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Objective. Ligands and antagonists of the WNT pathway are linked to osteoporosis and osteoarthritis. In particular, polymorphisms in the FRZB gene, a secreted WNT antagonist, have been associated with osteoarthritis. The aim of this study was to examine cartilage and bone in Frzb ؊/؊ mice. Methods. The Frzb gene in mice was inactivated using a Cre/loxP strategy. Three models of osteoarthritis were used: collagenase, papain, and methylated bovine serum albumin induced. Bone biology was studied using density measurements and microfocal computed tomography. Bone stiffness and mechanical loading-induced bone adaptation were studied by compression of the ulnae.Results. Targeted deletion of the Frzb gene in mice increased articular cartilage loss during arthritis triggered by instability, enzymatic injury, or inflammation. Cartilage damage in Frzb ؊/؊ mice was associated with increased WNT signaling and matrix metalloproteinase 3 (MMP-3) expression and activity. Frzb ؊/؊ mice had increased cortical bone thickness and density, resulting in stiffer bones, as demonstrated by stressstrain relationship analyses. Moreover, Frzb ؊/؊ mice had an increased periosteal anabolic response to mechanical loading as compared with wild-type mice.Conclusion. The genetic association between osteoarthritis and FRZB polymorphisms is corroborated by increased cartilage proteoglycan loss in 3 different models of arthritis in Frzb ؊/؊ mice. Loss of Frzb may contribute to cartilage damage by increasing the expression and activity of MMPs, in a WNT-dependent and WNT-independent manner. FRZB deficiency also resulted in thicker cortical bone, with increased stiffness and higher cortical appositional bone formation after loading. This may contribute to the development of osteoarthritis by producing increased strain on the articular cartilage during normal locomotion but may protect against osteoporotic fractures.Osteoarthritis and osteoporosis are common joint and bone diseases that cause significant morbidity and disability in the aging population. Osteoarthritis is primarily characterized by degeneration of the articular cartilage and leads to loss of joint function, and patients often require surgery for placement of a prosthesis to correct it (1). Drugs that convincingly affect the disease process beyond pain relief are not yet available. Osteoporosis is defined by decreased cortical and trabecular bone density and typically results in hip and vertebral fractures (2). Current antiosteoporosis agents inhibit osteoclast-driven bone resorption or stimulate osteoblast-driven bone synthesis, but their long-term use can cause drug safety problems (2). Clinical observations suggest that there is an inverse relationship between osteoarthritis and osteoporosis (3), but this hypothesis remains controversial, particularly since it is not supported by a known molecular mechanism.A role of ligands and antagonists of the WNT