Identification of a central role for complement in osteoarthritis

被引：497

作者：

Wang, Qian ^{[1
,2
,3
]}

Rozelle, Andrew L. ^{[1
,2
,3
]}

Lepus, Christin M. ^{[1
,2
,3
]}

Scanzello, Carla R. ^{[4
]}

Song, Jason J. ^{[1
,2
,3
]}

Larsen, D. Meegan ^{[1
,2
,3
]}

Crish, James F. ^{[5
]}

Bebek, Gurkan ^{[5
,6
]}

Ritter, Susan Y. ^{[7
,8
]}

Lindstrom, Tamsin M. ^{[1
,2
,3
]}

Hwang, Inyong ^{[1
,2
,3
]}

Wong, Heidi H. ^{[1
,2
,3
]}

Punzi, Leonardo ^{[9
]}

Encarnacion, Angelo ^{[10
]}

Shamloo, Mehrdad ^{[10
]}

Goodman, Stuart B. ^{[11
]}

Wyss-Coray, Tony ^{[1
,2
,12
]}

Goldring, Steven R. ^{[13
]}

Banda, Nirmal K. ^{[14
,15
]}

Thurman, Joshua M. ^{[14
,15
]}

Gobezie, Reuben ^{[16
]}

Crow, Mary K. ^{[13
]}

Holers, V. Michael ^{[14
,15
]}

Lee, David M. ^{[7
,8
,17
]}

Robinson, William H. ^{[1
,2
,3
]}

机构：

[1] Vet Affairs Palo Alto Hlth Care Syst, Geriatr Res Educ Ctr, Palo Alto, CA USA

[2] Vet Affairs Palo Alto Hlth Care Syst, Ctr Clin, Palo Alto, CA USA

[3] Stanford Univ, Sch Med, Div Rheumatol & Immunol, Stanford, CA 94305 USA

[4] Rush Univ, Med Ctr, Rheumatol Sect, Chicago, IL 60612 USA

[5] Case Western Reserve Univ, Sch Med, Ctr Prote & Bioinformat, Cleveland, OH USA

[6] Cleveland Clin, Genom Med Inst, Cleveland, OH 44106 USA

[7] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA

[8] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA

[9] Univ Padua, Rheumatol Unit, Dept Clin & Expt Med, Padua, Italy

[10] Stanford Univ, Behav & Funct Neurosci Lab, Sch Med, Stanford, CA 94305 USA

[11] Stanford Univ, Sch Med, Dept Orthopaed Surg, Stanford, CA 94305 USA

[12] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA

[13] Hosp Special Surg, Dept Rheumatol, New York, NY 10021 USA

[14] Univ Colorado, Dept Immunol, Hlth Sci Ctr, Aurora, CO USA

[15] Univ Colorado, Dept Med, Hlth Sci Ctr, Aurora, CO USA

[16] Case Western Reserve Univ, Dept Orthopaed Surg, Sch Med, Cleveland, OH 44106 USA

[17] Novartis Pharma AG, Novartis Inst Biomed Res, Basel, Switzerland

来源：

NATURE MEDICINE | 2011年 / 17卷 / 12期

基金：

美国国家卫生研究院;

关键词：

OLIGOMERIC MATRIX PROTEIN; RHEUMATOID-ARTHRITIS; CARTILAGE DEGRADATION; KNEE OSTEOARTHRITIS; SYNOVIAL-FLUID; IN-VIVO; ACTIVATION; EXPRESSION; GENERATION; INDUCTION;

D O I：

10.1038/nm.2543

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Osteoarthritis, characterized by the breakdown of articular cartilage in synovial joints, has long been viewed as the result of 'wear and tear'(1). Although low-grade inflammation is detected in osteoarthritis, its role is unclear(2-4). Here we identify a central role for the inflammatory complement system in the pathogenesis of osteoarthritis. Through proteomic and transcriptomic analyses of synovial fluids and membranes from individuals with osteoarthritis, we find that expression and activation of complement is abnormally high in human osteoarthritic joints. Using mice genetically deficient in complement component 5 (C5), C6 or the complement regulatory protein CD59a, we show that complement, specifically, the membrane attack complex (MAC)-mediated arm of complement, is crucial to the development of arthritis in three different mouse models of osteoarthritis. Pharmacological modulation of complement in wild-type mice confirmed the results obtained with genetically deficient mice. Expression of inflammatory and degradative molecules was lower in chondrocytes from destabilized joints from C5-deficient mice than C5-sufficient mice, and MAC induced production of these molecules in cultured chondrocytes. Further, MAC colocalized with matrix metalloprotease 13 (MMP13) and with activated extracellular signal-regulated kinase (ERK) around chondrocytes in human osteoarthritic cartilage. Our findings indicate that dysregulation of complement in synovial joints has a key role in the pathogenesis of osteoarthritis.

引用

页码：1674 / U196

页数：7

共 41 条

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Prostaglandin E2 exerts catabolic effects in osteoarthritis cartilage:: Evidence for signaling via the EP4 receptor [J].