Does the GH/IGF-1 axis contribute to skeletal sexual dimorphism? Evidence from mouse studies

Abstract

The contribution of the gonadotropic axis to skeletal sexual dimorphism (SSD) was clarified in recent years. Studies with animal models of estrogen receptor (ER) or androgen receptor (AR) null mice, as well as mice with bone cell-specific ablation of ER or AR, revealed that both hormones play major roles in skeletal acquisition, and that estrogen regulates skeletal accrual in both sexes. The growth hormone (GH) and its downstream effector, the insulin-like growth factor-1 (IGF-1) are also major determinants of peak bone mass during puberty and young adulthood, and play important roles in maintaining bone integrity during aging. A few studies in both humans and animal models suggest that in addition to the differences in sex steroid actions on bone, sex-specific effects of GH and IGF-1 play essential roles in SSD. However, the contributions of the somatotropic (GH/IGF-1) axis to SSD are controversial and data is difficult to interpret. GH/IGF-1 are pleotropic hormones that act in an endocrine and autocrine/paracrine fashion on multiple tissues, affecting body composition as well as metabolism. Thus, understanding the contribution of the somatotropic axis to SSD requires the use of mouse models that will differentiate between these two modes of action. Elucidation of the relative contribution of GH/IGF-1 axis to SSD is significant because GH is approved for the treatment of normal children with short stature and children with congenital growth disorders. Thus, if the GH/IGF-1 axis determines SSD, treatment with GH may be tailored according to sex. In the following review, we give an overview of the roles of sex steroids in determining SSD and how they may interact with the GH/IGF-1 axis in bone. We summarize several mouse models with impaired somatotropic axis and speculate on the possible contribution of that axis to SSD.

Keywords: Bone; Growth hormone receptor (GHR); Insulin-like growth factor-1 (IGF-1); Micro-computed tomography; Osteocyte; Parathyroid hormone (PTH); Skeletal sexual dimorphism (SSD).

Figure 1. Manipulations of endocrine IGF-1 do not contribute to SSD

A. Serum IGF-1 levels of mice at 16 weeks of age, determined by RIA in control (n=12 per sex), liver IGF-1 deficient, LID mice (n=12 per sex), hepatic IGF-1 transgenic, HIT mice (n=9 per sex), and IGF-1 null mice expressing the HIT, IGF-1KO-HIT mice (n=9 per sex). B. Body weight of mice at 16 weeks of age; Controls, LID, HIT, and IGF-1KO-HIT mice (n>15 per sex in each genotype). C–D. Micro-CT data of femurs from 16 weeks old mice on FVB/N genetic background, acquired using the eXplore Locus SP Pre-Clinical Specimen MicroComputed Tomography system (GE Healthcare, London, Ontario) at 8.7micron voxel resolution; Controls (female n=15, male n=9), LID (female n=8, male n=9), HIT (female n=14, male n=11), and IGF-1KO-HIT (female n=13, male n=10) mice. Data presented as mean±SEM for serum IGF-1 levels and body weight, while for skeletal traits by mCT we report mean±SD. Statistical difference between sexes was determined by t-test, where significance accepted at p<0.05.

Figure 2. Reductions/elevations in serum IGF-1 or inactivation of the GH/IGF-1 axis in osteocytes do not contribute to SSD

A., E. Serum IGF-1 levels of mice at 16 weeks of age, determined by RIA in control, hepatic IGF-1 transgenic, HIT mice, GHRKO, GHRKO mice expressing the HIT, GHRKO-HIT mice, GHR floxed mice, DMP-1-GHRKO mice, IGF-1R floxed mice, DMP-1-IGF-1RKO mice, IGF-1 floxed mice, and DMP-1-IGF-1KO mice (n>8 per sex in each genotype). B., F. Body weight of mice at 16 weeks of age; Controls, hepatic IGF-1 transgenic, HIT mice, GHRKO, GHRKO mice expressing the HIT, GHRKO-HIT mice, GHR floxed mice, DMP-1-GHRKO mice, IGF-1R floxed mice, DMP-1-IGF-1RKO mice, IGF-1 floxed mice, and DMP-1-IGF-1KO mice (n>15 per sex in each genotype). C-H. Micro-CT data of femurs from 16 weeks old mice on C57Bl/6 genetic background, acquired using the SkyScan 1172 (Microphotonics) system at 9.7micron voxel resolution. Controls (female n=14, male n=14), hepatic IGF-1 transgenic, HIT mice (female n=12, male n=12), GHRKO (female n=12, male n=12), GHRKO mice expressing the HIT, GHRKO-HIT mice (female n=8, male n=15), GHR floxed mice (female n=10, male n=13), DMP-1-GHRKO mice (female n=13, male n=16), IGF-1R floxed mice (female n=7, male n=10), DMP-1-IGF-1RKO mice (female n=7, male n=7), IGF-1 floxed mice (female n=11, male n=10), and DMP-1-IGF-1KO mice (female n=12, male n=11). Data presented as mean±SEM for serum IGF-1 levels and body weight, while for skeletal traits by mCT we report mean±SD. Statistical difference between sexes was determined by t-test, where significance accepted at p<0.05.

Figure 3. Integrations of signals from the gonadotropic and somatotropic axes regulate radial bone growth in males and females

Pubertal growth associates with increases in serum sex steroids as well as increases in the levels of GH and IGF-1. During that period both males and females increase linear and radial bone growth and accumulate bone mineral that reaches its peak when growth is ceased. A. During puberty males increase periosteal bone apposition and endosteal bone resorption leading to overall increase in bone diameter and a more robust skeleton. During that period both the somatotropic and the gonadotropic axes activate periosteal bone apposition in males. B. In contrast, during pubertal growth in females, periosteal bone apposition is slower than in males, while endosteal bone resorption decreases leading to preservation of the amount of cortical bone. During that period the somatotropic axis enhances endosteal bone apposition in females, while the gonadotropic axis (estrogen) inhibits periosteal bone apposition.