler
Susan J
SJ
Kelly
Michael S
MS
Hershfield
Gary E
GE
McDaniel
R Edward
RE
Coleman
Virginia B
VB
Kraus
D000368:Aged; D002352:Carrier Proteins / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000097:blood; D020382:Interleukin-18 / Q000096:biosynthesis; D007717:Knee / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010003:Osteoarthritis / Q000097:blood* / Q000235:genetics / Q000276:immunology; D012307:Risk Factors; D012720:Severity of Illness Index; D014527:Uric Acid / Q000097:blood*
D002352:Carrier Proteins; D007375:Interleukin-1; D020382:Interleukin-18; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D014527:Uric Acid
Scand J Rheumatol. 2000;29(6):380-6
11132207
Rheumatology (Oxford). 2009 Jul;48(7):711-5
19398486
Biochem J. 1987 May 1;243(3):803-8
3663100
J Immunol. 1991 Jun 15;146(12):4289-94
1645760
Cleve Clin J Med. 2008 Jul;75 Suppl 5:S2-4
18822468
J Rheumatol. 2008 Jun;35(6):1108-17
18412302
Arthritis Rheum. 1992 May;35(5):530-40
1533521
Osteoarthritis Cartilage. 2008 Feb;16(2):212-8
17662626
Ann Rheum Dis. 2003 Nov;62 Suppl 2:ii48-50
14532149
Arthritis Rheum. 2005 Jun;52(6):1730-5
15934069
J Immunol. 2009 Feb 15;182(4):1912-8
19201844
Rheum Dis Clin North Am. 2006 May;32(2):401-12, vii
16716886
J Clin Invest. 2010 Jun;120(6):1809-11
20501951
Curr Biol. 2004 Jan 6;14(1):R30-2
14711433
Nature. 1964 Jun 27;202:1334
14210970
Nature. 2006 Mar 9;440(7081):237-41
16407889
Arthritis Res Ther. 2006;8(6):R187
17177994
Ann Rheum Dis. 2011 Jun;70(6):1163-4
20971716
J Clin Invest. 1991 Apr;87(4):1375-81
2010550
Annu Rev Immunol. 1994;12:991-1045
8011301
Pain. 2009 Dec 15;147(1-3):277-86
19853379
Osteoarthritis Cartilage. 2009 Aug;17(8):1040-8
19289234
J Rheumatol. 1991 Jul;18(7):1042-5
1717687
Arthritis Rheum. 2004 Feb;50(2):432-43
14872485
Ann Rheum Dis. 2007 Oct;66(10):1374-7
17284542
Nature. 2003 Oct 2;425(6957):516-21
14520412
Osteoarthritis Cartilage. 1995 Sep;3 Suppl A:3-70
8581752
Clin Chem. 1999 Jun;45(6 Pt 1):901-4
10352002
Arthritis Rheum. 2010 Mar;62(3):791-801
20187128
Semin Arthritis Rheum. 1990 Dec;20(3 Suppl 1):34-41
2287947
Science. 2002 Apr 12;296(5566):301-5
11951032
Proc Natl Acad Sci U S A. 1981 Nov;78(11):6858-62
6947260
Ann Rheum Dis. 1957 Dec;16(4):494-502
13498604
Arthritis Rheum. 2002 Feb;46(2):420-7
11840444
Int Orthop. 2006 Feb;30(1):43-7
16333657
J Leukoc Biol. 2006 Mar;79(3):482-8
16387838
Curr Drug Targets. 2007 Feb;8(2):271-82
17305505
Ann Rheum Dis. 1986 Oct;45(10):858-64
3098195
Ann Rheum Dis. 1992 Jun;51(6):731-4
1616355
Arthritis Rheum. 2005 Sep;52(9):2936-46
16142712
J Immunol. 1987 May 15;138(10):3213-8
3033070
J Rheumatol. 1995 Jun;22(6):1118-23
7674240
Science. 1993 Jul 23;261(5120):472-5
8332913
Osteoarthritis Cartilage. 2003 Nov;11(11):801-9
14609533
Ann Rheum Dis. 1980 Jun;39(3):222-7
6251756
Endocr J. 1999 Oct;46(5):643-9
10670749
Ann Intern Med. 2005 Oct 4;143(7):499-516
16204163
Osteoarthritis Cartilage. 2008 Apr;16(4):515-21
18203633
Chem Biol Interact. 1990;73(2-3):235-47
2155712
Biol Chem. 2010 May;391(5):571-9
20180636
Expert Opin Ther Targets. 2003 Dec;7(6):701-24
14640907
J Clin Invest. 1984 Jun;73(6):1719-30
6725556
J Biol Chem. 2000 Dec 22;275(51):40307-15
11007768
Brain Behav Immun. 2007 Jul;21(5):535-43
17194566
Arthritis Rheum. 1989 Nov;32(11):1443-52
2554932
Trends Cell Biol. 2009 Sep;19(9):455-64
19716304
Clin Exp Med. 2009 Sep;9(3):215-21
19225717
Scand J Rheumatol. 2005 Nov-Dec;34(6):433-6
16393763
Nat Clin Pract Rheumatol. 2007 Jul;3(7):391-9
17599073
Ann Rheum Dis. 2009 Nov;68(11):1673-9
18981032
J Clin Invest. 1999 Nov;104(10):1393-401
10562301
J Rheumatol Suppl. 1991 Feb;27:10-2
2027107
J Clin Invest. 2010 Jun;120(6):1939-49
20501947