In healthy cartilage of Frzb-/- mice, four genes were consistently expressed at lower levels than in the wild-type mice: Ctnnb1, Ctbp1, Fosl1 and Myc. In contrast, Wnt8b expression was upregulated in healthy cartilage in 2/3 samples from Frzb-/- versus wild-type mice and in all samples in affected versus healthy wild-type cartilage. Ctbp1 and Fosl1 were also downregulated in all samples from arthritic wild-type mice versus healthy ones. In addition, Wnt8b appears to be downregulated in arthritic versus healthy joints of Frzb-/- mice, suggesting a distinct regulation of Wnt ligand expression in the genetic model as compared with the wild-type mice. Cartilage damage in Frzb-/- mice is associated with increased canonical Wnt signaling, matrix metalloproteinase-3 expression and activity. In addition, the Frzb-/- mice have an increased cortical bone thickness and density, resulting in stiffer bones as demonstrated by a different stress–strain relationship in Frzb-/- mice. Moreover, the periosteal anabolic response to mechanical loading is significantly greater in Frzb-/- mice than in wild-type mice. FRZB is expressed in the periosteum.