NFAT and Osterix cooperatively regulate bone formation
NFAT and Osterix cooperatively regulate bone formation
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DOI：
10.1038/nm1270
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发表时间：
2005-08-01
期刊：
影响因子：
82.9
通讯作者：
Takayanagi, H
中科院分区：
文献类型：
--
作者：
Koga, T;Matsui, Y;Takayanagi, H
免疫抑制剂在预防与同种异体器官移植相关的有害免疫反应方面至关重要，但它们通常会对许多生物系统（包括骨骼系统）造成不良影响（1，2）。钙调磷酸酶抑制剂FK 506和环孢菌素A抑制活化T细胞核因子（NFAT）活性并诱导强烈的免疫抑制（3-5）。在NFAT蛋白中，NFATc 1对于骨吸收破骨细胞的分化至关重要（6，7）。在这里，我们显示，尽管FK 506给药阻断破骨细胞分化，但仍诱导骨量减少。这种减少是由骨形成的严重损害引起的，表明NFAT转录因子在成骨细胞的转录程序中也具有重要作用。事实上，在Nfatc 1和Nfatc 2缺陷细胞以及FK 506处理的成骨细胞中，骨形成受到抑制。NFATc 1的过表达刺激Col 1a 1（编码I型胶原）启动子的Osterix（8）依赖性激活，但不刺激Bglap 1（编码骨钙素）启动子的Runx 2依赖性激活（9）。NFAT和Osterix形成结合DNA的复合物，这种相互作用对Osterix的转录活性很重要。因此，NFAT和Osterix协同控制成骨细胞骨形成。这些结果可能为移植后骨质疏松症的治疗提供重要的见解，并为促进骨质减少性疾病的骨再生提供新的策略。
Immunosuppressants are crucial in the prevention of detrimental immune reactions associated with allogenic organ transplantation, but they often cause adverse effects in a number of biological systems, including the skeletal system(1,2). Calcineurin inhibitors FK506 and cyclosporin A inhibit nuclear factor of activated T cells (NFAT) activity and induce strong immunosuppression(3-5). Among NFAT proteins, NFATc1 is crucial for the differentiation of bone-resorbing osteoclasts(6,7). Here we show FK506 administration induces the reduction of bone mass despite a blockade of osteoclast differentiation. This reduction is caused by severe impairment of bone formation, suggesting that NFAT transcription factors also have an important role in the transcriptional program of osteoblasts. In fact, bone formation is inhibited in Nfatc1- and Nfatc2-deficient cells as well as in FK506-treated osteoblasts. Overexpression of NFATc1 stimulates Osterix(8)-dependent activation of the Col1a1 (encoding type I collagen) promoter, but not Runx2-dependent activation of the Bglap1 (encoding osteocalcin) promoter(9). NFAT and Osterix form a complex that binds to DNA, and this interaction is important for the transcriptional activity of Osterix. Thus, NFAT and Osterix cooperatively control osteoblastic bone formation. These results may provide important insight into the management of post-transplantation osteoporosis as well as a new strategy for promoting bone regeneration in osteopenic disease.