title: Alpha-1 Antitrypsin Gene Therapy Ameliorates Bone Loss in Ovariectomy-Induced Osteoporosis Mouse Model.
abstract: Osteoporosis is a major healthcare burden affecting mostly postmenopausal women characterized by compromised bone strength and increased risk of fragility fracture. Although pathogenesis of this disease is complex, elevated proinflammatory cytokine production is clearly involved in bone loss at menopause. Therefore, anti-inflammatory strategies hold a great potential for the prevention of postmenopausal osteoporosis. In this study, we investigated the effect of gene therapy of recombinant adeno-associated virus (rAAV)-mediated human alpha-1 antitrypsin (hAAT), a multifunctional protein that has anti-inflammatory property, on bone loss in an ovariectomy-induced osteoporosis mouse model. Adult ovariectomized (OVX) mice were intraperitoneally (i.p.) injected with hAAT (protein therapy), rAAV8-CB-hAAT (gene therapy), or phosphate buffer saline (PBS). Age-matched and sham-operated animals were used as controls. Eight weeks after the treatment, animals were sacrificed and bone-related biomarkers and vertebral bone structure were evaluated. Results showed that hAAT gene therapy significantly decreased serum IL-6 level and receptor activator of NF-κB (RANK) gene expression in bone. Importantly, hAAT gene therapy increased bone volume/total volume and decreased structure model index (SMI) compared to PBS injection in OVX mice. These results demonstrate that hAAT gene therapy by rAAV vector efficiently mitigates bone loss possibly through inhibition of proinflammatory cytokine IL-6 and RANK gene expression. Considering the safety profile of hAAT and rAAV vector in humans, our results provide a new alternative for the treatment of osteoporosis.
authors.affiliation: 1 Department of Pharmaceutics, University of Florida , Gainesville, Florida.
authors.forename: Mohammad Ahsanul
authors.initials: MA
authors.lastname: Akbar
authors.affiliation: 2 USDA, ARS Grand Fork Human Nutrition Research Center , Grand Fork, North Dakota.
authors.forename: Jay J
authors.initials: JJ
authors.lastname: Cao
authors.affiliation: 3 Department of Medicine, University of Florida , Gainesville, Florida.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Lu
authors.affiliation: 1 Department of Pharmaceutics, University of Florida , Gainesville, Florida.
authors.forename: David
authors.initials: D
authors.lastname: Nardo
authors.affiliation: 1 Department of Pharmaceutics, University of Florida , Gainesville, Florida.
authors.forename: Mong-Jen
authors.initials: MJ
authors.lastname: Chen
authors.affiliation: 1 Department of Pharmaceutics, University of Florida , Gainesville, Florida.
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Elshikha
authors.affiliation: 1 Department of Pharmaceutics, University of Florida , Gainesville, Florida.
authors.forename: Rubina
authors.initials: R
authors.lastname: Ahamed
authors.affiliation: 3 Department of Medicine, University of Florida , Gainesville, Florida.
authors.forename: Mark
authors.initials: M
authors.lastname: Brantly
authors.affiliation: 4 Department of Orthodontics, University of Florida , Gainesville, Florida.
authors.forename: L Shannon
authors.initials: LS
authors.lastname: Holliday
authors.affiliation: 1 Department of Pharmaceutics, University of Florida , Gainesville, Florida.
authors.forename: Sihong
authors.initials: S
authors.lastname: Song
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D010024:Osteoporosis / Q000209:etiology / Q000517:prevention & control*; D010052:Ovariectomy / Q000009:adverse effects*; D000515:alpha 1-Antitrypsin / Q000235:genetics*
chemical_list: D000515:alpha 1-Antitrypsin