IGF-1 Receptor Expression on Circulating Osteoblast Progenitor Cells Predicts Tissue-Based Bone Formation Rate and Response to Teriparatide in Premenopausal Women With Idiopathic Osteoporosis

Adi Cohen, Stavroula Kousteni, Brygida Bisikirska, Jayesh G. Shah, J. Sanil Manavalan, Robert R. Recker, Joan M. Lappe, David W. Dempster, Hua Zhou, Donald J. Mcmahon, Mariana Bucovsky, Mafo Kamanda-Kosseh, Julie Stubby, Elizabeth Shane

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

We have previously reported that premenopausal women with idiopathic osteoporosis (IOP) have profound microarchitectural deficiencies and heterogeneous bone remodeling. Those with the lowest bone formation rate have higher baseline serum insulin-like growth factor-1 (IGF-1) levels and less robust response to teriparatide. Because IGF-1 stimulates bone formation and is critical for teriparatide action on osteoblasts, these findings suggest a state of IGF-1 resistance in some IOP women. To further investigate the hypothesis that osteoblast and IGF-1-related mechanisms mediate differential responsiveness to teriparatide in IOP, we studied circulating osteoblast progenitor (COP) cells and their IGF-1 receptor (IGF-1R) expression. In premenopausal women with IOP, peripheral blood mononuclear cells (PBMCs) were obtained at baseline (n=25) and over 24 months of teriparatide treatment (n=11). Flow cytometry was used to identify and quantify COPs (non-hematopoetic lineage cells expressing osteocalcin and RUNX2) and to quantify IGF-1R expression levels. At baseline, both the percent of PBMCs that were COPs (%COP) and COP cell-surface IGF-1R expression correlated directly with several histomorphometric indices of bone formation in tetracycline-labeled transiliac biopsies. In treated subjects, both %COP and IGF-1R expression increased promptly after teriparatide, returning toward baseline by 18 months. Although neither baseline %COP nor increase in %COP after 3 months predicted the bone mineral density (BMD) response to teriparatide, the percent increase in IGF-1R expression on COPs at 3 months correlated directly with the BMD response to teriparatide. Additionally, lower IGF-1R expression after teriparatide was associated with higher body fat, suggesting links between teriparatide resistance, body composition, and the GH/IGF-1 axis. In conclusion, these assays may be useful to characterize bone remodeling noninvasively and may serve to predict early response to teriparatide and possibly other bone formation-stimulating medications. These new tools may also have utility in the mechanistic investigation of teriparatide resistance in premenopausal IOP and perhaps in other populations.

Original languageEnglish (US)
JournalJournal of Bone and Mineral Research
DOIs
StateAccepted/In press - 2017

Fingerprint

Teriparatide
Somatomedin Receptors
Osteoblasts
Osteogenesis
Osteoporosis
Stem Cells
IGF Type 1 Receptor
Somatomedins
Bone Remodeling
Bone Density
Blood Cells
Osteocalcin
Body Composition
Tetracycline
Adipose Tissue
Flow Cytometry

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

IGF-1 Receptor Expression on Circulating Osteoblast Progenitor Cells Predicts Tissue-Based Bone Formation Rate and Response to Teriparatide in Premenopausal Women With Idiopathic Osteoporosis. / Cohen, Adi; Kousteni, Stavroula; Bisikirska, Brygida; Shah, Jayesh G.; Manavalan, J. Sanil; Recker, Robert R.; Lappe, Joan M.; Dempster, David W.; Zhou, Hua; Mcmahon, Donald J.; Bucovsky, Mariana; Kamanda-Kosseh, Mafo; Stubby, Julie; Shane, Elizabeth.

In: Journal of Bone and Mineral Research, 2017.

Research output: Contribution to journalArticle

Cohen, Adi ; Kousteni, Stavroula ; Bisikirska, Brygida ; Shah, Jayesh G. ; Manavalan, J. Sanil ; Recker, Robert R. ; Lappe, Joan M. ; Dempster, David W. ; Zhou, Hua ; Mcmahon, Donald J. ; Bucovsky, Mariana ; Kamanda-Kosseh, Mafo ; Stubby, Julie ; Shane, Elizabeth. / IGF-1 Receptor Expression on Circulating Osteoblast Progenitor Cells Predicts Tissue-Based Bone Formation Rate and Response to Teriparatide in Premenopausal Women With Idiopathic Osteoporosis. In: Journal of Bone and Mineral Research. 2017.
@article{abdbb39e33ee4fe2b78036abd4d498e2,
title = "IGF-1 Receptor Expression on Circulating Osteoblast Progenitor Cells Predicts Tissue-Based Bone Formation Rate and Response to Teriparatide in Premenopausal Women With Idiopathic Osteoporosis",
abstract = "We have previously reported that premenopausal women with idiopathic osteoporosis (IOP) have profound microarchitectural deficiencies and heterogeneous bone remodeling. Those with the lowest bone formation rate have higher baseline serum insulin-like growth factor-1 (IGF-1) levels and less robust response to teriparatide. Because IGF-1 stimulates bone formation and is critical for teriparatide action on osteoblasts, these findings suggest a state of IGF-1 resistance in some IOP women. To further investigate the hypothesis that osteoblast and IGF-1-related mechanisms mediate differential responsiveness to teriparatide in IOP, we studied circulating osteoblast progenitor (COP) cells and their IGF-1 receptor (IGF-1R) expression. In premenopausal women with IOP, peripheral blood mononuclear cells (PBMCs) were obtained at baseline (n=25) and over 24 months of teriparatide treatment (n=11). Flow cytometry was used to identify and quantify COPs (non-hematopoetic lineage cells expressing osteocalcin and RUNX2) and to quantify IGF-1R expression levels. At baseline, both the percent of PBMCs that were COPs ({\%}COP) and COP cell-surface IGF-1R expression correlated directly with several histomorphometric indices of bone formation in tetracycline-labeled transiliac biopsies. In treated subjects, both {\%}COP and IGF-1R expression increased promptly after teriparatide, returning toward baseline by 18 months. Although neither baseline {\%}COP nor increase in {\%}COP after 3 months predicted the bone mineral density (BMD) response to teriparatide, the percent increase in IGF-1R expression on COPs at 3 months correlated directly with the BMD response to teriparatide. Additionally, lower IGF-1R expression after teriparatide was associated with higher body fat, suggesting links between teriparatide resistance, body composition, and the GH/IGF-1 axis. In conclusion, these assays may be useful to characterize bone remodeling noninvasively and may serve to predict early response to teriparatide and possibly other bone formation-stimulating medications. These new tools may also have utility in the mechanistic investigation of teriparatide resistance in premenopausal IOP and perhaps in other populations.",
author = "Adi Cohen and Stavroula Kousteni and Brygida Bisikirska and Shah, {Jayesh G.} and Manavalan, {J. Sanil} and Recker, {Robert R.} and Lappe, {Joan M.} and Dempster, {David W.} and Hua Zhou and Mcmahon, {Donald J.} and Mariana Bucovsky and Mafo Kamanda-Kosseh and Julie Stubby and Elizabeth Shane",
year = "2017",
doi = "10.1002/jbmr.3109",
language = "English (US)",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - IGF-1 Receptor Expression on Circulating Osteoblast Progenitor Cells Predicts Tissue-Based Bone Formation Rate and Response to Teriparatide in Premenopausal Women With Idiopathic Osteoporosis

AU - Cohen, Adi

AU - Kousteni, Stavroula

AU - Bisikirska, Brygida

AU - Shah, Jayesh G.

AU - Manavalan, J. Sanil

AU - Recker, Robert R.

AU - Lappe, Joan M.

AU - Dempster, David W.

AU - Zhou, Hua

AU - Mcmahon, Donald J.

AU - Bucovsky, Mariana

AU - Kamanda-Kosseh, Mafo

AU - Stubby, Julie

AU - Shane, Elizabeth

PY - 2017

Y1 - 2017

N2 - We have previously reported that premenopausal women with idiopathic osteoporosis (IOP) have profound microarchitectural deficiencies and heterogeneous bone remodeling. Those with the lowest bone formation rate have higher baseline serum insulin-like growth factor-1 (IGF-1) levels and less robust response to teriparatide. Because IGF-1 stimulates bone formation and is critical for teriparatide action on osteoblasts, these findings suggest a state of IGF-1 resistance in some IOP women. To further investigate the hypothesis that osteoblast and IGF-1-related mechanisms mediate differential responsiveness to teriparatide in IOP, we studied circulating osteoblast progenitor (COP) cells and their IGF-1 receptor (IGF-1R) expression. In premenopausal women with IOP, peripheral blood mononuclear cells (PBMCs) were obtained at baseline (n=25) and over 24 months of teriparatide treatment (n=11). Flow cytometry was used to identify and quantify COPs (non-hematopoetic lineage cells expressing osteocalcin and RUNX2) and to quantify IGF-1R expression levels. At baseline, both the percent of PBMCs that were COPs (%COP) and COP cell-surface IGF-1R expression correlated directly with several histomorphometric indices of bone formation in tetracycline-labeled transiliac biopsies. In treated subjects, both %COP and IGF-1R expression increased promptly after teriparatide, returning toward baseline by 18 months. Although neither baseline %COP nor increase in %COP after 3 months predicted the bone mineral density (BMD) response to teriparatide, the percent increase in IGF-1R expression on COPs at 3 months correlated directly with the BMD response to teriparatide. Additionally, lower IGF-1R expression after teriparatide was associated with higher body fat, suggesting links between teriparatide resistance, body composition, and the GH/IGF-1 axis. In conclusion, these assays may be useful to characterize bone remodeling noninvasively and may serve to predict early response to teriparatide and possibly other bone formation-stimulating medications. These new tools may also have utility in the mechanistic investigation of teriparatide resistance in premenopausal IOP and perhaps in other populations.

AB - We have previously reported that premenopausal women with idiopathic osteoporosis (IOP) have profound microarchitectural deficiencies and heterogeneous bone remodeling. Those with the lowest bone formation rate have higher baseline serum insulin-like growth factor-1 (IGF-1) levels and less robust response to teriparatide. Because IGF-1 stimulates bone formation and is critical for teriparatide action on osteoblasts, these findings suggest a state of IGF-1 resistance in some IOP women. To further investigate the hypothesis that osteoblast and IGF-1-related mechanisms mediate differential responsiveness to teriparatide in IOP, we studied circulating osteoblast progenitor (COP) cells and their IGF-1 receptor (IGF-1R) expression. In premenopausal women with IOP, peripheral blood mononuclear cells (PBMCs) were obtained at baseline (n=25) and over 24 months of teriparatide treatment (n=11). Flow cytometry was used to identify and quantify COPs (non-hematopoetic lineage cells expressing osteocalcin and RUNX2) and to quantify IGF-1R expression levels. At baseline, both the percent of PBMCs that were COPs (%COP) and COP cell-surface IGF-1R expression correlated directly with several histomorphometric indices of bone formation in tetracycline-labeled transiliac biopsies. In treated subjects, both %COP and IGF-1R expression increased promptly after teriparatide, returning toward baseline by 18 months. Although neither baseline %COP nor increase in %COP after 3 months predicted the bone mineral density (BMD) response to teriparatide, the percent increase in IGF-1R expression on COPs at 3 months correlated directly with the BMD response to teriparatide. Additionally, lower IGF-1R expression after teriparatide was associated with higher body fat, suggesting links between teriparatide resistance, body composition, and the GH/IGF-1 axis. In conclusion, these assays may be useful to characterize bone remodeling noninvasively and may serve to predict early response to teriparatide and possibly other bone formation-stimulating medications. These new tools may also have utility in the mechanistic investigation of teriparatide resistance in premenopausal IOP and perhaps in other populations.

UR - http://www.scopus.com/inward/record.url?scp=85017113919&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85017113919&partnerID=8YFLogxK

U2 - 10.1002/jbmr.3109

DO - 10.1002/jbmr.3109

M3 - Article

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

ER -