Non-synonymous WNT16 polymorphisms alleles are associated with different osteoarthritis phenotypes

Hereditary factors have a strong influence on osteoarthritis (OA). The Wnt pathway is involved in bone and cartilage homeostasis. Hence, we hypothesized that allelic variations of WNT16 could influence the OA phenotype. We studied 509 Caucasian patients undergoing joint replacement due to severe primary OA. Radiographs were used to classify the OA as atrophic or hypertrophic. Two nonsynonymous polymorphisms of WNT16 (rs2707466 and rs2908004) were analyzed. The association between the genotypes and the OA phenotype was analyzed by logistic regression and adjusted for age and body mass index. A genotype-phenotype association was found in the sex-stratified analysis. Thus, there was a significant difference in the genotypic frequencies of rs2707466 between hypertrophic and atrophic hip OA in males (p = 0.003), with overrepresentation of G alleles in the hypertrophic phenotype (OR 2.08; CI 1.28-3.38). An association in the same direction was observed between these alleles and the type of knee OA, with G alleles being more common in the hypertrophic than in atrophic knee phenotypes (p = 0.008; OR 1.956, CI 1.19-3.19). Similar associations were found for the rs2908004 SNP, but it only reached statistical significance for knee OA (p = 0.017; OR 0.92, CI 0.86-0.989). This is the first study attempting to explore the association of genetic variants with the OA phenotype. These data suggest the need to consider the OA phenotype in future genetic association studies of OA

Osterix and RUNX2 are Transcriptional Regulators of Sclerostin in Human Bone

Sclerostin, encoded by the SOST gene, works as an inhibitor of the Wnt pathway and therefore is an important regulator of bone homeostasis. Due to its potent action as an inhibitor of bone formation, blocking sclerostin activity is the purpose of recently developed antiosteoporotic treatments. Two bone-specific transcription factors, RUNX2 and OSX, have been shown to interact and co-ordinately regulate the expression of bone-specific genes. Although it has been recently shown that sclerostin is targeted by OSX in mice, there is currently no information of whether this is also the case in human cells. We have identified SP-protein family and AML1 consensus binding sequences at the human SOST promoter and have shown that OSX, together with RUNX2, binds to a specific region close to the transcription start site. Furthermore, we show that OSX and RUNX2 activate SOST expression in a co-ordinated manner in vitro and that SOST expression levels show a significant positive correlation with OSX/ RUNX2 expression levels in human bone. We also confirmed previous results showing an association of several SOST/RUNX2 polymorphisms with bone mineral density