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ARS Home » Plains Area » Grand Forks, North Dakota » Grand Forks Human Nutrition Research Center » Dietary Prevention of Obesity-related Disease Research » Research » Publications at this Location » Publication #329943

Research Project: Food Factors to Prevent Obesity and Related Diseases

Location: Dietary Prevention of Obesity-related Disease Research

Title: Alpha-1 antitrypsin gene therapy prevented bone loss in ovariectomy induced osteoporosis mouse model

Author
item Akbar, Mohammad - University Of Florida
item Cao, Jay
item Lu, Yuanqing - University Of Florida
item Nardo, David - University Of Florida
item Chen, Mong-jen - University Of Florida
item Elshikha, Ahmed - University Of Florida
item Ahamed, Rubina - University Of Florida
item Brantly, Mark - University Of Florida
item Holliday, L. Shannon - University Of Florida
item Song, Sihong - University Of Florida

Submitted to: Human Gene Therapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/22/2016
Publication Date: 6/24/2016
Publication URL: http://handle.nal.usda.gov/10113/62932
Citation: Akbar, M., Cao, J.J., Lu, Y., Nardo, D., Chen, M., Elshikha, A.S., Ahamed, R., Brantly, M., Holliday, L., Song, S. 2016. Alpha-1 antitrypsin gene therapy prevented bone loss in ovariectomy induced osteoporosis mouse model. Human Gene Therapy. DOI: 10.1089/hum.2016.029.

Interpretive Summary: We investigated how gene therapy of recombinant adeno-associated virus (rAAV) human alpha-1 antitrypsin (hAAT) affects bone loss in a mouse model with estrogen deficiency. Human alpha-1 antitrypsin is a protein with multiple functions and has anti-inflammatory property. We found that estrogen deficiency is detrimental to bone structure and produced significant bone loss. Both human alpha-1 antitrypsin protein injection at 2 mg/mouse, every 3 days for 8 weeks or human alpha-1 antitrypsin gene therapy with a single injection decreased serum proinflammatory cytokines and increased trabecular bone volume/total volume at 2nd lumbar vertebra. We conclude that human alpha-1 antitrypsin gene therapy decreases inflammation and reduces bone loss due to estrogen deficiency. With human alpha-1 antitrypsin protein or gene therapy being considered safe in humans, our results provide a new way to treat osteoporosis.

Technical 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 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 control. 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-kappaB (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 new alternative for the treatment of osteoporosis.