title: Claudin 18 is a novel negative regulator of bone resorption and osteoclast differentiation.
abstract: Claudin 18 (Cldn-18) belongs to a large family of transmembrane proteins that are important components of tight junction strands. Although several claudin members are expressed in bone, the functional role for any claudin member in bone is unknown. Here we demonstrate that disruption of Cldn-18 in mice markedly decreased total body bone mineral density, trabecular bone volume, and cortical thickness in Cldn-18(-/-) mice. Histomorphometric studies revealed that bone resorption parameters were increased significantly in Cldn-18(-/-) mice without changes in bone formation. Serum levels of tartrate-resistant acid phosphatase 5b (TRAP5b) and mRNA expression levels of osteoclast specific markers and signaling molecules were also increased. Loss of Cldn-18 further exacerbated calcium deficiency induced bone loss by influencing bone resorption, thereby resulting in mechanically weaker bone. In vitro studies with bone marrow macrophages revealed Cldn-18 disruption markedly enhanced receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation but not macrophage colony-stimulating factor (MCSF)-induced bone marrow macrophage (BMM) proliferation. Consistent with a direct role for Cldn-18 in regulating osteoclast differentiation, overexpression of wild type but not PDZ binding motif deleted Cldn-18 inhibited RANKL-induced osteoclast differentiation. Furthermore, our findings indicate that Cldn-18 interacts with Zonula occludens 2 (ZO-2) to modulate RANKL signaling in osteoclasts. In conclusion, we demonstrate that Cldn-18 is a novel negative regulator of bone resorption and osteoclast differentiation.
authors.affiliation: Musculoskeletal Disease Center, Jerry L Pettis Memorial Veterans Affairs Medical Center, Loma Linda, CA 92357, USA.
authors.forename: Gabriel R
authors.initials: GR
authors.lastname: Linares
authors.forename: Robert
authors.initials: R
authors.lastname: Brommage
authors.forename: David R
authors.initials: DR
authors.lastname: Powell
authors.forename: Weirong
authors.initials: W
authors.lastname: Xing
authors.forename: Shin-Tai
authors.initials: ST
authors.lastname: Chen
authors.forename: Fatima Z
authors.initials: FZ
authors.lastname: Alshbool
authors.forename: K-H William
authors.initials: KH
authors.lastname: Lau
authors.forename: Jon E
authors.initials: JE
authors.lastname: Wergedal
authors.forename: Subburaman
authors.initials: S
authors.lastname: Mohan
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D001862:Bone Resorption; D002454:Cell Differentiation; D049109:Cell Proliferation; D057167:Claudins / Q000096:biosynthesis* / Q000502:physiology*; D005260:Female; D005838:Genotype; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000166:cytology*; D053245:RANK Ligand / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism; D062827:Zonula Occludens-2 Protein
chemical_list: D057167:Claudins; C438899:Cldn18 protein, mouse; D008565:Membrane Proteins; D053245:RANK Ligand; C569047:Tjp2 protein, mouse; D062827:Zonula Occludens-2 Protein