title: Lack of SIRPα phosphorylation and concomitantly reduced SHP-2-PI3K-Akt2 signaling decrease osteoblast differentiation.
abstract: Normal differentiation of bone forming osteoblasts is a prerequisite for maintenance of skeletal health and is dependent on intricate cellular signaling pathways, including the essential transcription factor Runx2. The cell surface glycoprotein CD47 and its receptor signal regulatory protein alpha (SIRPα) have both been suggested to regulate bone cell differentiation. Here we investigated osteoblastic differentiation of bone marrow stromal cells from SIRPα mutant mice lacking the cytoplasmic signaling domain of SIRPα. An impaired osteoblastogenesis in SIRPα-mutant cell cultures was demonstrated by lower alkaline phosphatase activity and less mineral formation compared to wild-type cultures. This reduced osteoblastic differentiation potential in SIRPα-mutant stromal cells was associated with a significantly reduced expression of Runx2, osterix, osteocalcin, and alkaline phosphatase mRNA, as well as a reduced phosphorylation of SHP-2 and Akt2, as compared with that in wild-type stromal cells. Addition of a PI3K-inhibitor to wild-type stromal cells could mimic the impaired osteoblastogenesis seen in SIRPα-mutant cells. In conclusion, our data suggest that SIRPα signaling through SHP-2-PI3K-Akt2 strongly influences osteoblast differentiation from bone marrow stromal cells.
authors.affiliation: Odontology, Section for Molecular Periodontology, Umeå University, 90187, Sweden. Electronic address: cecilia.koskinen@umu.se.
authors.forename: Cecilia Koskinen
authors.initials: CK
authors.lastname: Holm
authors.affiliation: Odontology, Section for Molecular Periodontology, Umeå University, 90187, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Engman
authors.affiliation: Odontology, Section for Molecular Periodontology, Umeå University, 90187, Sweden.
authors.forename: Rima
authors.initials: R
authors.lastname: Sulniute
authors.affiliation: Biochemistry and Molecular Biology, Division of Molecular and Cellular Signaling, Kobe University, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matozaki
authors.affiliation: Integrative Medical Biology, Umeå University, Sweden.
authors.forename: Per-Arne
authors.initials: PA
authors.lastname: Oldenborg
authors.affiliation: Odontology, Section for Molecular Periodontology, Umeå University, 90187, Sweden.
authors.forename: Pernilla
authors.initials: P
authors.lastname: Lundberg
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse
keywords: Akt2; Osteoblast; PI3K; SIRPalpha; Stromal cell