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Osteoclast formation is strongly reduced both in vivo and in vitro in the absence of CD47/SIRPalpha-interaction
Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
Umeå University, Faculty of Medicine, Department of Odontology.
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2007 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 352, no 2, 444-448 p.Article in journal (Refereed) Published
Abstract [en]

Physical interaction between the cell surface receptors CD47 and signal regulatory protein alpha (SIRPalpha) was reported to regulate cell migration, phagocytosis, cytokine production, and macrophage fusion. However, it is unclear if the CD47/SIRPalpha-interaction can also regulate macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor (NF)-kappaB ligand (RANKL)-stimulated formation of osteoclasts. Here, we show that functional blocking antibodies to either CD47 or SIRPalpha strongly reduced formation of multinucleated tartrate-resistant acid phosphatase (TRAP)+ osteoclasts in cultures of murine hematopoietic cells, stimulated in vitro by M-CSF and RANKL. In addition, the numbers of osteoclasts formed in M-CSF/RANKL-stimulated bone marrow macrophage cultures from CD47-/- mice were strongly reduced, and bones of CD47-/- mice exhibited significantly reduced osteoclast numbers, as compared with wild-type controls. We conclude that the CD47/SIRPalpha interaction is important for M-CSF/RANKL-stimulated osteoclast formation both in vivo and in vitro, and that absence of CD47 results in decreased numbers of osteoclasts in CD47-/- mice.

Place, publisher, year, edition, pages
2007. Vol. 352, no 2, 444-448 p.
Keyword [en]
Animals, Antigens; CD47/*metabolism, Cell Differentiation, Cells; Cultured, Male, Mesenchymal Stem Cells/*cytology/*metabolism, Mice, Mice; Inbred C57BL, Osteoclasts/*cytology/*metabolism, Osteogenesis/*physiology, Protein Binding, Receptors; Immunologic/*metabolism
National Category
Cell and Molecular Biology Dentistry
URN: urn:nbn:se:umu:diva-12288DOI: 10.1016/j.bbrc.2006.11.057PubMedID: 17126807OAI: diva2:151959
Available from: 2007-11-27 Created: 2007-11-27 Last updated: 2014-02-21Bibliographically approved
In thesis
1. CD47–SIRPα: an interaction of importance for bone cell differentiation
Open this publication in new window or tab >>CD47–SIRPα: an interaction of importance for bone cell differentiation
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[en]
CD47–SIRPα : en interaktion av betydelse för skelettcellers differentiering
Abstract [en]

Bone tissue is continuously remodeled by bone-forming osteoblasts and bone-resorbing osteoclasts, in processes tightly regulated by hormones, cytokines and growth factors. CD47, a ubiquitously expressed protein, and one of its ligands, signal-regulatory protein alpha (SIRPα), are two cell-surface proteins belonging to the immunoglobulin (Ig)-superfamily. The interaction between CD47 and SIRPα is important for, amongst other processes, the fusion of macrophages into giant cells, which are closely related to osteoclasts.

The aim of the present study was to gain knowledge about the role of CD47–SIRPα interaction and resultant downstream signaling pathways in bone cell differentiation, formation and function.

The addition of antibodies against CD47 or SIRPα inhibited the formation of multinucleated osteoclasts from bone marrow monocytes (BMMs) in culture. Moreover, a significant decrease in the number of osteoclasts was detected in CD47-/- BMM cultures compared to CD47+/+ cultures. In line with these in vitro results, we found fewer osteoclasts in vivo in the trabecular bone of CD47-/- mice, as compared to CD47+/+ bone. Interestingly, an extended analysis of the trabecular bone of CD47-/- mice revealed that the bone volume, mineralizing surface, mineral apposition rate, bone formation rate and osteoblast number were also significantly reduced compared with CD47+/+ mice, indicating the importance of CD47 in osteoblast differentiation. In vitro studies of bone marrow stromal (BMS) cells from CD47-/- mice or SIRPα-mutant mice (mice lacking the signaling domain of SIRPa) showed a blunted expression of osteoblast-associated genes. Moreover, these altered genotypes were associated with reduced activity of the bone mineralization-associated enzyme alkaline phosphatase as well as a reduced ability to form mineral. To reveal the molecular mechanisms by which CD47 activation of SIRPα is important for BMS cell differentiation, we studied signaling downstream of SIRPα in the absence of CD47. In BMS cells lacking CD47, a considerable reduction in the levels of tyrosine phosphorylated SIRPα was detected, and the subsequent recruitment of the Src-homology-2 (SH2) domain-containing protein tyrosine phosphatase (SHP-2)–phosphoinositide 3-kinase (PI3K)–Akt2 signaling module was nearly abolished.

In conclusion, the interaction between CD47 and SIRPα results in the activation of the SHP-2–PI3K–Akt2 pathway, which is necessary for normal osteoblast differentiation. In CD47-/- mice and SIRPα-mutant mice, this interaction is perturbed, which prevents normal osteoblast differentiation and subsequent mineral formation. In addition, the altered BMS cell phenotype results in an impaired ability to stimulate osteoclast differentiation. 

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2014. 50 p.
Umeå University odontological dissertations, ISSN 0345-7532 ; 132
CD47, SIRPalpha, osteoblast, osteoclast, SHP-2, Akt2
National Category
Basic Medicine
Research subject
urn:nbn:se:umu:diva-85912 (URN)978-91-7601-000-6 (ISBN)
Public defence
2014-03-14, Sal B, 9 tr Tandläkarhögskolan, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Available from: 2014-02-21 Created: 2014-02-13 Last updated: 2014-02-21Bibliographically approved

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Lundberg, PernillaKoskinen, CeciliaStenberg, ÅsaLerner, UlfOldenborg, Per-Arne
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