C/ebpα controls osteoclast terminal differentiation, activation, function, and postnatal bone homeostasis through direct regulation of Nfatc1.
C/ebpα controls osteoclast terminal differentiation, activation, function, and postnatal bone homeostasis through direct regulation of Nfatc1.
复制标题
DOI：
10.1002/path.5001
复制
发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Li YP
中科院分区：
文献类型：
--
作者：
Chen W;Zhu G;Tang J;Zhou HD;Li YP
尽管转录因子控制破骨细胞末端分化、激活和功能的机制尚不清楚，但破骨细胞谱系承诺和分化已被广泛研究。CCAAT/增强子结合蛋白α (C/ebpα)已被报道为破骨细胞谱系承诺的关键调节因子，但在生理或病理条件下，C/ebpα在破骨细胞末端分化、激活、功能和骨稳态中的作用尚未被研究，因为新生的C/ebpα缺失小鼠在出生后数小时内死亡。此外，C/ebpα在破骨细胞终末分化、活化和功能中的作用在很大程度上是未知的。在此，我们通过Ctsk-Cre小鼠建立并分析了破骨细胞特异性C/ebpα条件敲除（CKO）小鼠模型，发现C/ebpα缺陷小鼠由于破骨细胞末端分化、激活和功能受损而表现出严重的骨质疏松表型，包括破骨细胞数量轻度减少、破骨细胞极化、肌动蛋白形成和骨吸收受损，这证明了C/ebpα在细胞功能和末端分化中的新功能。有趣的是，C/ebpα缺乏不影响骨形成或单核细胞/巨噬细胞的发育。我们的研究结果进一步表明，C/ebpα缺乏抑制破骨细胞功能基因（如编码Cathepsin K （Ctsk）、Atp6i (Tcirg1)）和破骨细胞调节基因（如编码C - Fos （Fos）、活化t细胞核因子1 (Nfatc1)）的表达，而对Pu.1 （Spi1）的表达没有影响。启动子活性图谱和ChIP分析确定了Nfatc1启动子区域的关键顺式调控元件（critical cis-regulatory element， CCRE），并表明CCRE与C/ebpα直接相关，从而增强了启动子的活性。破骨细胞中缺乏C/ebpα可完全阻断卵巢切除术引起的骨质流失，表明C/ebpα是治疗溶骨疾病的一个有希望的新靶点。
Osteoclast lineage commitment and differentiation have been studied extensively, although the mechanism by which transcription factor(s) control osteoclast terminal differentiation, activation and function remains unclear. CCAAT/enhancer-binding protein α (C/ebpα) has been reported to be a key regulator of osteoclast cell lineage commitment, yet C/ebpα’s roles in osteoclast terminal differentiation, activation and function and bone homeostasis, under physiological or pathological conditions, have not been studied because newborn C/ebpα null mice die within several hours after birth. Furthermore, the function of C/ebpα in osteoclast terminal differentiation, activation and function are largely unknown. Herein, we generated and analyzed an osteoclast-specific C/ebpα conditional knockout (CKO) mouse model via Ctsk-Cre mice and found that C/ebpα-deficient mice exhibited a severe osteopetrosis phenotype due to impaired osteoclast terminal differentiation, activation and function, including mildly reduced osteoclast number, impaired osteoclast polarization, actin formation, and bone resorption, which demonstrated the novel function of C/ebpα in cell function and terminal differentiation. Interestingly, C/ebpα deficiency did not affect bone formation or monocyte/macrophage development. Our results further demonstrated that C/ebpα deficiency suppressed the expression of osteoclast functional genes, e.g. encoding Cathepsin K (Ctsk), Atp6i (Tcirg1) and osteoclast regulator genes, e.g. encoding c-fos (Fos), and nuclear factor of activated T-cells 1 (Nfatc1), while having no effect on Pu.1 (Spi1) expression. Promoter activity mapping and ChIP assay defined the critical cis-regulatory element (CCRE) in the promoter region of Nfatc1, and also showed that the CCREs were directly associated with C/ebpα, which enhanced the promoter’s activity. The deficiency of C/ebpα in osteoclasts completely blocked ovariectomy-induced bone loss, indicating C/ebpα is a promising new target for the treatment of osteolytic diseases.
登录
查看更多内容
DOI：
10.1073/pnas.0711961105
发表时间：
2008-04-22
影响因子：
11.1
作者：
Feng, Ru;Desbordes, Sabrina C.;Graf, Thomas
通讯作者：
Graf, Thomas
DOI：
10.1152/ajpgi.00041.2010
发表时间：
2011-04-01
影响因子：
4.5
作者：
Allaire, Joannie M.;Darsigny, Mathieu;Perreault, Nathalie
通讯作者：
Perreault, Nathalie
DOI：
10.1073/pnas.1211383110
发表时间：
2013-04-30
影响因子：
11.1
作者：
Chen, Wei;Zhu, Guochun;Li, Yi-Ping
通讯作者：
Li, Yi-Ping
影响因子：
2.1
作者：
Friedman AD
通讯作者：
Friedman AD
影响因子：
2.3
作者：
Friedman, Alan D.
通讯作者：
Friedman, Alan D.