title: PDGFB-based stem cell gene therapy increases bone strength in the mouse.
abstract: Substantial advances have been made in the past two decades in the management of osteoporosis. However, none of the current medications can eliminate the risk of fracture and rejuvenate the skeleton. To this end, we recently reported that transplantation of hematopoietic stem/progenitor cells (HSCs) or Sca1(+) cells engineered to overexpress FGF2 results in a significant increase in lamellar bone matrix formation at the endosteum; but this increase was attended by the development of secondary hyperparathyroidism and severe osteomalacia. Here we switch the therapeutic gene to PDGFB, another potent mitogen for mesenchymal stem cells (MSCs) but potentially safer than FGF2. We found that modest overexpression of PDGFB using a relatively weak phosphoglycerate kinase (PGK) promoter completely avoided osteomalacia and secondary hyperparathyroidism, and simultaneously increased trabecular bone formation and trabecular connectivity, and decreased cortical porosity. These effects led to a 45% increase in the bone strength. Transplantation of PGK-PDGFB-transduced Sca1(+) cells increased MSC proliferation, raising the possibility that PDGF-BB enhances expansion of MSC in the vicinity of the hematopoietic niche where the osteogenic milieu propels the differentiation of MSCs toward an osteogenic destination. Our therapy should have potential clinical applications for patients undergoing HSC transplantation, who are at high risk for osteoporosis and bone fractures after total body irradiation preconditioning. It could eventually have wider application once the therapy can be applied without the preconditioning.
authors.affiliation: Department of Medicine, Loma Linda University, Loma Linda, CA 92354;
authors.forename: Wanqiu
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Medicine, Loma Linda University, Loma Linda, CA 92354;
authors.forename: David J
authors.initials: DJ
authors.lastname: Baylink
authors.affiliation: Department of Medicine, Loma Linda University, Loma Linda, CA 92354;
authors.forename: Justin
authors.initials: J
authors.lastname: Brier-Jones
authors.affiliation: Department of Medicine, Loma Linda University, Loma Linda, CA 92354;
authors.forename: Amanda
authors.initials: A
authors.lastname: Neises
authors.affiliation: Department of Medicine, Loma Linda University, Loma Linda, CA 92354;
authors.forename: Jason B
authors.initials: JB
authors.lastname: Kiroyan
authors.affiliation: Department of Medicine, Loma Linda University, Loma Linda, CA 92354; Musculoskeletal Disease Center, Jerry L. Pettis Memorial VA Medical Center, Loma Linda, CA 92357.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Rundle
authors.affiliation: Department of Medicine, Loma Linda University, Loma Linda, CA 92354; Musculoskeletal Disease Center, Jerry L. Pettis Memorial VA Medical Center, Loma Linda, CA 92357.
authors.forename: Kin-Hing William
authors.identifier: http://orcid.org/0000-0003-1109-5052
authors.initials: KH
authors.lastname: Lau
authors.affiliation: Department of Medicine, Loma Linda University, Loma Linda, CA 92354; xzhang@llu.edu.
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Zhang
mesh_terms: D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001835:Body Weight; D016723:Bone Remodeling; D001842:Bone and Bones / Q000503:physiopathology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D015316:Genetic Therapy; D018380:Hematopoietic Stem Cell Transplantation; D006961:Hyperparathyroidism / Q000150:complications / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D019394:Ki-67 Antigen / Q000378:metabolism; D016086:Lentivirus / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D008954:Models, Biological; D018919:Neovascularization, Physiologic; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D015675:Osteocalcin / Q000097:blood; D010012:Osteogenesis; D010018:Osteomalacia / Q000150:complications / Q000503:physiopathology; D010735:Phosphoglycerate Kinase / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics* / Q000627:therapeutic use*; D013155:Spleen Focus-Forming Viruses / Q000378:metabolism; D014161:Transduction, Genetic; D019076:Transgenes; D016474:Weight-Bearing
chemical_list: D000950:Antigens, Ly; D019394:Ki-67 Antigen; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D020574:Proto-Oncogene Proteins c-sis; D015675:Osteocalcin; D010735:Phosphoglycerate Kinase; D000469:Alkaline Phosphatase
keywords: PDGFB; bone formation; gene therapy; hematopoietic stem cells