Analysis of regulatory mechanisms of bone metabolism utilizing TAK1-conditional knockout mice

破骨细胞是一种特殊分化的多核巨噬细胞，可吸收骨基质。它们的功能对正常的骨代谢至关重要；它们的功能障碍导致骨质疏松症，其功能亢进可导致骨质疏松症或类风湿性关节炎中观察到的骨破坏。因此，了解它们的分化机制和功能是很重要的。我们之前报道了一种转录因子NFATc1在体外破骨细胞形成过程中被强烈诱导。在本研究期间，我们发现(1)体内破骨细胞生成确实需要NFATc1，(2)免疫受体之一OSCAR是NFATc1的靶标，同时它参与NFATc1的激活，从而构成了一个新的正反馈系统。我们还发现了一种新的T辅助细胞亚群，现在称为Th17细胞，它可以促进破骨细胞的发生。Th1和Th2细胞强烈地抑制破骨细胞的发生，使人们怀疑以骨破坏为特征之一的类风湿关节炎（RA）是Th1疾病。由Th17细胞产生的IL-17和Th17细胞扩增所需的IL-23可能是治疗RA的有希望的靶点。最后，我们发现钙/钙调素依赖性激酶（CaMKs）参与破骨细胞的形成。其中，我们通过敲低实验证明了CaMKIV是特别重要的。事实上，CaMKIV KO小鼠由于破骨细胞生成减少而表现出骨量增加（骨质疏松）。CaMKIV的分子靶点似乎是转录因子CREB，这是NFATc1诱导所必需的，因为在体外CaMK抑制剂存在的情况下，强制表达组成型活性CREB可以挽救破骨细胞的分化。在小鼠模型骨破坏（LPS注射模型）和骨质疏松症（卵巢切除模型）中，CaMK抑制剂抑制了这两种疾病。因此，CaMK-CREB通路也是骨病治疗的一个有希望的靶点。少

Osteoclasts are specially differentiated multinucleated macrophages that resorb bone matrix. Their function is essential for normal bone metabolism ; their dysfunction causes osteopetrosis and their hyper-function can lead to osteoporosis or bone destruction observed in rheumatoid arthritis. Thus, it is important to understand the mechanisms of their differentiation and functions.We previously reported that a transcription factor NFATc1 is strongly induced in the course of osteoclastogenesis in vitro. During the period covered by this grant, we showed that (1) NFATc1 is indeed required for osteoclastogenesis in vivo and that (2) one of immunoreceptors, OSCAR, is a target of NFATc1 whilst it is involved in activation of NFATc1, thus constituting a novel positive feedback system. We also discovered a novel T helper cell subset, now called Th17 cells, which can enhance osteoclastogenesis. Th1 and Th2 cells strongly suppressed osteoclastogenesis, casting doubt on the notion that rheumatoid … More arthritis (RA), in which bone destruction is one of the characteristics, is a Th1 disease. IL-17 that is produced by Th17 cells and IL-23 that is required for Th17 cell expansion could be promising targets for the treatment of RA. Finally, we found that calcium/calmodulin-dependent kinases (CaMKs) are involved in osteoclastogenesis. Among them, we showed through knockdown experiments that CaMKIV is especially important. In fact, CaMKIV KO mice showed increased bone mass (osteopetrosis) because of reduced osteoclastogenesis. The molecular target of CaMKIV seems to be a transcription factor CREB, which is required for NFATc1 induction, because forced expression of constitutive active CREB can rescue osteoclast differentiation in the presence of CaMK inhibitor in vitro. In mouse models bone destruction (an LPS injection model) and osteoporosis (an ovariectomy model), the CaMK inhibitor ameriolated both of the diseases. Thus, CaMK-CREB pathway is also a promising target in the treatment of bone diseases. Less