Lack of CD47 Impairs Bone Cell Differentiation and Results in an Osteopenic Phenotype in Vivo due to Impaired Signal Regulatory Protein α (SIRPα) Signaling
| Autor: | Paul A. Baldock, Pernilla Lundberg, Ingrid Boström, Åsa Stenberg, Cecilia Koskinen, Takashi Matozaki, Emelie Persson, Per-Arne Oldenborg |
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| Rok vydání: | 2013 |
| Předmět: |
musculoskeletal diseases
Stromal cell Cellular differentiation Blotting Western education Cell Osteoclasts Bone Marrow Cells CD47 Antigen Biochemistry Bone and Bones Mice Osteogenesis Osteoclast In vivo Bone cell medicine Animals Receptors Immunologic Molecular Biology Cells Cultured Myeloid Progenitor Cells Mice Knockout Regulation of gene expression Mice Inbred BALB C Osteoblasts Reverse Transcriptase Polymerase Chain Reaction Chemistry CD47 Cell Differentiation Cell Biology Coculture Techniques Cell biology Mice Inbred C57BL Bone Diseases Metabolic Phenotype medicine.anatomical_structure Mutation Immunology Stromal Cells Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 288:29333-29344 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m113.494591 |
| Popis: | Here, we investigated whether the cell surface glycoprotein CD47 was required for normal formation of osteoblasts and osteoclasts and to maintain normal bone formation activity in vitro and in vivo. In parathyroid hormone or 1α,25(OH)2-vitamin D3 (D3)-stimulated bone marrow cultures (BMC) from CD47(-/-) mice, we found a strongly reduced formation of multinuclear tartrate-resistant acid phosphatase (TRAP)(+) osteoclasts, associated with reduced expression of osteoclastogenic genes (nfatc1, Oscar, Trap/Acp, ctr, catK, and dc-stamp). The production of M-CSF and RANKL (receptor activator of nuclear factor κβ ligand) was reduced in CD47(-/-) BMC, as compared with CD47(+/+) BMC. The stromal cell phenotype in CD47(-/-) BMC involved a blunted expression of the osteoblast-associated genes osterix, Alp/Akp1, and α-1-collagen, and reduced mineral deposition, as compared with that in CD47(+/+) BMC. CD47 is a ligand for SIRPα (signal regulatory protein α), which showed strongly reduced tyrosine phosphorylation in CD47(-/-) bone marrow stromal cells. In addition, stromal cells lacking the signaling SIRPα cytoplasmic domain also had a defect in osteogenic differentiation, and both CD47(-/-) and non-signaling SIRPα mutant stromal cells showed a markedly reduced ability to support osteoclastogenesis in wild-type bone marrow macrophages, demonstrating that CD47-induced SIRPα signaling is critical for stromal cell support of osteoclast formation. In vivo, femoral bones of 18- or 28-week-old CD47(-/-) mice showed significantly reduced osteoclast and osteoblast numbers and exhibited an osteopenic bone phenotype. In conclusion, lack of CD47 strongly impairs SIRPα-dependent osteoblast differentiation, deteriorate bone formation, and cause reduced formation of osteoclasts. |
| Databáze: | OpenAIRE |
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