Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Egypt.
Mol Med. 2017 May;23:57-69. doi: 10.2119/molmed.2016.00170. Epub 2017 Mar 21.
Osteoporosis is a global public health problem affecting more than 200 million people worldwide. We previously showed that treatment with alpha-1 antitrypsin (AAT), a multifunctional protein with anti-inflammatory properties, mitigated bone loss in an ovariectomized mouse model. However, the underlying mechanisms of the protective effect of AAT on bone tissue are largely unknown. In this study, we investigated the effect of AAT on osteoclast formation and function . Our results showed that AAT dose-dependently inhibited the formation of RANKL (receptor activator of nuclear factor κB ligand) induced osteoclasts derived from mouse bone marrow macrophages/monocyte (BMM) lineage cells and the murine macrophage cell line, RAW 264.7 cells. In order to elucidate the possible mechanisms underlying this inhibition, we tested the effect of AAT on the gene expression of cell surface molecules, transcription factors, and cytokines associated with osteoclast formation. We showed that AAT inhibited M-CSF (macrophage colony-stimulating factor) induced cell surface RANK expression in osteoclast precursor cells. In addition, AAT inhibited RANKL-induced TNF-α production, cell surface CD9 expression, and dendritic cell-specific transmembrane protein () gene expression. Importantly, AAT treatment significantly inhibited osteoclast-associated mineral resorption. Together, these results uncovered new mechanisms for the protective effects of AAT and strongly support the notion that AAT has therapeutic potential for the treatment of osteoporosis.
骨质疏松症是一个全球性的公共健康问题，影响着全球超过 2 亿人。我们之前的研究表明，具有抗炎特性的多功能蛋白α-1 抗胰蛋白酶（AAT）的治疗可以减轻去卵巢小鼠模型中的骨质流失。然而，AAT 对骨组织的保护作用的潜在机制在很大程度上尚不清楚。在这项研究中，我们研究了 AAT 对破骨细胞形成和功能的影响。我们的结果表明，AAT 呈剂量依赖性地抑制了核因子κB 配体受体激活剂（receptor activator of nuclear factor κB ligand，RANKL）诱导的源自小鼠骨髓巨噬细胞/单核细胞（bone marrow macrophage/monocyte，BMM）系细胞和鼠巨噬细胞系 RAW 264.7 细胞的破骨细胞的形成。为了阐明这种抑制作用的可能机制，我们测试了 AAT 对与破骨细胞形成相关的细胞表面分子、转录因子和细胞因子的基因表达的影响。我们表明，AAT 抑制了破骨细胞前体细胞中巨噬细胞集落刺激因子（macrophage colony-stimulating factor，M-CSF）诱导的细胞表面 RANK 表达。此外，AAT 抑制了 RANKL 诱导的 TNF-α 产生、细胞表面 CD9 表达和树突状细胞特异性跨膜蛋白（dendritic cell-specific transmembrane protein ，DC-STAMP）基因表达。重要的是，AAT 治疗显著抑制了破骨细胞相关的矿物质吸收。综上所述，这些结果揭示了 AAT 保护作用的新机制，并强烈支持 AAT 具有治疗骨质疏松症的治疗潜力的观点。
