NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism
NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism
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DOI：
10.1172/jci35711
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发表时间：
2008-11-01
影响因子：
15.9
通讯作者：
Glimcher, Laurie H.
中科院分区：
文献类型：
--
作者：
Aliprantis, Antonios O.;Ueki, Yasuyoshi;Glimcher, Laurie H.
骨质疏松症是由于骨骼重塑的不平衡导致的，这种不平衡有利于骨吸收而不是骨形成。骨基质被破骨细胞降解，破骨细胞响应于细胞因子RANKL而从骨髓前体细胞分化。为了深入了解生长和疾病过程中骨吸收的转录调控，我们产生了活化T细胞c1（Nfatc 1）的转录因子核因子的条件性敲除。Nfatc 1基因的缺失导致小鼠体内和体外的骨硬化症和破骨细胞生成的抑制。转录谱显示NFATc 1作为破骨细胞转录组的主要调节因子，促进骨吸收所需的许多基因的表达。此外，NFATc 1直接抑制破骨细胞祖细胞的骨保护素表达，骨保护素是RANKL的诱饵受体，以前被认为是成骨细胞衍生的骨吸收抑制剂。在SH 3-结构域结合蛋白2（Sb 3bp 2）中携带功能获得性突变的“肥胖症小鼠”发展出骨质疏松症和依赖于促炎细胞因子TNF-α的广泛炎症。有趣的是，Nfatc 1的缺失保护了巨颌症小鼠的全身性骨丢失，但没有抑制炎症。综上所述，我们的研究表明，NFATc 1是生长和成人骨骼重塑所必需的，并表明NFATc 1可能是与炎症状态相关的骨质疏松症的有效治疗靶点。
Osteoporosis results from an imbalance in skeletal remodeling that favors bone resorption over bone formation. Bone matrix is degraded by osteoclasts, which differentiate from myeloid precursors in response to the cytokine RANKL. To gain insight into the transcriptional regulation of bone resorption during growth and disease, we generated a conditional knockout of the transcription factor nuclear factor of activated T cells c1 (Nfatc1). Deletion of Nfatc1 in young mice resulted in osteopetrosis and inhibition of osteoclastogenesis in vivo and in vitro. Transcriptional profiling revealed NFATc1 as a master regulator of the osteoclast transcriptome, promoting the expression of numerous genes needed for bone resorption. In addition, NFATc1 directly repressed osteoclast progenitor expression of osteoprotegerin, a decoy receptor for RANKL previously thought to be an osteoblast-derived inhibitor of bone resorption. "Cherubism mice", which carry a gain-of-function mutation in SH3-domain binding protein 2 (Sb3bp2), develop osteoporosis and widespread inflammation dependent on the proinflammatory cytokine, TNF-alpha. Interestingly, deletion of Nfatc1 protected cherubism mice from systemic bone loss but did not inhibit inflammation. Taken together, our study demonstrates that NFATc1 is required for remodeling of the growing and adult skeleton and suggests that NFATc1 may be an effective therapeutic target for osteoporosis associated with inflammatory states.