REVIEW WNT Signaling and Cartilage: Of Mice and Men Bin Ma • Ellie B. M. Landman • Razvan L. Miclea • Jan M. Wit • Els C. Robanus-Maandag • Janine N. Post • Marcel Karperien Received: 6 August 2012 / Accepted: 3 November 2012 / Published online: 2 December 2012 Ó Springer Science+Business Media New York 2012 Abstract In adult articular cartilage, the extracellular matrix is maintained by a balance between the degradation and the synthesis of matrix components. Chondrocytes that sparsely reside in the matrix and rarely proliferate are the key cellular mediators for cartilage homeostasis. There are indications for the involvement of the WNT signaling pathway in maintaining articular cartilage. Various WNTs are involved in the subsequent stages of chondrocyte dif- ferentiation during development, and deregulation of WNT signaling was observed in cartilage degeneration. Even though gene expression and protein synthesis can be acti- vated upon injury, articular cartilage has a limited ability of self-repair and efforts to regenerate articular cartilage have so far not been successful. Because WNT signaling was found to be involved in the development and maintenance of cartilage as well as in the degeneration of cartilage, interfering with this pathway might contribute to improv- ing cartilage regeneration. However, most of the studies on elucidating the role of WNT signaling in these processes were conducted using in vitro or in vivo animal models. Discrepancies have been found in the role of WNT sig- naling between chondrocytes of mouse and human origin, and extrapolation of results from mouse models to the human situation remains a challenge. Elucidation of detailed WNT signaling functions will provide knowledge to improve cartilage regeneration. Keywords Cartilage Á Degeneration Á Development Á WNT Introduction Adult articular cartilage is an avascular tissue composed of a dense extracellular matrix (ECM) predominantly composed of collagens, proteoglycans and glycosaminoglycans, which provide compressive and tensile strength to the cartilage tissue. The chondrocytes residing in this ECM maintain it by remodeling. Because the metabolic activity of chondrocytes is relatively low and cartilage is scarcely populated with cells, cartilage remodeling is a slow process. Articular car- tilage is composed of four distinct regions, the superficial zone which faces the synovial cavity, the middle zone, the deep zone and the calcified cartilage zone adjacent to the subchondral bone plate. These zones differ in cell density and matrix composition. Also the chondrocyte morphology differs between zones, as chondrocytes in the superficial zone are small and flattened, middle zone chondrocytes are more rounded and in the deep zone chondrocytes are grouped in columns or clusters. Because chondrocytes rarely divide and are separated from each other by the matrix, it is unclear how they are regulated to maintain the ECM under homeo- static conditions. It is known, however, that gene expression and protein synthesis can be activated upon injury. The first three authors contributed equally, and all should be considered first author. The authors report that they have no conflict of interest. B. Ma Á E. B. M. Landman Á J. N. Post Á M. Karperien (&) Department of Developmental BioEngineering, University of Twente, Drienerlolaan 5, 7522NB Enschede, The Netherlands e-mail: h.b.j.karperien@utwente.nl R. L. Miclea Á J. M. Wit Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands E. C. Robanus-Maandag Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands 123 Calcif Tissue Int (2013) 92:399–411 DOI 10.1007/s00223-012-9675-5