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. 2004 Jun 29;101(26):9757-62.
doi: 10.1073/pnas.0403456101. Epub 2004 Jun 21.

Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females (V体育2025版)

John Loughlin  1 , Barbara Dowling, Kay Chapman, Lucy Marcelline, Zehra Mustafa, Lorraine Southam, Athena Ferreira, Cathleen Ciesielski, Dennis A Carson, Maripat Corr
Affiliations

Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females (V体育官网入口)

John Loughlin et al. Proc Natl Acad Sci U S A. .

Abstract

Osteoarthritis (OA) is a leading cause of disability in Western society with multiple risk factors, including a complex genetic pattern. Identifying loci involved in the heredity of OA might lead to insights into the molecular pathogenesis of this common disorder. A previous genome scan mapped a primary hip OA susceptibility locus to chromosome 2q with a maximum multipoint logarithm of odds score of 1. 6 in 378 affected sibling pair families. Here, microsatellite targeting of eight candidate genes in this region from 2q23-2q32 demonstrated significant associations with the tumor necrosis factor alpha-induced protein 6 gene in all probands and the integrin alpha 6 and frizzled motif associated with bone development (FRZB) genes in female probands. However, genotyping showed lack of association for a nonsynonymous single-nucleotide polymorphism in tumor necrosis factor alpha-induced protein 6, whereas a single-nucleotide polymorphism in FRZB resulting in an Arg324Gly substitution at the carboxyl terminus was associated with hip OA in the female probands (P = 0. 04). This association was confirmed in an independent cohort of female hip cases (n = 338; P = 0. 04). In addition, a haplotype coding for substitutions of two highly conserved arginine residues (Arg200Trp and Arg324Gly) in FRZB was a strong risk factor for primary hip OA, with an odds ratio of 4. 1 (P = 0 VSports手机版. 004). FRZB encodes secreted frizzled-related protein 3, which is a soluble antagonist of wingless (wnt) signaling. Variant secreted frizzled-related protein 3 with the Arg324Gly substitution had diminished ability to antagonize wnt signaling in vitro. Hence, functional polymorphisms within FRZB confer susceptibility for hip OA in females and implicate the wnt signaling pathway in the pathogenesis of this disease. .

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Figures (VSports app下载)

Fig. 1.
Fig. 1.
The effect of FRZB SNPs on the original multipoint linkage plot. The thick black line is the original multipoint linkage plot of chromosome 2q for the 378 hip OA families (6). The dashed line is the plot for the 92 families from the 378 who contributed a female proband who carried either a T allele of the exon 4 [+6] SNP (47 families), a G allele of the exon 6 [+109] SNP (31 families), or a copy of both alleles (14 families). Also shown is the plot for the 11 families from the 378 who contributed a female proband carrying a T-G haplotype (gray line). The thin black line is the linkage plot for the remaining 286 families. The position of FRZB is marked. The genetic position on the x axis was determined by using the deCODE Genetics (Reykjavik, Iceland) sex-averaged map (35). cM, centimorgans.
Fig. 2.
Fig. 2.
sFRP3 expression in human chondrocytes. Human cartilage from an OA patient undergoing total knee replacement was harvested intraoperatively, embedded in OCT compound, frozen, and sectioned. The sections were immunostained with polyclonal goat serum (A) or goat anti-human sFRP3 (B) and are shown at ×400 original magnification. The arrows indicate some of the chondrocytes expressing sFRP3.
Fig. 3.
Fig. 3.
sFRP3 with the Arg324Gly substitution is less efficient at antagonizing wnt signaling. (A) HEK293 cells were transfected with 1.0 μg, 0.5 μg, 0.25 μg, or 0.125 μg of wild-type (wt) pcFRZB, pcFRZB-Arg200Trp, pcFRZB-Arg324Gly, or pcFRZB Arg200Trp/Arg324Gly or were left untransfected (Control, C). After 24 h, the cells were lysed and 30 μg of protein was separated by SDS/PAGE under reducing conditions. The protein was transferred to a polyvinylidine difloride membrane and then serially probed with anti-sFRP3 and β-actin. (B) HEK293 cells were cotransfected in triplicate with 0.25 μg of pTOPFLASH-Luc, 0.025 μg of pACB-Z, 0.25 μg of pUSE-Wnt1, and 1 μg of either pcFRZB, pcFRZB-Arg200Trp, pcFRZB-Arg324Gly, pcFRZB-Arg200Trp/Arg324Gly, or vector DNA. (C) Similar transfections were performed with 0.25 μg of a β-catenin-expressing plasmid instead of the Wnt1-expressing plasmid. Control cultures were transfected with pTOPFLASH-Luc and pACB-Z to establish basal enzyme activity levels. Additional control cultures were transfected with pTOPFLASH-Luc, which confirmed specificity of the assay (data not shown). After 24 h, the cells were lysed and the normalized luciferase activities were determined. The fold induction values are the ratios of the normalized luciferase activities in cells transfected with both expression and reporter plasmids compared with activities in cells receiving the respective reporter plasmids alone. Shown are the mean ± SEM of triplicates. (D) Triplicate cultures of HEK293 cells were transfected with 1 μg, 0.3 μg, or 0.1 μg of pcFRZB or pcFRZB-Arg324Gly. Control cultures were transfected with empty vector. After 48 h, the cells were lysed and the cytosolic and nuclear fractions were separated by SDS/PAGE, transferred to a polyvinylidine difloride membrane, and then probed with antibodies for β-catenin and β-actin.
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V体育2025版 - References

    1. Spector, T. D. & MacGregor, A. J. (2004) Osteoarthritis Cartilage 12, Suppl., S39-S44. - PubMed
    1. Loughlin, J. (2002) Rheum. Dis. Clin. N. Am. 28, 95-109. - "VSports app下载" PubMed
    1. Loughlin, J. (2003) Curr. Opin. Pharmacol. 3, 295-299. - PubMed (V体育安卓版)
    1. Demissie, S., Cupples, L. A., Myers, R., Aliabadi, P., Levy, D. & Felson, D. T. (2002) Arthritis Rheum. 46, 946-952. - PubMed
    1. Stefansson, S. E., Jonsson, H., Ingvarsson, T., Manolescu, I., Jonsson, H. H., Olafsdottir, G., Palsdottir, E., Stefansdottir, G., Sveinbjornsdottir, G., Frigge, M. L., et al. (2003) Am. J. Hum. Genet. 72, 1448-1459. - V体育官网 - PMC - PubMed

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