Differential Effects of PTH (1-34), PTHrP (1-36), and Abaloparatide on the Murine Osteoblast Transcriptome

Michael J. Mosca, Zhiming He, Florante R. Ricarte, Carole Le Henaff, Nicola C. Partridge

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numberbvad156
JournalJournal of the Endocrine Society
Volume8
Issue number1
DOIs
StatePublished - Jan 1 2024

Keywords

  • RNA-Seq
  • abaloparatide
  • osteoblast
  • osteoporosis
  • parathyroid hormone (PTH)
  • signal transduction

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism

Fingerprint

Dive into the research topics of 'Differential Effects of PTH (1-34), PTHrP (1-36), and Abaloparatide on the Murine Osteoblast Transcriptome'. Together they form a unique fingerprint.

Cite this