Identification and Functional Characterization of RSPO2 as a Susceptibility Gene for Ossification of the Posterior Longitudinal Ligament of the Spine.

ABSTRACT: Ossification of the posterior longitudinal ligament of the spine (OPLL) is a common spinal disorder that results from ectopic ossification of the posterior longitudinal ligament and causes intractable myelopathy and radiculopathy. In a previous genome-wide association study (GWAS), we found six loci associated with OPLL; however, susceptibility genes in these loci have not been identified yet. Here, we examined one of the GWAS loci and identified RSPO2 (encoding R-spondin 2) as a susceptibility gene for OPLL. R-spondin 2 is a secreted agonist of canonical Wnt-?-catenin signaling. RSPO2 was decreased in the early stage of chondrocyte differentiation. R-spondin 2 inhibited expression of genes encoding early chondrocyte differentiation markers by activating Wnt-?-catenin signaling. rs374810, the most significantly associated SNP in the GWAS locus in chromosomal region 8q23.1 was located in the chondrocyte promoter region of RSPO2. A transcription factor, CCAAT-enhancer-binding protein ? (C/EBP?), specifically bound to the RSPO2 core promoter region containing rs374810 and increased RSPO2 expression. The risk allele of rs374810 affected the binding of the promoter with C/EBP? and decreased the RSPO2 transcription in vitro and in vivo. Our genetic and functional data indicate that RSPO2 is a susceptibility gene for OPLL.

SUBMITTER: Nakajima M 

PROVIDER: S-EPMC5005442 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature