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

Background and objectives The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older ($65 years, n=1005) and younger (,65 years, n=2878) patients.Design, setting, participants, & measurements Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified.Results Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were .3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups. ConclusionsIn the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.

In view of the reported associations between osteoporosis and polymorphisms of the vitamin D receptor (VDR), collagen Ialpha1 (COLIA1) and estrogen receptor (ER) genes, an association study was performed between VDR, COLLIA1, and ER genotypes and bone mineral density, biochemical markers of bone turnover and hip fracture occurrence in Belgian older postmenopausal women. The gene polymorphisms were evaluated by restriction fragment length polymorphism analyses, using the restriction enzymes BsmI (VDR), AccB7I (COLIA1), and PvuII and XbaI (ER), respectively. As expected, bone mineral density and biochemical analyses demonstrated significant differences between hip fracture patients and elderly controls. However, no significant differences in genotype distributions or allele frequencies were observed between the cases (n = 135, age 78 +/- 9 years) and controls (n = 239, age 76 +/- 4 years) for any of the gene polymorphisms. Stratification of both study populations according to VDR, COLIA1 or ER genotype did not reveal any statistically significant difference in bone density or bone turnover between subgroups with different genotypes. In conclusion, despite its limited statistical power the outcome of this study does not support the hypothesis of a major contribution of the VDR, COLIA1 or ER polymorphisms to explain variations in bone mineral density or bone turnover, or to identify elderly women at risk of osteoporotic hip fracture.

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Objective: To study the effect of frizzled-related protein (Frzb) deletion in mice on voluntary running wheel exercise performance and osteoarthritis. Methods: At the age of 7 weeks, Frzb À/À and wild-type mice were grouped and a running wheel was introduced into the cage. At week 8, all mice were caged solitarily with a running wheel available. Mice were allowed free exercise for 6e12 months and distances run were recorded daily. Non-running mice were used as additional control group. X-rays of knees and hips were taken at different time points. At the end of the experiment, mice were sacrificed and joints were processed for histological evaluation. Cartilage damage, synovitis and osteophyte formation were scored. Muscle fiber composition of the soleus and extensor digitorum longus was studied by immunofluorescence. Results: At the age of 6 months, both female and male wild-type mice showed a significantly greater exercise performance than the Frzb À/À mice (P < 0.05). At 1 year, the difference was still significant for male mice, but not for females. Running exercise did not significantly affect severity of osteoarthritis. No statistical differences in osteoarthritis severity were seen between Frzb À/À mice and wild-type mice. No differences were seen in muscle composition between Frzb À/À mice and wild-type mice. Conclusion: Absence of Frzb in mice reduced voluntary exercise performance in running wheels. These experiments demonstrate that the effects of genes in mice can also be evaluated using functional outcomes such as running wheel exercise performance, similar to evolving practice in human clinical trials.