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

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.

Pregnancy-Associated Plasma Protein (PAPP)-A2 in Physiology and Disease

“…In contrast, when specific Pappa2 deletion was triggered at 20 weeks of age by tamoxifen-induced Cre -mediated recombination (resulting in whole body Pappa2 deletion), no difference between genotypes in body weight was detected [ 69 ]. Recently, using the second mouse model for constitutive Pappa2 deletion, our research group also reported a sex-independent reduction in body length of Pappa2 KO mice at 8 months of age [ 70 ]. A constitutive knock-in mouse model employing the human p.Ala1033Val mutation in PAPP-A2 was generated using the CRISPR/Cas9 system [ 67 ].…”

“…In contrast, increased circulating levels of Igfbp3 and Igfals were found in Pappa2 KI mice at 4 months of age [ 67 ]. We found a genotype effect on Igfbp3 mRNA levels in the bone of 8-month-old Pappa2 KO mice with female Pappa2 KO mice having higher Igfbp3 mRNA levels in the tibia than female WT littermates [ 70 ].…”

“…We found sex-specific reductions in proportional lengths and weights of the femur and tibia (relative to bone weight and body weight) of Pappa2 KO mice at 8 months of age [ 70 ]. The role of the GH/IGF1 axis in sex differences in bone growth is still under question and some data are difficult to interpret [ 78 ].…”

“…In this regard, we recently described sex-specific changes at 8 months of age in femur composition of the same Pappa2 KO mouse model. By using X-ray powder diffraction (XRD) and attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), male Pappa2 KO femur was found to have alterations in mineral crystallinity and relative content of bone compounds containing phosphates and carbonates, while female Pappa2 KO femur had a reduction in collagen maturity only [ 70 ]. This study suggested that alteration of femur mineral composition associated with Pappa2 deficiency may denote bone fragility and immaturity.…”

Recovery of the maternal skeleton after lactation is impaired by advanced maternal age but not by reduced IGF availability in the mouse

“…Loss-of-function mutations in the human PAPPA2 gene cause short stature and reduced bone density [ 34 , 35 ], and these conditions are improved by treatment with IGF-I [ 36 – 38 ]. In mice, deletion of Pappa2 reduces the linear growth of bones [ 39 – 41 ] and affects bone composition and microarchitecture [ 42 , 43 ].…”