title: 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-β-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-β-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 β (C/EBPβ), 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/EBPβ and decreased the RSPO2 transcription in vitro and in vivo. Our genetic and functional data indicate that RSPO2 is a susceptibility gene for OPLL.
authors.affiliation: Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo 108-8639, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo 108-8639, Japan.
authors.forename: Ikuyo
authors.initials: I
authors.lastname: Kou
authors.affiliation: Division of Medical Genetics, Saitama Children's Medical Center, Saitama 339-8551, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ohashi
authors.affiliation: Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo 108-8639, Japan. Electronic address: sikegawa@ims.u-tokyo.ac.jp.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
mesh_terms: D002460:Cell Line; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D017887:Ossification of Posterior Longitudinal Ligament / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism; D000098907:R-Spondins
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D051176:beta Catenin; C557408:Rspo2 protein, human; D000098907:R-Spondins