Alpha-1 Antitrypsin Gene Therapy Ameliorates Bone Loss in Ovariectomy-Induced Osteoporosis Mouse Model
Alpha-1 Antitrypsin Gene Therapy Ameliorates Bone Loss in Ovariectomy-Induced Osteoporosis Mouse Model
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DOI：
10.1089/hum.2016.029
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发表时间：
2016-09-01
影响因子：
4.2
通讯作者：
Song, Sihong
中科院分区：
文献类型：
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作者：
Akbar, Mohammad Ahsanul;Cao, Jay J.;Song, Sihong
骨质疏松症是一种主要的医疗负担，主要影响绝经后妇女，其特征是骨强度受损和脆性骨折风险增加。尽管这种疾病的发病机制很复杂，但促炎细胞因子产生的升高显然与绝经期骨质流失有关。因此，抗炎策略对于预防绝经后骨质疏松症具有巨大潜力。在这项研究中，我们研究了重组腺相关病毒（rAAV）介导的人α-1抗胰蛋白酶（hAAT）（一种具有抗炎特性的多功能蛋白）的基因治疗对卵巢切除诱导的骨质疏松小鼠模型骨质流失的影响。成年卵巢切除 (OVX) 小鼠腹腔 (i.p.) 注射 hAAT（蛋白质疗法）、rAAV8-CB-hAAT（基因疗法）或磷酸盐缓冲盐水 (PBS)。使用年龄匹配的和假手术的动物作为对照。治疗八周后，处死动物并评估骨相关生物标志物和椎骨结构。结果显示，hAAT 基因治疗显着降低血清 IL-6 水平和骨中 NF-κ B 受体激活剂 (RANK) 基因表达。重要的是，与注射 PBS 的 OVX 小鼠相比，hAAT 基因治疗增加了骨体积/总体积并降低了结构模型指数 (SMI)。这些结果表明，rAAV 载体的 hAAT 基因治疗可能通过抑制促炎细胞因子 IL-6 和 RANK 基因表达来有效减轻骨质流失。考虑到 hAAT 和 rAAV 载体在人类中的安全性，我们的结果为骨质疏松症的治疗提供了一种新的替代方案。
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-kappa B (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.