DKK-1: UPSETTING THE BALANCE IN RHEUMATOID ARTHRITIS

Arthritis, defined as inflammation of the joints, occurs in many forms.¹ Although most arthritic conditions include joint remodeling, a distinguishing feature of rheumatoid arthritis (RA) is the presence of bone erosion without signs of repair. For example, bony growths called osteophytes are present in osteoarthritis (degenerative arthritis) and other forms of arthritis, yet absent in RA. Thus, RA includes both excessive bone resorption and inadequate bone replacement. Many proposed or recently initiated treatments for RA are aimed either at reducing inflammation or at curbing bone resorption, while less progress has been made toward enhancing bone replacement. A recent paper by Diarra and coworkers identifies suppression of signaling in the Wnt pathway as a key factor in the imbalance between bone resorption and replacement signals in RA joints.³

Signaling via the classical Wnt pathway is critical for bone deposition, both during development and bone remodeling in the adult.^3,4 This signaling is under tight control and is limited by multiple endogenous mechanisms. In one such regulation, Dickkopf proteins (Dkk) bind and promote the internalization of lipoprotein receptor-related protein (LRP)-5 or LRP-6. Blocking these Wnt receptor components effectively downregulates Wnt signaling. Diarra and coworkers have discovered that overexpression of Dkk-1 in RA joints leads to excess inhibition of classical Wnt signaling, and is a critical factor in the bone erosion seen in RA.²

The authors reported increased Dkk-1 expression in the serum or synovial fluid of three mouse models of RA, including one transgenic model that overexpresses the human inflammatory mediator TNF-alpha (hTNFtg). Dkk-1 expression was also increased in human RA, but was low in ankylosing spondylitis, a joint disease with a high prevalence of osteophytes. Treatment of hTNFtg mice with a Dkk-1 neutralizing antibody reversed the process of bone erosion but did not alter indicators of inflammation, suggesting that erosion is not a direct result of inflammation.

Figure 1. In normal joints, bone deposition by osteoblasts is in balance with bone resorption by osteoclasts. Wnt signaling is not over-inhibited by Dkk-1, and osteoclast formation is controlled by balanced amounts of RANKL/TRANCE and OPG. In rheumatoid arthritis, TNF-alpha promotes Dkk-1 overexpression, which in turn causes decreased OPG expression. These signaling events inhibit osteoblasts, while promoting osteoclasts and tipping the balance toward bone resorption.

In addition to attenuation of bone loss, hTNFtg mice treated with Dkk-1 antibody exhibited osteophyte formation, suggesting an onset of bone deposition. Osteoblasts, the cells responsible for bone deposition, rely on Wnt signaling for their maturation.⁴ Osteoblasts also control production of osteoclasts, the cells responsible for bone resorption. This occurs via production of the osteoclast-promoting growth factors M-CSF and RANKL/TRANCE, as well as the osteoclast-limiting RANKL/TRANCE antagonist, osteoprotegerin (OPG).^4,5 Wnt signaling enhances OPG production, while inhibiting RANKL/TRANCE. In the mouse arthritis model, inhibition of Dkk-1 allows increased production of OPG, increased population of osteoblasts, and decreased numbers of osteoclasts within the joint,² thus favoring bone replacement.

High Dkk-1 expression may be pathogenic and has been shown in other bone-reducing conditions such as multiple myeloma, Paget's disease and glucocorticoid-induced osteoporosis.^6-8 Several studies have proposed that Dkk-1 antagonism promotes bone deposition in these pathologies.^2,9 As TNF-alpha signaling is upstream of increased Dkk-1 production, therapeutic inhibition of TNF-alpha (an effective treatment of RA) is also likely to modulate Dkk-1 production.^1,2 In RA models, however, it has yet to be shown that a normal balance between resorption and deposition of bone can be re-established without incurring the production of osteophytes.

References

1. Walsh, N.C. et al. (2005) Immunol. Rev. 208:228.
2. Diarra, D. et al. (2007) Nat. Med. 13:156.
3. Glass, D.A. II & G. Karsenty (2007) Endocrinology 148:2630.
4. Holmen, S. L. et al. (2005) J. Biol. Chem. 280:21162.
5. Glass, D.A. II et al. (2005) Dev. Cell 8:751.
6. Tian, E. et al. (2003) N. Engl. J. Med. 349:2483.
7. Naot, D. et al. (2007) J. Bone Miner. Res. 22:298.
8. Ohnaka, K. et al. (2005) Biochem. Biophys. Res. Commun. 329:177.
9. Yaccoby, S. et al. (2007) Blood 109:2106.

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