Identification of a central role for complement in osteoarthritis
Tools
Tools
Lee, David and Robinson, William (2011) Identification of a central role for complement in osteoarthritis. Nature Medicine, 17 (12). pp. 1674-1680. ISSN 1078-8956
Abstract
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 unclear2,3. Here, by studying human osteoarthritic samples and mice in which osteoarthritis was surgically induced, 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, we find that expression and activation of complement is abnormally high in human osteoarthritic joints. Using mice deficient in C5, C6, or CD59, we show that complement, and specifically the membrane attack complex (MAC)-mediated arm of complement, is critical to the development of murine osteoarthritis. In human osteoarthritic cartilage, MAC was deposited around chondrocytes, localizing with activated ERK and with matrix metalloproteinase (MMP)-13. MAC deposition on chondrocytes in vitro induced production of inflammatory and degradative mediators, and expression of these mediators was lower in the destabilized joints of C5- deficient mice than in those of C5-sufficient mice, suggesting that MAC directly promotes inflammation in osteoarthritis. Our results suggest that local dysregulation of complement in synovial joints plays a critical role in the pathogenesis of osteoarthritis.
| Item Type: | Article |
|---|---|
| Related URLs: | |
| Additional Information: | author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used |
| Related URLs: | |
| Date Deposited: | 13 Oct 2015 13:15 |
| Last Modified: | 13 Oct 2015 13:15 |
| URI: | https://oak.novartis.com/id/eprint/5774 |