title: Inhibited Wnt signaling causes age-dependent abnormalities in the bone matrix mineralization in the Apert syndrome FGFR2(S252W/+) mice.
abstract: Apert syndrome (AS) is a type of autosomal dominant disease characterized by premature fusion of the cranial sutures, severe syndactyly, and other abnormalities in internal organs. Approximately 70% of AS cases are caused by a single mutation, S252W, in fibroblast growth factor receptor 2 (FGFR2). Two groups have generated FGFR2 knock-in mice Fgfr2S252W/+ that exhibit features of AS. During the present study of AS using the Fgfr2S252W/+ mouse model, an age-related phenotype of bone homeostasis was discovered. The long bone mass was lower in 2 month old mutant mice than in age-matched controls but higher in 5 month old mutant mice. This unusual phenotype suggested that bone marrow-derived mesenchymal stem cells (BMSCs), which are vital to maintain bone homeostasis, might be involved. BMSCs were isolated from Fgfr2S252W/+ mice and found that S252W mutation could impair osteogenic differentiation BMSCs but enhance mineralization of more mature osteoblasts. A microarray analysis revealed that Wnt pathway inhibitors SRFP1/2/4 were up-regulated in mutant BMSCs. This work provides evidence to show that the Wnt/β-catenin pathway is inhibited in both mutant BMSCs and osteoblasts, and differentiation defects of these cells can be ameliorated by Wnt3a treatment. The present study suggested that the bone abnormalities caused by deregulation of Wnt pathway may underlie the symptoms of AS.
authors.affiliation: Department of Stomatology, Daping Hospital & Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China; Department 4, Daping Hospital & Research Institute of Surgery, Third Military Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing 400042, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department 4, Daping Hospital & Research Institute of Surgery, Third Military Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing 400042, China; Neurosurgery Department, PLA 324 Hospital, Chongqing, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Stomatology, Daping Hospital & Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department 4, Daping Hospital & Research Institute of Surgery, Third Military Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing 400042, China.
authors.forename: Tujun
authors.initials: T
authors.lastname: Weng
authors.affiliation: Department 4, Daping Hospital & Research Institute of Surgery, Third Military Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing 400042, China.
authors.forename: Shichang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Stomatology, Daping Hospital & Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department 4, Daping Hospital & Research Institute of Surgery, Third Military Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing 400042, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Stomatology, Daping Hospital & Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China.
authors.forename: Luchuan
authors.initials: L
authors.lastname: Liu
mesh_terms: D000168:Acrocephalosyndactylia / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001857:Bone Matrix / Q000378:metabolism* / Q000473:pathology; D002113:Calcification, Physiologic / Q000235:genetics / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2