title: Bone morphogenetic protein receptor type Ia localization causes increased BMP2 signaling in mice exhibiting increased peak bone mass phenotype.
abstract: Bone morphogenetic protein 2 (BMP2) is a growth factor that initiates osteoblast differentiation. Recent studies show that BMP2 signaling regulates bone mineral density (BMD). BMP2 interacts with BMP receptor type Ia (BMPRIa) and type II receptor leading to the activation of the Smad signaling pathway. BMPRIa must shuttle between distinct plasma membrane domains, enriched of Caveolin-1 alpha and Caveolin-1 beta isoforms, and receptor activation occurs in these domains. Yet it remains unknown whether the molecular mechanism that regulates BMP2 signaling is driving mineralization and BMD. Therefore, the B6.C3H-1-12 congenic mouse model with increased BMD and osteoblast mineralization was utilized in this study. Using the family image correlation spectroscopy, we determined if BMP2 led to a significant re-localization of BMPRIa to caveolae of the alpha/beta isoforms in bone marrow stromal cells (BMSCs) isolated from B6.C3H-1-12 mice compared to the C57BL/6J mice, which served as controls. The control, C57BL/6J mice, was selected due to only 4 Mb of chromosome 1 from the C3H/HeJ mouse was backcrossed to a C57BL/6J background. Using reporter gene assays, the B6.C3H-1-12 BMSCs responded to BMP2 with increased Smad activation. Furthermore, disrupting caveolae reduced the BMP2-induced Smad signaling in BMSCs isolated from B6.C3H-1-12 and C57BL/6J. This study suggests for the first time a regulatory mechanism of BMPRIa signaling at the plasma membrane of BMSCs that (i) associated with genetic differences in the distal Chromosome 1 segment carried by the B6.C3H-1-12 congenic and (ii) contributes to increase BMD of the B6.C3H-1-12 compared to the C57BL/6J control mice.
authors.affiliation: Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Bragdon
authors.forename: Jeremy
authors.initials: J
authors.lastname: Bonor
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Shultz
authors.forename: Wesley G
authors.initials: WG
authors.lastname: Beamer
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Rosen
authors.forename: Anja
authors.initials: A
authors.lastname: Nohe
mesh_terms: D000818:Animals; D015519:Bone Density; D001853:Bone Marrow / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism*; D001842:Bone and Bones / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000502:physiology; D021941:Caveolae / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D051379:Mice; D020297:Mice, Congenic; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010012:Osteogenesis / Q000502:physiology; D010641:Phenotype; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology; D051785:Smad Proteins / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D051242:Caveolin 1; D020033:Protein Isoforms; D051785:Smad Proteins; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I