Remodeling the Joint

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Science  02 Feb 2007:
Vol. 315, Issue 5812, pp. 574
DOI: 10.1126/science.315.5812.574b

Rheumatoid arthritis is a debilitating autoimmune disorder that is characterized by a profound remodeling of tissue architecture at the joint, which results, most notably, in a permanent loss of bone. Therapies that reduce joint inflammation have been somewhat successful in delaying the onset and progression of the disease, but they have not been able to reverse joint damage once it has occurred. Because the recovery of joint function in rheumatoid arthritis will probably require therapeutic approaches that trigger the formation of new bone, there is growing interest in understanding the molecular mechanisms that regulate bone remodeling within the joint.

Following up on previous evidence that identified the Wnt signaling pathway as a determinant of bone mass, Diarra et al. investigated whether manipulation of this pathway would affect joint pathology in mice overexpressing the pro-inflammatory molecule tumor necrosis factor-α (TNF-α), a widely used animal model of human rheumatoid arthritis. They found that the antibody- mediated blockade of Dickkopf-1 (DKK-1), which is an endogenous inhibitor of Wnt signaling, induced the formation of osteophytes (bone spurs) at the inflamed joints and also prevented the resorption of bone by specialized cells called osteoclasts. As was consistent with the mouse data, they observed that DKK-1 was expressed at aberrantly high levels in joint specimens from humans with rheumatoid arthritis and that in both species DKK-1 expression was induced by TNF-α. These results identify the Wnt pathway as an important regulator of joint remodeling in rheumatoid arthritis. Because Wnt signals influence both the formation and the destruction of bone, future therapies targeting this pathway could in principle be applied not only to rheumatoid arthritis, which is characterized by bone loss, but also to osteoarthritis and other diseases of the joint. — PAK

Nat. Med. 10.1038/nm1538 (2007).

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