title: N-cadherin/wnt interaction controls bone marrow mesenchymal cell fate and bone mass during aging.
abstract: Age-related bone loss is characterized by reduced osteoblastogenesis and excessive bone marrow adipogenesis. The mechanisms governing bone marrow mesenchymal stromal cell (BMSC) differentiation into adipocytes or osteoblasts during aging are unknown. We show here that overexpressing N-cadherin (Cadh2) in osteoblasts increased BMSC adipocyte differentiation and reduced osteoblast differentiation in young transgenic (Tg) mice whereas this phenotype was fully reversed with aging. The reversed phenotype with age was associated with enhanced Wnt5a and Wnt10b expression in osteoblasts and a concomitant increase in BMSC osteogenic differentiation. Consistent with this mechanism, conditioned media from young wild type osteoblasts inhibited adipogenesis and promoted osteoblast differentiation in BMSC from old Cadh2 Tg mice, and this response was abolished by Wnt5a and Wnt10b silencing. Transplantation of BMSC from old Cadh2 Tg mice into young Tg recipients increased Wnt5a and Wnt10b expression and rescued BMSC osteogenic differentiation. In senescent osteopenic mice, blocking the CADH2-Wnt interaction using an antagonist peptide increased Wnt5a and Wnt10b expression, bone formation, and bone mass. The data indicate that Cadh2/Wnt interaction in osteoblasts regulates BMSC lineage determination, bone formation, and bone mass and suggest a therapeutic target for promoting bone formation in the aging skeleton.
authors.affiliation: Inserm UMR-1132, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Haÿ
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Dieudonné
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Saidak
authors.forename: Caroline
authors.initials: C
authors.lastname: Marty
authors.forename: Julia
authors.initials: J
authors.lastname: Brun
authors.forename: Sophie
authors.initials: S
authors.lastname: Da Nascimento
authors.forename: Pascal
authors.initials: P
authors.lastname: Sonnet
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Marie
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D050156:Adipogenesis; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D001862:Bone Resorption / Q000473:pathology; D015820:Cadherins / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis; D011485:Protein Binding; D015398:Signal Transduction; D033581:Stem Cell Transplantation; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein
chemical_list: D015820:Cadherins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C102068:Wnt10b protein, mouse; C438615:Wnt5a protein, mouse