title: Lrp6 hypomorphic mutation affects bone mass through bone resorption in mice and impairs interaction with Mesd.
abstract: Low-density lipoprotein receptor-related protein 5 (LRP5) regulates bone acquisition by controlling bone formation. Because roles of LRP6, another co-receptor for Wnts, in postnatal bone metabolism have not been fully elucidated, we studied bone phenotype in mice harboring an Lrp6 hypomorphic mutation, ringelschwanz (rs), and characterized the mutant protein. First, we performed pQCT, bone histomorphometry, and immunohistochemistry on tibias of Lrp6(rs/rs) and Lrp6(+/+) mice and determined biochemical parameters for bone turnover. Lrp6(rs/rs) mice exhibited reduced trabecular BMD in pQCT. Bone histomorphometry showed low bone volume and decreased trabecular number, which were associated with increased eroded surface. Urinary deoxypyridinoline excretion was increased in Lrp6(rs/rs) mice, whereas levels of serum osteocalcin were comparable between Lrp6(rs/rs) mice and wildtype littermates. Increase in cell number and mineralization of calvariae-derived osteoblasts were not impaired in Lrp6(rs/rs) osteoblasts. Rankl expression was increased in Lrp6(rs/rs) osteoblasts both in vivo and in vitro, and osteoclastogenesis and bone-resorbing activity in vitro were accelerated in Lrp6(rs/rs) cells. Treatment with canonical Wnt suppressed Rankl expression in both in primary osteoblasts and ST2 cells. Overexpression of Lrp6 also suppressed Rankl expression, whereas the Lrp6 rs mutant protein did not. Functional analyses of the Lrp6 rs mutant showed decreased targeting to plasma membrane because of reduced interaction with Mesoderm development (Mesd), a chaperone for Lrp6, leading to impaired Wnt/beta-catenin signaling. These results indicate that Lrp6-mediated signaling controls postnatal bone mass, at least partly through the regulation of bone resorption. It is also suggested that the interaction with Mesd is critical for Lrp6 to function.
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Takuo
authors.initials: T
authors.lastname: Kubota
authors.forename: Toshimi
authors.initials: T
authors.lastname: Michigami
authors.forename: Naoko
authors.initials: N
authors.lastname: Sakaguchi
authors.forename: Chikara
authors.initials: C
authors.lastname: Kokubu
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Namba
authors.forename: Norio
authors.initials: N
authors.lastname: Sakai
authors.forename: Shigeo
authors.initials: S
authors.lastname: Nakajima
authors.forename: Kenji
authors.initials: K
authors.lastname: Imai
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ozono
mesh_terms: D000818:Animals; D015519:Bone Density / Q000235:genetics*; D001862:Bone Resorption; D002460:Cell Line; D007150:Immunohistochemistry; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051379:Mice; D008807:Mice, Inbred BALB C; D018832:Molecular Chaperones / Q000378:metabolism*; D009154:Mutation; D014057:Tomography, X-Ray Computed
chemical_list: D026502:LDL-Receptor Related Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; C472170:MESD protein, mouse; D018832:Molecular Chaperones