PDF(Pubmed)
Abstract：
Teriparatide (PTH (1-34)), PTHrP (1-36), and abaloparatide (ABL) have been used for the treatment of osteoporosis, but their efficacy long term is significantly limited. The 3 peptides exert time- and dose-dependent differential responses in osteoblasts, leading us to hypothesize they may also differentially modulate the osteoblast transcriptome. Treatment of mouse calvarial osteoblasts with 1 nM of the peptides for 4 hours results in RNA sequencing data with PTH (1-34) regulating 367 genes, including 194 unique genes; PTHrP (1-36) regulating 117 genes, including 15 unique genes; and ABL regulating 179 genes, including 20 unique genes. There were 83 genes shared among all 3 peptides. Gene ontology analyses showed similarities in Wnt signaling, cAMP-mediated signaling, ossification, but differences in morphogenesis of a branching structure in biological processes; receptor ligand activity, transcription factor activity, and cytokine receptor/binding activity in molecular functions. The peptides increased Vdr, Cited1, and Pde10a messenger RNAs (mRNAs) in a pattern similar to Rankl, that is, PTH (1-34) greater than ABL greater than PTHrP (1-36). mRNA abundance of other genes, including Wnt4, Wnt7, Wnt11, Sfrp4, Dkk1, Kcnk10, Hdac4, Epn3, Tcf7, Crem, Fzd5, Ppp2r2a, and Dvl3, showed that some genes were regulated similarly by all 3 peptides; others were not. Finally, small interfering RNA knockdowns of SIK1/2/3 and CRTC1/2/3 in PTH (1-34)-treated cells revealed that Vdr and Wnt4 genes are regulated by salt-inducible kinases (SIKs) and CREB-regulated transcriptional coactivators (CRTCs), while others are not. Although many studies have examined PTH signaling in the osteoblast/osteocyte, ours is the first to compare the global effects of these peptides on the osteoblast transcriptome or to analyze the roles of the SIKs and CRTCs.
摘要：
特立帕肽（PTH（1-34）），PTHrP(1-36),和阿巴罗帕拉肽（ABL）已用于治疗骨质疏松症，但其长期疗效明显有限。3肽在成骨细胞中发挥时间和剂量依赖性的差异反应，引导我们假设它们也可能差异调节成骨细胞转录组。用1nM的肽处理小鼠颅骨成骨细胞4小时，结果是用PTH（1-34）调节367个基因的RNA测序数据，包括194个独特基因；PTHrP（1-36）调节117个基因，包括15个独特基因；ABL调节179个基因，包括20个独特的基因.在所有3个肽中共有83个基因。基因本体论分析显示Wnt信号的相似性，cAMP介导的信号，骨化,但生物过程中分支结构的形态发生差异;受体配体活性，转录因子活性，和分子功能中的细胞因子受体/结合活性。肽增加了Vdr，Cited1和Pde10a信使RNA（mRNA）的模式类似于Rankl，也就是说,PTH(1-34)大于ABL大于PTHrP(1-36)。其他基因的mRNA丰度，包括Wnt4,Wnt7,Wnt11,Sfrp4,Dkk1,Kcnk10,Hdac4,Epn3,Tcf7,Crem,Fzd5,Ppp2r2a,和Dvl3，表明一些基因受到所有3种肽的类似调控；其他则不然。最后,在PTH（1-34）处理的细胞中SIK1/2/3和CRTC1/2/3的小干扰RNA敲除表明，Vdr和Wnt4基因受盐诱导激酶（SIK）和CREB调节的转录共激活因子（CRTC）调节，而其他人不是。尽管许多研究已经检查了成骨细胞/骨细胞中的PTH信号,我们是第一个比较这些肽对成骨细胞转录组的整体影响或分析SIK和CRTC的作用。
