Serum Dickkopf-1 (DKK-1) Levels in Primary Knee Osteoarthritis and its Relation to Disease Severity

Abstract

SUMMARY AND CONCLUSION O steoarthritis is the most common form of chronic arthritis, and it is a major cause of pain, disability and decreased of quality of life. OA can be clinically described as joint pain and reduced mobility, associated radiographically with JSN, subchondral bone sclerosis and osteophyte formation. The factors that initiate OA are not well understood, and the course of joint degeneration in OA is variable. There is a disagreement on defining the primary trigger of OA with some animal models pointing towards changes in articular cartilage occurring first, while others suggesting underlying bone changes first. The close physical relationship between the cartilage and subchondral bone in joints introduced the concept that there is molecular crosstalk between chondrocytes and bone cells (osteoblasts, osteoclasts and osteocytes) and if it exists, the extent to which it may contribute to the progression of OA. The Wnt pathway involves Wnt proteins which are family of secreted proteins. The Wnt family members are classically divided into canonical and non-canonical pathway components. The Canonical Wnt pathway is activated upon binding of Wnt to a coreceptor complex located at the cell surface, comprising LRP 5/6 and a member of Fz family of proteins. This interaction finally leads to an increase of the intracellular β -catenin levels through inhibition of the β-catenin degradation. The regulatory mechanisms of canonical Wnt signaling pathway are very complex. This pathway is regulated by several soluble inhibitors such as Dkk-1, sclerostin, and sFRP and some activators as canonical Wnts and Dvl. Dkk-1 inhibits Canonical Wnt pathway through binding LRP5/6 and Kremen (a receptor that does not transduce intracellular signal) and their complex is internalized, leading to depletion of cell surface from LRP5/6 receptors; which become unavailable for binding the Wnt proteins, resulting in inhibition of the pathway. Dkk-1 has been suggested to play a role in OA pathogenesis. Its role in human OA has not been explored in detail and its function in OA cartilage destruction is a subject of controversy. Activation of Wnt signaling by blocking of the Wnt antagonist Dkk-1 leads to increased osteophyte formation suggesting that Wnt activation can induce new bone formation in arthritic joints and also allow the growth of osteophyte. When invesigators studied cartilage specimens from patients with OA and femoral fractures they found that Dkk-1 expression increased in OA cartilage and correlated with chondrocyte apoptosis as blocking β- catenin increased apoptosis and when Dkk-1 was blocked chondrocyte apoptosis decreased. On contrary other investigators found negative effect of Wnt signaling on cartilage formation and that it activates cartilage degeneration.