The parathyroid hormone-regulated transcriptome in osteocytes: parallel actions with 1,25-dihydroxyvitamin D3 to oppose gene expression changes during differentiation and to promote mature cell function.
The parathyroid hormone-regulated transcriptome in osteocytes: parallel actions with 1,25-dihydroxyvitamin D3 to oppose gene expression changes during differentiation and to promote mature cell function.
复制标题
DOI：
10.1016/j.bone.2014.11.010
复制
发表时间：
2015-03
期刊：
影响因子：
4.1
通讯作者：
Pike, J. Wesley
中科院分区：
文献类型：
--
作者：
St John, Hillary C.;Meyer, Mark B.;Benkusky, Nancy A.;Carlson, Alex H.;Prideaux, Mathew;Bonewald, Lynda F.;Pike, J. Wesley
虽然骨细胞定位于骨的矿化基质，但它能够对促钙激素1，25(OH)2D3和PTH等全身因子产生反应。在目前的研究中，我们在一个骨细胞模型中检测了甲状旁腺素的转录反应，发现这种激素调节着广泛的一组基因。令人惊讶的是，甲状旁腺素独特地调节了两组基因，一组表达与成骨细胞向骨细胞的转变有关，另一组仅在成熟的骨细胞中表达。有趣的是，甲状旁腺素的作用主要是在前一组中反对分化相关基因的表达，而在后一组中增强骨细胞特异性基因的表达。将PTH的转录效应与之前用1，25(OH)2D3获得的转录效应进行比较，发现了一个高度重叠的基因子集。虽然1，25(OH)2D3增强了骨细胞特异性基因的表达，与甲状旁腺素相似，但这两种激素之间的重叠更有限。其他实验证实了PKA激活的磷酸化CREB(PCREB)信号通路，揭示了许多与分化相关的PTH调节基因是PKA介导的信号通路的明显靶点，而与骨细胞特异性PTH靶点相关的pCREB结合的减少似乎涉及替代的PTH激活途径。位于重要激素调控基因群附近的pCREB结合活性定位于基因的控制区，这一点因表观遗传增强子签名的存在而得到加强，组蛋白H3和H4的独特修饰就是例证。这些研究表明，PTH和1，25(OH)2D3在限制成骨细胞向其前体分化的同时，在调节成熟骨细胞功能方面可能起着重要的或可能是协同的作用。我们的结果为转录因子相关机制提供了新的见解，PTH和1，25(OH)2D3通过这些机制调节对成骨细胞/骨细胞谱系至关重要的过多基因。
Although localized to the mineralized matrix of bone, osteocytes are able to respond to systemic factors such as the calciotropic hormones 1,25(OH)2D3 and PTH. In the present studies, we examine the transcriptomic response to PTH in an osteocyte cell model and found that this hormone regulated an extensive panel of genes. Surprisingly, PTH uniquely modulated two cohorts of genes, one that was expressed and associated with the osteoblast to osteocyte transition and the other a cohort that was expressed only in the mature osteocyte. Interestingly, PTH’s effects were largely to oppose the expression of differentiation-related genes in the former cohort, while potentiating the expression of osteocyte-specific genes in the latter cohort. A comparison of the transcriptional effects of PTH with those obtained previously with 1,25(OH)2D3 revealed a subset of genes that was strongly overlapping. While 1,25(OH)2D3 potentiated the expression of osteocyte-specific genes similar to that seen with PTH, the overlap between the two hormones was more limited. Additional experiments identified the PKA-activated phospho-CREB (pCREB) cistrome, revealing that while many of the differentiation-related PTH regulated genes were apparent targets of a PKA-mediated signaling pathway, a reduction in pCREB binding at sites associated with osteocyte-specific PTH targets appeared to involve alternative PTH activation pathways. That pCREB binding activities positioned near important hormone-regulated gene cohorts were localized to control regions of genes was reinforced by the presence of epigenetic enhancer signatures exemplified by unique modifications at histones H3 and H4. These studies suggest that both PTH and 1,25(OH)2D3 may play important and perhaps cooperative roles in limiting osteocyte differentiation from its precursors while simultaneously exerting distinct roles in regulating mature osteocyte function. Our results provide new insight into transcription factor-associated mechanisms through which PTH and 1,25(OH)2D3 regulate a plethora of genes important to the osteoblast/osteocyte lineage.
登录
查看更多内容
影响因子：
5.3
作者：
Kim, Sungtae;Yamazaki, Miwa;Pike, J. Wesley
通讯作者：
Pike, J. Wesley
DOI：
10.1073/pnas.89.6.2489
发表时间：
1992-03-15
影响因子：
11.1
作者：
HATADA, EN;NIETERS, A;SCHEIDEREIT, C
通讯作者：
SCHEIDEREIT, C
DOI：
10.1073/pnas.88.5.1815
发表时间：
1991-03-01
影响因子：
11.1
作者：
CHRISTY, BA;SANDERS, LK;NATHANS, D
通讯作者：
NATHANS, D
影响因子：
4.1
作者：
Bellido T;Saini V;Pajevic PD
通讯作者：
Pajevic PD
影响因子：
4.8
作者：
Meyer, Mark B.;Benkusky, Nancy A.;Pike, J. Wesley
通讯作者：
Pike, J. Wesley