The ternary IGF complex influences postnatal bone acquisition and the skeletal response to intermittent parathyroid hormone

Shoshana Yakar, Mary L. Bouxsein, Ernesto Canalis, Hui (Herb) Sun, Vaida Glatt, Caren Gundberg, Pinchas Cohen, David Hwang, Yves Boisclair, Derek LeRoith, Clifford J. Rosen

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

The role of circulating IGF-I in skeletal acquisition and the anabolic response to PTH is not well understood. We generated IGF-I-deficient mice by gene deletions of IGF ternary complex components including: (1) liver-specific deletion of the IGF-I gene (LID), (2) global deletion of the acid-labile (ALS) gene (ALSKO), and (3) both liver IGF-I and ALS inactivated genes (LA). Twelve-week-old male control (CTL), LID, ALSKO, and LA mice were treated with vehicle (VEH) or human PTH(1-34) for 4 weeks. VEH-treated IGF-I-deficient mice (i.e. LID, ALSKO and LA mice) exhibited reduced cortical cross-sectional area (P=0.001) compared with CTL mice; in contrast, femoral trabecular bone volume fractions (BV/TV) of the IGF-I-deficient mice were consistently greater than CTL (P<0.01). ALSKO mice exhibited markedly reduced osteoblast number and surface (P<0.05), as well as mineral apposition rate compared with other IGF-I-deficient and CTL mice. Adherent bone marrow stromal cells, cultured in β-glycerol phosphate and ascorbic acid, showed no strain differences in secreted IGF-I. In response to PTH, there were both compartment- and strain-specific effects. Cortical bone area was increased by PTH in CTL and ALSKO mice, but not in LID or LA mice. In the trabecular compartment, PTH increased femoral and vertebral BV/TV in LID, but not in ALSKO or LA mice. In conclusion, we demonstrated that the presentation of IGF-I as a circulating complex is essential for skeletal remodeling and the anabolic response to PTH. We postulate that the ternary complex itself, rather than IGF-I alone, influences bone acquisition in a compartment-specific manner (i.e. cortical vs trabecular bone).

Original languageEnglish (US)
Pages (from-to)289-299
Number of pages11
JournalJournal of Endocrinology
Volume189
Issue number2
DOIs
StatePublished - May 2006
Externally publishedYes

Fingerprint

Parathyroid Hormone
Insulin-Like Growth Factor I
Bone and Bones
Thigh
Genes
Liver
Gene Deletion
Osteoblasts
Mesenchymal Stromal Cells
Glycerol
Ascorbic Acid
Minerals
Phosphates
Acids

ASJC Scopus subject areas

  • Endocrinology

Cite this

The ternary IGF complex influences postnatal bone acquisition and the skeletal response to intermittent parathyroid hormone. / Yakar, Shoshana; Bouxsein, Mary L.; Canalis, Ernesto; Sun, Hui (Herb); Glatt, Vaida; Gundberg, Caren; Cohen, Pinchas; Hwang, David; Boisclair, Yves; LeRoith, Derek; Rosen, Clifford J.

In: Journal of Endocrinology, Vol. 189, No. 2, 05.2006, p. 289-299.

Research output: Contribution to journalArticle

Yakar, S, Bouxsein, ML, Canalis, E, Sun, HH, Glatt, V, Gundberg, C, Cohen, P, Hwang, D, Boisclair, Y, LeRoith, D & Rosen, CJ 2006, 'The ternary IGF complex influences postnatal bone acquisition and the skeletal response to intermittent parathyroid hormone', Journal of Endocrinology, vol. 189, no. 2, pp. 289-299. https://doi.org/10.1677/joe.1.06657
Yakar, Shoshana ; Bouxsein, Mary L. ; Canalis, Ernesto ; Sun, Hui (Herb) ; Glatt, Vaida ; Gundberg, Caren ; Cohen, Pinchas ; Hwang, David ; Boisclair, Yves ; LeRoith, Derek ; Rosen, Clifford J. / The ternary IGF complex influences postnatal bone acquisition and the skeletal response to intermittent parathyroid hormone. In: Journal of Endocrinology. 2006 ; Vol. 189, No. 2. pp. 289-299.
@article{9fb3e62f1e754e1aa499d048e587d708,
title = "The ternary IGF complex influences postnatal bone acquisition and the skeletal response to intermittent parathyroid hormone",
abstract = "The role of circulating IGF-I in skeletal acquisition and the anabolic response to PTH is not well understood. We generated IGF-I-deficient mice by gene deletions of IGF ternary complex components including: (1) liver-specific deletion of the IGF-I gene (LID), (2) global deletion of the acid-labile (ALS) gene (ALSKO), and (3) both liver IGF-I and ALS inactivated genes (LA). Twelve-week-old male control (CTL), LID, ALSKO, and LA mice were treated with vehicle (VEH) or human PTH(1-34) for 4 weeks. VEH-treated IGF-I-deficient mice (i.e. LID, ALSKO and LA mice) exhibited reduced cortical cross-sectional area (P=0.001) compared with CTL mice; in contrast, femoral trabecular bone volume fractions (BV/TV) of the IGF-I-deficient mice were consistently greater than CTL (P<0.01). ALSKO mice exhibited markedly reduced osteoblast number and surface (P<0.05), as well as mineral apposition rate compared with other IGF-I-deficient and CTL mice. Adherent bone marrow stromal cells, cultured in β-glycerol phosphate and ascorbic acid, showed no strain differences in secreted IGF-I. In response to PTH, there were both compartment- and strain-specific effects. Cortical bone area was increased by PTH in CTL and ALSKO mice, but not in LID or LA mice. In the trabecular compartment, PTH increased femoral and vertebral BV/TV in LID, but not in ALSKO or LA mice. In conclusion, we demonstrated that the presentation of IGF-I as a circulating complex is essential for skeletal remodeling and the anabolic response to PTH. We postulate that the ternary complex itself, rather than IGF-I alone, influences bone acquisition in a compartment-specific manner (i.e. cortical vs trabecular bone).",
author = "Shoshana Yakar and Bouxsein, {Mary L.} and Ernesto Canalis and Sun, {Hui (Herb)} and Vaida Glatt and Caren Gundberg and Pinchas Cohen and David Hwang and Yves Boisclair and Derek LeRoith and Rosen, {Clifford J.}",
year = "2006",
month = "5",
doi = "10.1677/joe.1.06657",
language = "English (US)",
volume = "189",
pages = "289--299",
journal = "Journal of Endocrinology",
issn = "0022-0795",
publisher = "Society for Endocrinology",
number = "2",

}

TY - JOUR

T1 - The ternary IGF complex influences postnatal bone acquisition and the skeletal response to intermittent parathyroid hormone

AU - Yakar, Shoshana

AU - Bouxsein, Mary L.

AU - Canalis, Ernesto

AU - Sun, Hui (Herb)

AU - Glatt, Vaida

AU - Gundberg, Caren

AU - Cohen, Pinchas

AU - Hwang, David

AU - Boisclair, Yves

AU - LeRoith, Derek

AU - Rosen, Clifford J.

PY - 2006/5

Y1 - 2006/5

N2 - The role of circulating IGF-I in skeletal acquisition and the anabolic response to PTH is not well understood. We generated IGF-I-deficient mice by gene deletions of IGF ternary complex components including: (1) liver-specific deletion of the IGF-I gene (LID), (2) global deletion of the acid-labile (ALS) gene (ALSKO), and (3) both liver IGF-I and ALS inactivated genes (LA). Twelve-week-old male control (CTL), LID, ALSKO, and LA mice were treated with vehicle (VEH) or human PTH(1-34) for 4 weeks. VEH-treated IGF-I-deficient mice (i.e. LID, ALSKO and LA mice) exhibited reduced cortical cross-sectional area (P=0.001) compared with CTL mice; in contrast, femoral trabecular bone volume fractions (BV/TV) of the IGF-I-deficient mice were consistently greater than CTL (P<0.01). ALSKO mice exhibited markedly reduced osteoblast number and surface (P<0.05), as well as mineral apposition rate compared with other IGF-I-deficient and CTL mice. Adherent bone marrow stromal cells, cultured in β-glycerol phosphate and ascorbic acid, showed no strain differences in secreted IGF-I. In response to PTH, there were both compartment- and strain-specific effects. Cortical bone area was increased by PTH in CTL and ALSKO mice, but not in LID or LA mice. In the trabecular compartment, PTH increased femoral and vertebral BV/TV in LID, but not in ALSKO or LA mice. In conclusion, we demonstrated that the presentation of IGF-I as a circulating complex is essential for skeletal remodeling and the anabolic response to PTH. We postulate that the ternary complex itself, rather than IGF-I alone, influences bone acquisition in a compartment-specific manner (i.e. cortical vs trabecular bone).

AB - The role of circulating IGF-I in skeletal acquisition and the anabolic response to PTH is not well understood. We generated IGF-I-deficient mice by gene deletions of IGF ternary complex components including: (1) liver-specific deletion of the IGF-I gene (LID), (2) global deletion of the acid-labile (ALS) gene (ALSKO), and (3) both liver IGF-I and ALS inactivated genes (LA). Twelve-week-old male control (CTL), LID, ALSKO, and LA mice were treated with vehicle (VEH) or human PTH(1-34) for 4 weeks. VEH-treated IGF-I-deficient mice (i.e. LID, ALSKO and LA mice) exhibited reduced cortical cross-sectional area (P=0.001) compared with CTL mice; in contrast, femoral trabecular bone volume fractions (BV/TV) of the IGF-I-deficient mice were consistently greater than CTL (P<0.01). ALSKO mice exhibited markedly reduced osteoblast number and surface (P<0.05), as well as mineral apposition rate compared with other IGF-I-deficient and CTL mice. Adherent bone marrow stromal cells, cultured in β-glycerol phosphate and ascorbic acid, showed no strain differences in secreted IGF-I. In response to PTH, there were both compartment- and strain-specific effects. Cortical bone area was increased by PTH in CTL and ALSKO mice, but not in LID or LA mice. In the trabecular compartment, PTH increased femoral and vertebral BV/TV in LID, but not in ALSKO or LA mice. In conclusion, we demonstrated that the presentation of IGF-I as a circulating complex is essential for skeletal remodeling and the anabolic response to PTH. We postulate that the ternary complex itself, rather than IGF-I alone, influences bone acquisition in a compartment-specific manner (i.e. cortical vs trabecular bone).

UR - http://www.scopus.com/inward/record.url?scp=33646802630&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33646802630&partnerID=8YFLogxK

U2 - 10.1677/joe.1.06657

DO - 10.1677/joe.1.06657

M3 - Article

VL - 189

SP - 289

EP - 299

JO - Journal of Endocrinology

JF - Journal of Endocrinology

SN - 0022-0795

IS - 2

ER -