The Wnt-beta-catenin signaling pathway that regulates bone density is also involved in cartilage development and homeostasis in vivo. Here, we assumed that genetic variation in Wnt-beta-catenin signaling genes can affect the pathogenesis of cartilage related diseases, such as osteoarthritis. Wnt-1-induced secreted protein 1 (WISP1) is a target of the Wnt pathway and directly regulated by beta-catenin. In the present study, we analyzed the association of a single nucleotide polymorphism (SNP) in the WISP1 3'-UTR region with the development of radiographically observable osteoarthritis of the spine. For this purpose, we evaluated the presence of osteophytes, endplate sclerosis, and narrowing of disc spaces in 304 postmenopausal Japanese women. We compared those who carried the G allele (GG or GA, n = 184) with those who did not (AA, n = 120). We found that the subjects without the G allele (AA) were significantly over-represented in the subjects having higher endplate sclerosis score (P = 0.0069; odds ratio, 2.91; 95% confidence interval, 1.34-6.30 by logistic regression analysis). On the other hand, the occurrence of disc narrowing and osteophyte formation did not significantly differ between those with and without at least one G allele. Thus, we suggest that a genetic variation in the WISP1 gene locus is associated with spinal osteoarthritis, in line with the involvement of the Wnt-beta-catenin-regulated gene in bone and cartilage metabolism.
We suggest that a genetic variation at the IGF1R gene locus is associated with spinal disc degeneration, in line with the involvement of the IGF1R gene in the cartilage metabolism.
We suggest that a genetic variation at the LRP5 gene locus is associated with spinal osteoarthritis, in line with the involvement of the LRP5 gene in the bone and cartilage metabolism.
gate phenotype used in the research for osteoporosis. BMD is a complex trait that is influenced by both genetic and environmental factors. Heritability studies in families and studies of twins have shown that genetic factors account for 50%-90% of the variance in BMD [2][3][4][5][6]. So far, several genes for osteoporosis have been established. These genes include the vitamin D receptor (VDR) gene [7], estrogen receptor α (ERα) gene [8], and collagen type Iα1 (COLIA1) gene [9]. We need to clarify more genetic factors of BMD, considering the polygenetic nature of BMD distribution and the multiplicity of endocrine factors known to regulate bone mass and bone turnover.The Wnt signaling pathway plays a important role , and is associated with lumbar spine, femoral neck, and radial bone mineral density (BMD), and incidence of fracture. These data suggest that the A1330V variation in the LRP5 gene may affect the pathogenesis of osteoporosis. However, the functional basis of the A1330V variation remains unclear. In the present study, we analyzed the effect of the A1330V variation on Wnt activity. We also investigated the association between this LRP5 SnP and total body BMD using 739 postmenopausal women. LRP5 with the A1330V SnP were transiently coexpressed with Wnt3a in 293T cells and their activity was evaluated by the TCF-Lef reporter assay. In vitro, the TCF-Lef activity in presence of Wnt3a in cells expressing LRP5 and carrying the T allele (Valine at 1330 (V1330)) of exon 18 was significantly reduced as compared to the wild-type allele. The association between the A1330V SnP and total body BMD were replicated in 739 postmenopausal Japanese women (AA vs. VV; P = 0.0026). These data suggest that the V1330 variant in the LRP5 gene decreases Wnt activity, which in turn decreases the BMD.
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