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Contribution of genetic and epigenetic mechanisms to Wnt pathway activity in prevalent skeletal disorders

Abstract: We reported previously that the expression of Wnt-related genes is lower in osteoporotic hip fractures than in osteoarthritis. We aimed to confirm those results by analyzing B-catenin levels and explored potential genetic and epigenetic mechanisms involved. B-Catenin gene expression and nuclear levels were analyzed by real time PCR and confocal immunofluorescence. Increased nuclear B-catenin was found in osteoblasts isolated from patients with osteoarthritis (99 ± 4 units vs. 76 ± 12, p = 0.01, n = 10), without differences in gene transcription, which is consistent with a post-translational down-regulation of B-catenin and decreased Wnt pathway activity. Twenty four single nucleotide polymorphisms (SNPs) of genes showing differential expression between fractures and osteoarthritis (WNT4, WNT10A, WNT16 and SFRP1) were analyzed in DNA isolated from blood of 853 patients. The genotypic frequencies were similar in both groups of patients, with no significant differences. Methylation of Wnt pathway genes was analyzed in bone tissue samples (15 with fractures and 15 with osteoarthritis) by interrogating a CpG-based methylation array. Six genes showed significant methylation differences between both groups of patients: FZD10, TBL1X, CSNK1E, WNT8A, CSNK1A1L and SFRP4. The DNA demethylating agent 5-deoxycytidine up-regulated 8 genes, including FZD10, in an osteoblast-like cell line, whereas it down-regulated other 16 genes. In conclusion,Wnt activity is reduced in patients with hip fractures, in comparison with those with osteoarthritis. It does not appear to be related to differences in the allele frequencies of the Wnt genes studied. On the other hand, methylation differences between both groups could contribute to explain the differences in Wnt activity.

 Autoría: García-Ibarbia C., Delgado-Calle J., Casafont I., Velasco J., Arozamena J., Pérez-Núñez M.I., Alonso M.A., Berciano M.T., Ortiz F., Pérez-Castrillón J.L., Fernández A.F., Fraga M.F., Zarrabeitia M.T., Riancho J.A.,

 Fuente: Gene, 2013, 532, 165-172

Editorial: Elsevier

 Año de publicación: 2013

Nº de páginas: 8

Tipo de publicación: Artículo de Revista

 DOI: 10.1016/j.gene.2013.09.080

ISSN: 0378-1119,1879-0038

 Proyecto español: FIS 06/0034, 09/0539

Url de la publicación: https://doi.org/10.1016/j.gene.2013.09.080

Autoría

DELGADO-CALLE, JESÚS

VELASCO, JAVIER

JANA AROZAMENA GARCIA

MARIA ANGELES ALONSO AGUIRRE

MARIA TERESA BERCIANO BLANCO

FERNANDO ORTIZ FLORES

PÉREZ-CASTRILLÓN, JOSÉ

FERÁNDEZ, AGUSTÍN F.

FRAGA, MARIO F.

MARIA TERESA ZARRABEITIA CIMIANO