Differential effects of PTH (1-34), PTHrP (1-36) and abaloparatide on the murine osteoblast transcriptome
This study shows that Teriparatide (PTH(1-34)) regulates a significant number of genes in osteoblasts compared to its analogs, but the findings are based on mouse models and may not directly apply to humans.
Where it sits
this study against the rest of the teriparatide (pth 1-34) corpusSummary and findings
This study examined the differential effects of Teriparatide (PTH(1-34)), PTHrP(1-36), and abaloparatide on the osteoblast transcriptome in mouse calvarial osteoblasts. The peptides were administered at a dose of 1 nM for 4 hours, resulting in the regulation of various genes. The findings suggest distinct regulatory patterns among the peptides, but no therapeutic claims are made.
Abstract
Teriparatide (PTH(1-34)) and its analogs, PTHrP(1-36) and abaloparatide (ABL) have been used for the treatment of osteoporosis, but their efficacy over long-term use is significantly limited. The 3 peptides exert time- and dose-dependent differential responses in osteoblasts, leading us to hypothesize that they may also differentially modulate the osteoblast transcriptome. We show that treatment of mouse calvarial osteoblasts with 1 nM of the 3 peptides for 4 h results in RNA-Seq 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 differences in Wnt signaling, cAMP-mediated signaling, bone mineralization, morphogenesis of a branching structure in biological processes; receptor ligand activity, transcription factor activity, cytokine receptor/binding activity and many other actions in molecular functions. The 3 peptides increased Vdr, Cited1 and Pde10a mRNAs in a pattern similar to Rankl , i.e., PTH(1-34) > ABL > PTHrP(1-36). mRNA abundance of other genes based on gene/pathway analyses, including Wnt4, Wnt7, Wnt11, Sfrp4, Dkk1, Kcnk10, Hdac4, Epha3, Tcf7, Crem, Fzd5, Pp2r2a , and Dvl3 showed that some genes were regulated similarly by all 3 peptides; others were not. Finally, siRNA knockdowns of SIK1/2/3 and CRTC1/2/3 in PTH(1-34)-treated cells revealed that Vdr and Wnt4 genes are regulated by SIKs and CRTCs, while others are not. Although many studies have examined PTH signaling in the osteoblast/osteocyte, ours is the first to examine the global effects of these peptides on the osteoblast transcriptome. Further delineation of which signaling events are attributable to PTH(1-34), PTHrP(1-36) or ABL exclusively and which are shared among all 3 will help improve our understanding of the effects these peptides have on the osteoblast and lead to the refinement of PTH-derived treatments for osteoporosis.