Recombinant IGF-1 Induces Sex-Specific Changes in Bone Composition and Remodeling in Adult Mice with Pappa2 Deficiency.

Leticia Rubio,Patricia Rivera,Jesús Argente,Rubén Tovar,Julie A Chowen,Antonio J López-Gambero,Juan Suárez,Fernando Rodríguez De Fonseca,Stella Martín-De-Las-Heras,Julian K Christians,Antonio Vargas

doi:10.3390/ijms22084048

Abstract

Deficiency of pregnancy-associated plasma protein-A2 (PAPP-A2), an IGF-1 availability regulator, causes postnatal growth failure and dysregulation of bone size and density. The present study aimed to determine the effects of recombinant murine IGF-1 (rmIGF-1) on bone composition and remodeling in constitutive Pappa2 knock-out (ko/ko) mice. To address this challenge, X-ray diffraction (XRD), attenuated total reflection-fourier transform infra-red (ATR-FTIR) spectroscopy and gene expression analysis of members of the IGF-1 system and bone resorption/formation were performed. Pappa2ko/ko mice (both sexes) had reduced body and bone length. Male Pappa2ko/ko mice had specific alterations in bone composition (mineral-to-matrix ratio, carbonate substitution and mineral crystallinity), but not in bone remodeling. In contrast, decreases in collagen maturity and increases in Igfbp3, osteopontin (resorption) and osteocalcin (formation) characterized the bone of Pappa2ko/ko females. A single rmIGF-1 administration (0.3 mg/kg) induced short-term changes in bone composition in Pappa2ko/ko mice (both sexes). rmIGF-1 treatment in Pappa2ko/ko females also increased collagen maturity, and Igfbp3, Igfbp5, Col1a1 and osteopontin expression. In summary, acute IGF-1 treatment modifies bone composition and local IGF-1 response to bone remodeling in mice with Pappa2 deficiency. These effects depend on sex and provide important insights into potential IGF-1 therapy for growth failure and bone loss and repair.

Highlights

The growth hormone (GH)/insulin-like growth factor 1 (IGF-1) signaling system constitutes a pleotropic axis required for bone development, mineral deposition and skeletal growth [1,2,3,4,5]
We employed two physical-chemical approaches: (1) X-ray powder diffraction (XRD) and Rietveld refinement for the quantitative analysis of crystallographic parameters, associated with biological hydroxyapatite-(CaOH); and (2) attenuated total reflection-fourier transform infra-red (ATR-FTIR) spectroscopy for the quantification of relevant parameters that reflect the relative content of bone compounds containing phosphates (v1v3PO43−), carbonates (v2CO32−) and amides I, such as mineral-to-matrix ratio, carbonate substitution, mineral crystallinity and collagen maturity in bone
Bone composition was analyzed using physical-chemical approaches to detect changes in bone crystallinity and relevant parameters that reflect the relative content of bone compounds containing phosphates (v1v3PO43−), carbonates (v2CO32−) and amides I, including mineral crystallinity and collagen maturity in bone

Summary

Introduction

The growth hormone (GH)/insulin-like growth factor 1 (IGF-1) signaling system constitutes a pleotropic axis required for bone development, mineral deposition and skeletal growth [1,2,3,4,5]. IGF-1 exerts its effects on skeletal growth and metabolism by interacting with other bone regulators like thyroid and parathyroid hormones and sex steroids, among others [6,7,8]. The rise in circulating levels of GH and IGF-1 during puberty is associated with peak bone acquisition, while their declining levels during aging are associated with bone loss. A reduction of IGF-1 signaling by ablation, inactivation or haploinsufficiency in mouse models causes severe growth retardation in a sex and age-dependent manner [3,10,11,12,13]. Mutations in IGF-1 and IGF-1 receptor result in intrauterine and postnatal growth retardation [14,15]

Objectives

Methods

Conclusion