Editors' ChoiceOsteoarthritis

A Joint Venture Between Complement and Chondrocytes

See allHide authors and affiliations

Science Translational Medicine  23 Nov 2011:
Vol. 3, Issue 110, pp. 110ec191
DOI: 10.1126/scitranslmed.3003459

By age 55, the moans and groans heard from adults climbing in and out of their cars are usually the result of osteoarthritis (OA), the most common joint disease affecting nearly all individuals after years of mechanical stress to our bones. Although inflammation has long been recognized as a part of OA, its significance has been largely unknown. Now, a new study by Wang et al. provides insight into the role of inflammation in OA.

First, the authors analyzed synovial fluid from patients with OA and healthy controls and observed that several complement components were elevated in patients with disease. To find a source of the complement, Wang and colleagues performed microarray studies on synovial tissue and found that patients with OA had increased expression of complement components and decreased expression of complement inhibitors. The authors next moved to three mouse models of OA to examine the role that specific complement components might play in propagating disease. They first examined mice deficient in the fifth complement component (C5), which links the alternative and classical “arms” of the cascade and is elevated in OA patients. When the C5 gene was removed, the mice had less cartilage loss, osteophyte formation, and synovitis than C5-sufficient mice. In addition, administration of a fusion protein that inhibits activation of C5 prevented OA in normal mice. They next examined mice deficient in C6—an integral component of the membrane attack complex (MAC) of the complement cascade—and found that C6-deficient mice were similarly protected. Furthermore, mice deficient in a MAC inhibitor developed OA and synovitis.

Having shown a crucial role for complement and the MAC, Wang and coauthors sought out which factors activate the complement cascade in OA. They took pulverized cartilage from OA patients and found that it could induce MAC formation in vitro. Interestingly, the addition of MAC to cultured human chondrocytes resulted in an increase in the expression of several genes that are implicated in OA, including those encoding cartilage-degrading enzymes and inflammatory cytokines; this indicates that the role of MAC is to induce a proinflammatory environment, rather than cell lysis or cell death. These intriguing data suggest that targeting this arm of the immune system might provide joint relief for those struggling with this disease.

Q. Wang et al., Identification of a central role for complement in osteoarthritis. Nat. Med. 6 November 2011 (10.1038/nm.2543). [Abstract]

Navigate This Article