title: N-cadherin Regulation of Bone Growth and Homeostasis Is Osteolineage Stage-Specific.
abstract: N-cadherin inhibits osteogenic cell differentiation and canonical Wnt/β-catenin signaling in vitro. However, in vivo both conditional Cdh2 ablation and overexpression in osteoblasts lead to low bone mass. We tested the hypothesis that N-cadherin has different effects on osteolineage cells depending upon their differentiation stage. Embryonic conditional osteolineage Cdh2 deletion in mice results in defective growth, low bone mass, and reduced osteoprogenitor number. These abnormalities are prevented by delaying Cdh2 ablation until 1 month of age, thus targeting only committed and mature osteoblasts, suggesting they are the consequence of N-cadherin deficiency in osteoprogenitors. Indeed, diaphyseal trabecularization actually increases when Cdh2 is ablated postnatally. The sclerostin-insensitive Lrp5A214Vmutant, associated with high bone mass, does not rescue the growth defect, but it overrides the low bone mass of embryonically Cdh2-deleted mice, suggesting N-cadherin interacts with Wnt signaling to control bone mass. Finally, bone accrual and β-catenin accumulation after administration of an anti-Dkk1 antibody are enhanced in N-cadherin-deficient mice. Thus, although lack of N-cadherin in embryonic and perinatal age is detrimental to bone growth and bone accrual, in adult mice loss of N-cadherin in osteolineage cells favors bone formation. Hence, N-cadherin inhibition may widen the therapeutic window of osteoanabolic agents. © 2017 American Society for Bone and Mineral Research.
authors.affiliation: Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fontana
authors.affiliation: Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Hickman-Brecks
authors.affiliation: Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA.|Department of Development Biology, Harvard School of Dental Medicine, Boston, MA, USA.
authors.forename: Valerie S
authors.initials: VS
authors.lastname: Salazar
authors.affiliation: Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA.|Department of Development Biology, Harvard School of Dental Medicine, Boston, MA, USA.
authors.forename: Leila
authors.initials: L
authors.lastname: Revollo
authors.affiliation: Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA.|Division of Oncology, Stem Cell Biology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Grazia
authors.initials: G
authors.lastname: Abou-Ezzi
authors.affiliation: Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Grimston
authors.affiliation: Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Sung Yeop
authors.initials: SY
authors.lastname: Jeong
authors.affiliation: Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Watkins
authors.affiliation: Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Manuela
authors.initials: M
authors.lastname: Fortunato
authors.affiliation: Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Yael
authors.initials: Y
authors.lastname: Alippe
authors.affiliation: Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA.|Division of Oncology, Stem Cell Biology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
authors.affiliation: Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mbalaviele
authors.affiliation: Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Civitelli
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001842:Bone and Bones / Q000473:pathology; D015820:Cadherins / Q000378:metabolism*; D002452:Cell Count; D019070:Cell Lineage; D004622:Embryo, Mammalian / Q000166:cytology; D000073659:Gain of Function Mutation; D017353:Gene Deletion; D006706:Homeostasis; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D018345:Mice, Knockout; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis; D010641:Phenotype; D000076182:Sp7 Transcription Factor / Q000378:metabolism
chemical_list: D015820:Cadherins; C489083:Cdh2 protein, mouse; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse
keywords: ANABOLICS; CELL-CELL INTERACTIONS; CELL/TISSUE SIGNALING; CELLS OF BONE; GENETIC ANIMAL MODELS; LRPS; PARACRINE PATHWAYS; STROMAL/STEM CELLS; THERAPEUTICS; WNT/BETA-CATENIN