| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
