title: An essential role for the association of CD47 to SHPS-1 in skeletal remodeling.
abstract: Integrin-associated protein (IAP/CD47) has been implicated in macrophage-macrophage fusion. To understand the actions of CD47 on skeletal remodeling, we compared Cd47(-/-) mice with Cd47(+/+) controls. Cd47(-/-) mice weighed less and had decreased areal bone mineral density compared with controls. Cd47(-/-) femurs were shorter in length with thinner cortices and exhibited lower trabecular bone volume owing to decreased trabecular number and thickness. Histomorphometry revealed reduced bone-formation and mineral apposition rates, accompanied by decreased osteoblast numbers. No differences in osteoclast number were observed despite a nonsignificant but 40% decrease in eroded surface/bone surface in Cd47(-/-) mice. In vitro, the number of functional osteoclasts formed by differentiating Cd47(-/-) bone marrow cells was significantly decreased compared with wild-type cultures and was associated with a decrease in bone-resorption capacity. Furthermore, by disrupting the CD47-SHPS-1 association, we found that osteoclastogenesis was markedly impaired. Assays for markers of osteoclast maturation suggested that the defect was at the point of fusion and not differentiation and was associated with a lack of SHPS-1 phosphorylation, SHP-1 phosphatase recruitment, and subsequent dephosphorylation of non-muscle cell myosin IIA. We also demonstrated a significant decrease in osteoblastogenesis in bone marrow stromal cells derived from Cd47(-/-) mice. Our finding of cell-autonomous defects in Cd47(-/-) osteoblast and osteoclast differentiation coupled with the pronounced skeletal phenotype of Cd47(-/-) mice support the conclusion that CD47 plays an important role in regulating skeletal acquisition and maintenance through its actions on both bone formation and bone resorption.
authors.affiliation: Division of Endocrinology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7170, USA. laura_maile@med.unc.edu
authors.forename: Laura A
authors.initials: LA
authors.lastname: Maile
authors.forename: Victoria E
authors.initials: VE
authors.lastname: DeMambro
authors.forename: Christine
authors.initials: C
authors.lastname: Wai
authors.forename: Sutada
authors.initials: S
authors.lastname: Lotinun
authors.forename: Ariel W
authors.initials: AW
authors.lastname: Aday
authors.forename: Byron E
authors.initials: BE
authors.lastname: Capps
authors.forename: Wesley G
authors.initials: WG
authors.lastname: Beamer
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Rosen
authors.forename: David R
authors.initials: DR
authors.lastname: Clemmons
mesh_terms: D000375:Aging / Q000097:blood / Q000187:drug effects; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001823:Body Composition / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects; D051928:CD47 Antigen / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D010641:Phenotype; D011485:Protein Binding / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000378:metabolism*; D014057:Tomography, X-Ray Computed
chemical_list: D015415:Biomarkers; D051928:CD47 Antigen; C497895:Cd47 protein, mouse; C501922:Sirpa protein, mouse; D053245:RANK Ligand; D011971:Receptors, Immunologic