632. Alpha-1 Antitrypsin Gene Therapy Prevented Bone Loss in an 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, inflammation is clearly involved in bone loss at menopause. Therefore, anti-inflammatory strategies hold great potential for the prevention of postmenopausal osteoporosis. Human alpha-1 antitrypsin (hAAT) is a multifunctional protein that has anti-inflammatory and cytoprotective properties. In this study, we investigated the protective effect of hAAT against bone loss. In vitro studies showed that hAAT significantly inhibited osteoclast formation and function in a dose-dependent manner. Treatment of hAAT inhibited M-CSF (macrophage colony-stimulating factor) induced cell surface RANK receptor expression by downregulating cFos mRNA expression. To test the protective effect of hAAT in an osteoporosis mouse model, we treated ovariectomized (OVX) mice with rAAV8-CB-hAAT, or mesenchymal stem cells (MSCs) infected with a lentiviral vector expressing hAAT (MSC-Lenti-hAAT) or phosphate buffer saline (PBS). Sham operated age-matched animals were used as controls. Eight weeks after the treatment, animals were sacrificed and subjected to µCT scanning for the evaluation of vertebral bone microarchitecture. Gene and stem cell-based hAAT therapies significantly increased bone volume density, trabecular number and decreased structure model index compared to PBS injection in OVX mice. Gene therapy also increased connectivity, density and trabecular thickness compared to PBS injection in OVX mice. We also observed that both therapies inhibited RANK gene expression in bone, which is consistent with the results of our in vitro study. These results demonstrate that hAAT gene and MSCs based therapies mitigate ovariectomy-induced bone loss in a mouse model, possibly through inhibition of osteoclast formation by reducing RANK gene expression. Considering the safety profile of the hAAT and rAAV vector in human, our results provide a new insight for the treatment of osteoporosis.