title: Apolipoprotein A-1 regulates osteoblast and lipoblast precursor cells in mice.
abstract: Imbalances in lipid metabolism affect bone homeostasis, altering bone mass and quality. A link between bone mass and high-density lipoprotein (HDL) has been proposed. Indeed, it has been recently shown that absence of the HDL receptor scavenger receptor class B type I (SR-B1) causes dense bone mediated by increased adrenocorticotropic hormone (ACTH). In the present study we aimed at further expanding the current knowledge as regards the fascinating bone-HDL connection studying bone turnover in apoA-1-deficient mice. Interestingly, we found that bone mass was greatly reduced in the apoA-1-deficient mice compared with their wild-type counterparts. More specifically, static and dynamic histomorphometry showed that the reduced bone mass in apoA-1(-/-) mice reflect decreased bone formation. Biochemical composition and biomechanical properties of ApoA-1(-/-) femora were significantly impaired. Mesenchymal stem cell (MSC) differentiation from the apoA-1(-/-) mice showed reduced osteoblasts, and increased adipocytes, relative to wild type, in identical differentiation conditions. This suggests a shift in MSC subtypes toward adipocyte precursors, a result that is in line with our finding of increased bone marrow adiposity in apoA-1(-/-) mouse femora. Notably, osteoclast differentiation in vitro and osteoclast surface in vivo were unaffected in the knock-out mice. In whole bone marrow, PPARγ was greatly increased, consistent with increased adipocytes and committed precursors. Further, in the apoA-1(-/-) mice marrow, CXCL12 and ANXA2 levels were significantly decreased, whereas CXCR4 were increased, consistent with reduced signaling in a pathway that supports MSC homing and osteoblast generation. In keeping, in the apoA-1(-/-) animals the osteoblast-related factors Runx2, osterix, and Col1a1 were also decreased. The apoA-1(-/-) phenotype also included augmented CEPBa levels, suggesting complex changes in growth and differentiation that deserve further investigation. We conclude that the apoA-1 deficiency generates changes in the bone cell precursor population that increase adipoblast, and decrease osteoblast production resulting in reduced bone mass and impaired bone quality in mice.
authors.affiliation: Pittsburgh VA Medical Center, Pittsburgh, PA, USA.|Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Harry C
authors.initials: HC
authors.lastname: Blair
authors.affiliation: Department of Anatomy-Histology-Embryology, Unit of Bone and Soft Tissue Studies, University of Patras School of Medicine, Patras, Greece.
authors.forename: Elena
authors.initials: E
authors.lastname: Kalyvioti
authors.affiliation: Department of Anatomy-Histology-Embryology, Unit of Bone and Soft Tissue Studies, University of Patras School of Medicine, Patras, Greece.
authors.forename: Nicholaos I
authors.initials: NI
authors.lastname: Papachristou
authors.affiliation: Pittsburgh VA Medical Center, Pittsburgh, PA, USA.|Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Irina L
authors.initials: IL
authors.lastname: Tourkova
authors.affiliation: Department of Anatomy-Histology-Embryology, Unit of Bone and Soft Tissue Studies, University of Patras School of Medicine, Patras, Greece.
authors.forename: Spryros A
authors.initials: SA
authors.lastname: Syggelos
authors.affiliation: Department of Mechanical Engineering and Aeronautics, University of Patras, Patras, Greece.
authors.forename: Despina
authors.initials: D
authors.lastname: Deligianni
authors.affiliation: Department of Pharmacy, University of Patras, Patras, Greece.
authors.forename: Malvina G
authors.initials: MG
authors.lastname: Orkoula
authors.affiliation: Department of Pharmacy, University of Patras, Patras, Greece.|Institute of Chemical Engineering Sciences, Foundation for Research and Technology-Hellas (FORTH/ICE-HT), Patras, Greece.
authors.forename: Christos G
authors.identifier: 0000-0003-0452-1957
authors.initials: CG
authors.lastname: Kontoyannis
authors.affiliation: Department of Pharmacology, University of Patras Medical School, Patras, Greece.
authors.forename: Eleni A
authors.initials: EA
authors.lastname: Karavia
authors.affiliation: Department of Pharmacology, University of Patras Medical School, Patras, Greece.
authors.forename: Kyriakos E
authors.initials: KE
authors.lastname: Kypreos
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Anatomy-Histology-Embryology, Unit of Bone and Soft Tissue Studies, University of Patras School of Medicine, Patras, Greece.
authors.forename: Dionysios J
authors.initials: DJ
authors.lastname: Papachristou
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D050156:Adipogenesis; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015519:Bone Density; D002454:Cell Differentiation; D054377:Chemokine CXCL12 / Q000235:genetics; D006854:Hydrocortisone / Q000096:biosynthesis; D008075:Lipoproteins, HDL / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics; D018110:Receptors, Lipoprotein / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000235:genetics
chemical_list: D016632:Apolipoprotein A-I; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D008075:Lipoproteins, HDL; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D018110:Receptors, Lipoprotein; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C031616:high density lipoprotein receptors; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone