Wnt and Rho GTPase signaling and their interaction

Th e disability burden and prevalence of osteoarthritis (OA) in both developed and developing countries is increasing due to an aging population. OA is a degenerative joint disease that is characterized by cartilage degradation and osteophyte formation. It involves multiple components of the joint, including the synovial joint lining, peri-articular bone and adjacent supporting connective tissue elements [1]. Current OA treatment modalities mainly function as intermittent symptom relief without long-term improvement in disease prognosis due to our current limited understanding of OA pathophysiology. Better understanding of the underlying mechanisms of OA initiation and progression might therefore facilitate identifi cation of appropriate therapeutic targets for OA treatment [2]. Th e mechanism of OA is currently not well defi ned, as multiple factors can in more than one way lead to articular cartilage destruction and loss of joint function. Recently, increasing numbers of studies have implicated chondrocyte terminal diff erentiation (hypertrophy-like changes) in the pathogenesis of OA. Th is is similar to the chondrocyte diff erentiation process during endochondral ossifi cation (EO). Th e close resemblance between terminal diff erentiation in OA cartilage and EO suggests that new OA therapeutic targets can potentially be identifi ed from EO biology. Normal articular chondrocytes located at the ends of long bones do not develop into the hypertrophic state, thus avoiding terminal diff erentiation. However, OA chondrocytes lose their stable phenotype and undergo hypertrophy, which is characterized by cell enlargement as well as expression of various chondrocyte maturation and osteogenesis markers such as COLX [3], matrix metalloproteinase (MMP)13 (also known as collagenase 3) [3-5], a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5 [6-8], osteopontin, osteocalcin, Indian Hedgehog [9], Runx2 [10], vascular endothelial growth factor (VEGF) [11], and trans glutaminase-2 (TG-2) [12]. Th e developmental biology of EO is of key importance in understanding the process of OA, and there is much scientifi c evidence indicating that signaling pathways modulating joint formation and homeostasis are of central importance in the pathogenesis of OA. Th e Wnt signaling pathway is well established to be a key regulator in EO [13,14], a process through which bone and articular cartilage are formed. At the same time, most studies support the notion that activation of Wnt/β-catenin signaling is associated with articular chondrocyte matrix catabolism and stable phenotype loss [15]. Recent years have also seen a number of studies indicating that Rho GTPases play central roles in both chondrocyte diff erentiation and articular chondrocyte physiology, which will be discussed below.