<scp>PTHR1</scp>
            in Bone

Hénaff, Carole Le; Partridge, Nicola C.

doi:10.1002/9781119564782.ch20

Cited by 2 publications

(2 citation statements)

References 213 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PTH, PTHrP, and ABL all bind the same G protein-coupled receptor, parathyroid hormone receptor type 1 (PTHR1) [25]. One study found that PTH (1-34), PTHrP (1-36), and ABL act through two PTHR1 conformations named R O and R G .…”

Section: Introductionmentioning

confidence: 99%

Differential effects of PTH (1-34), PTHrP (1-36) and abaloparatide on the murine osteoblast transcriptome

Mosca

Ricarte

et al. 2023

Preprint

View full text Add to dashboard Cite

Osteoporosis is a prevalent disease with substantial morbidity/mortality among the aging population. Due to gaps in knowledge, current therapeutics are limited in their ability to prevent degeneration of bone while also stimulating formation of new bone. Teriparatide (PTH (1-34)) and its analogs PTHrP (1-36) and abaloparatide (ABL), have been tested and/or utilized for treatment of osteoporosis but have significant limitations in efficacy over long-term use. Research from our laboratory has shown PTH (1-34), PTHrP (1-36), and ABL exert time and dose-dependent differential responses in the osteoblast, leading us to hypothesize they may also differentially modulate the osteoblast transcriptome. In this study we show that treatment of mouse calvarial osteoblasts with 1 nM of these peptides for 4 h results in differing effects on the osteoblast transcriptome by performing gene enrichment analysis of RNA-Seq data. Genes were selected with a Log2 fold change >1 and a false discovery rate <0.05. These data were analyzed and compiled into heat maps and smear/volcano plots for each peptide. RNA-Sequencing revealed that PTH (1-34) regulated 367 genes, 194 were unique; PTHrP (1-36) regulated 117 genes, 15 were unique; ABL regulated 179 genes, 20 were unique. There were 74 genes shared only among PTH(1-34) and ABL; 16 genes were shared only among PTH (1-34) and PTHrP; and 83 genes were shared among all three peptides. Gene ontology analyses show biological processes are similar between the three peptides but have some pathway-specific differences. Further analysis of the data illuminated that the three peptides increased expression of Vitamin D receptor (Vdr), Phosphodiesterase 10a (Pde10a), Cbp/p300-interacting transactivator 1 (Cited1), Wnt family member 11 (Wnt11), and Secreted frizzled related protein 4 (Sfrp4) mRNAs similarly to Rankl expression, i.e., in a differential expression pattern. These findings were confirmed via qRT-PCR of additional cultured samples of mouse calvarial osteoblasts, treated with 1 nM of PTH (1-34), PTHrP (1-36), or ABL for 4 h prior to harvest. Additionally, we analyzed mRNA abundance of several genes of interest, including Wnt4, Wnt7, Dkk1, Kcnk10, Hdac4, Epha3, Tcf7, Fzd5, Pp2r2a, and Dvl3 based on genes and pathways chosen from ontology analyses to be significantly regulated by each peptide. Our findings highlight the complexity of the genetic and functional events triggered by PTH (1-34) and its analogs. Many studies have examined PTH signaling in the osteoblast/osteocyte; ours is the first to examine global effects of these three peptides on the osteoblast transcriptome. Further delineation of which signaling events are attributable to PTH (1-34), PTHrP (1-36), and ABL exclusively and which are shared among all three will further our understanding of the effects these peptides have on the osteoblast and lead to refinement of PTH-derived treatments for osteoporosis.

show abstract

Section: Introductionmentioning

confidence: 99%

Differential effects of PTH (1-34), PTHrP (1-36) and abaloparatide on the murine osteoblast transcriptome

Mosca

Ricarte

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…PTH, PTHrP, and ABL all bind the same G protein–coupled receptor, PTH receptor type 1 (PTHR1, gene name PTH1R ) [ 7 ]. One study found that PTH (1-34), PTHrP (1-36), and ABL act through 2 PTHR1 conformations named R O and RG.…”

mentioning

confidence: 99%

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

Mosca,

He,

Ricarte

et al. 2023

Journal of the Endocrine Society

View full text Add to dashboard Cite

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.

show abstract

PTHR1 in Bone

Cited by 2 publications

References 213 publications

Differential effects of PTH (1-34), PTHrP (1-36) and abaloparatide on the murine osteoblast transcriptome

Differential effects of PTH (1-34), PTHrP (1-36) and abaloparatide on the murine osteoblast transcriptome

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

Contact Info

Product

Resources

About