title: Disruption of claudin-18 diminishes ovariectomy-induced bone loss in mice.
abstract: Claudin-18 (Cldn-18), a member of the tight junction family of proteins, is a negative regulator of RANKL-induced osteoclast differentiation and bone resorption (BR) in vivo. Since estrogen deficiency decreases bone mass in part by a RANKL-mediated increase in BR, we evaluated whether estrogen regulates Cldn-18 expression in bone. We found that Cldn-18 expression was reduced in the bones of estrogen deficient mice, whereas it was increased by estrogen treatment in osteoblasts and osteoclasts in vitro. We next evaluated the role of Cldn-18 in mediating estrogen-induced bone loss. Cldn-18 knockout (KO) and littermate wild-type (WT) mice were ovariectomized (OVX) or sham operated at 6 wk of age, and the skeletal phenotype was evaluated at 14 wk of age. PIXImus revealed that total body, femur, and lumbar BMD were reduced 8-13% (P < 0.05) after 8 wk of OVX compared with sham in WT mice. As expected, total body, femur, and lumbar BMD were reduced 14-21% (P < 0.05) in Cldn-18 KO sham mice compared with sham WT mice. However, ovariectomy failed to induce significant changes in BMD of total body, femur, or vertebra in the Cldn-18 KO mice. μCT analysis of the distal femur revealed that trabecular (Tb) bone volume was decreased 50% in the OVX WT mice compared with sham that was caused by a 26% decrease in Tb number and a 30% increase in Tb separation (all P < 0.05). By contrast, none of the Tb parameters were significantly different in OVX Cldn-18 KO mice compared with sham KO mice. Histomorphometric analyses at the Tb site revealed that neither osteoclast surface nor osteoclast perimeter was increased significantly as a consequence of OVX in either genotype at the time point examined. Based on our findings, we conclude that the estrogen effects on osteoclasts may in part be mediated via regulation of Cldn-18 signaling.
authors.affiliation: Musculoskeletal Disease Center, Loma Linda Veterans Affairs Healthcare System, Loma Linda, CA 923257, USA.
authors.forename: Ha-Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Catrina
authors.initials: C
authors.lastname: Alarcon
authors.forename: Sheila
authors.initials: S
authors.lastname: Pourteymour
authors.forename: Jon E
authors.initials: JE
authors.lastname: Wergedal
authors.forename: Subburaman
authors.initials: S
authors.lastname: Mohan
mesh_terms: D015502:Absorptiometry, Photon; D000135:Acid Phosphatase / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D015519:Bone Density / Q000502:physiology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D001862:Bone Resorption / Q000473:pathology* / Q000503:physiopathology; D001842:Bone and Bones / Q000033:anatomy & histology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D057167:Claudins / Q000235:genetics / Q000502:physiology*; D005260:Female; D015870:Gene Expression / Q000502:physiology; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000502:physiology; D010052:Ovariectomy; D053245:RANK Ligand / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D000071681:Tartrate-Resistant Acid Phosphatase; D014129:Trabecular Meshwork / Q000502:physiology
chemical_list: D057167:Claudins; C438899:Cldn18 protein, mouse; D007527:Isoenzymes; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D000469:Alkaline Phosphatase; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase