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• W2563754059 abstract "Osteoporosis, a serious public health problem affecting millions of Americans, is characterized by reduced bone mass and poor bone microarchitecture which can result in fractures. Although the etiology and pathogenesis of osteoporosis are complex and multifactorial, inflammation is clearly involved in the disease development. Therefore, anti-inflammatory strategy holds great potential for the prevention and treatment of this disease. Alpha 1 antitrypsin (AAT) is a multifunctional protein with anti-inflammatory, proteinase inhibitory and cytoprotective properties. We previously showed that AAT therapy had therapeutic effect in inflammation related disease models including type 1 diabetes, rheumatoid arthritis and stroke. In this study, we tested the effect of AAT on osteoclastogenesis and the therapeutic potential of AAT for preventing bone loss in an ovariectomized (OVX) mouse model. In vitro studies showed that AAT significantly inhibited osteoclast formation in a dose-dependent manner. AAT also inhibited the gene expressions of TNF-alpha and receptor activator of nuclear factor kappa B (RANK) in the early and late stages of osteoclast differentiation. To test the protective effect of AAT on osteoporosis, OVX mice were injected with either clinical grade AAT (2 mg/mouse/3 days), recombinant adeno associated virus vector expressing AAT (rAAV8-CB-AAT, 1×1011 particles/mouse), mesenchymal stem cells (MSCs) infected with lentiviral vector expressing AAT (MSC-Lenti-AAT) or PBS (100 microliter/mouse/3 days). We used age-matched and sham operated animals as a normal control. Eight weeks after the treatment, all animals were sacrificed and subjected to μCT scanning for the evaluation of vertebra bone microarchitecture including trabecular BV (bone volume), TV (Total volume), BV/TV (bone volume density), Tb.N (trabecular number), Tb.Th (trabecular thickness), Conn.Dn (connectivity density), Tb.Sp (trabecular separation) and SMI (structure model index). Results from this study showed that AAT therapies (protein, gene and stem cell-based) significantly increased TV/BV and Tb.N, and decreased SMI compared to PBS injection in OVX mice. Gene therapy also increased Conn.Dn and Tb.Th compared to PBS injection in OVX mice. These results demonstrate that AAT protein, gene and MSCs based therapies mitigate ovariectomy-induced bone loss in mouse model. Since AAT protein and gene therapies have been proven to be safe in humans, our results not only demonstrate novel functions of AAT, but also imply a new strategy for the treatment of osteoporosis." @default.
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• W2563754059 date "2015-05-01" @default.
• W2563754059 modified "2023-09-24" @default.
• W2563754059 title "508. Alpha-1 Antitrypsin (AAT) Gene and Stem Cell Based Therapies for the Treatment of Osteoporosis" @default.
• W2563754059 doi "https://doi.org/10.1016/s1525-0016(16)34117-x" @default.
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