Ezura Yoichi, Lin Xin, Hatta Arina, Izu Yayoi, Noda Masaki
Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 5-45 1-Chome, Yushima, Bunkyo-Ku, Tokyo, 113-8510, Japan.
Calcif Tissue Int. 2016 Aug;99(2):199-208. doi: 10.1007/s00223-016-0139-1. Epub 2016 Apr 16.
Heterotopic ossification (HO) in various tissues evokes clinical problems. Inflammatory responses of the stromal progenitor cells may be involved in its etiology. Previous report indicated that pro-inflammatory cytokines including IL-1β enhanced the in vitro calcification of human mesenchymal stem cells (MSCs), by suppressing the expression of ectonucleotide pyrophosphatase/phosphodiesterase-1 gene (ENPP1). However, possible contribution of other related factors had not been investigated. Here, we investigated the expression of regulators of extracellular pyrophosphate and nucleosides including Enpp1, Nt5e, Ank, Enptds, and Ent1, examining various connective tissue stromal progenitor cells, including bone marrow stromal cells and synovium derived cells from mouse, or bone marrow MSCs from human. Consistent with previous studies, we observed characteristic suppression of the osteoblastic marker genes by IL-1β during the osteogenic culture for 20 days. In addition, we observed a reduced expression of the important transporter genes, Ank and Ent1, whereas the alteration in Enpp1 and Nt5e levels was not always consistent among the cell types. Our results suggest that IL-1β suppresses not only the osteoblastic but also the negative regulators of soft-tissue calcification, including Ank and Ent1 in stromal progenitor cells, which may contribute to the mechanisms of HO in various disorders.
各种组织中的异位骨化（HO）会引发临床问题。基质祖细胞的炎症反应可能与其病因有关。先前的报告表明，包括白细胞介素-1β（IL-1β）在内的促炎细胞因子通过抑制胞外核苷酸焦磷酸酶/磷酸二酯酶-1基因（ENPP1）的表达，增强了人间充质干细胞（MSC）的体外钙化。然而，其他相关因素的可能作用尚未得到研究。在此，我们研究了包括Enpp1、Nt5e、Ank、Enptds和Ent1在内的细胞外焦磷酸和核苷调节因子的表达，检测了各种结缔组织基质祖细胞，包括小鼠的骨髓基质细胞和滑膜来源细胞，或人的骨髓间充质干细胞。与先前的研究一致，我们在成骨培养20天期间观察到IL-1β对成骨细胞标记基因的特征性抑制作用。此外，我们观察到重要转运蛋白基因Ank和Ent1的表达降低，而Enpp1和Nt5e水平的变化在不同细胞类型中并不总是一致的。我们的结果表明，IL-1β不仅抑制成骨细胞，还抑制基质祖细胞中包括Ank和Ent1在内的软组织钙化负调节因子，这可能有助于解释各种疾病中HO的发病机制。
