Sex-specific regulation of body size and bone slenderness by the acid labile subunit

Abstract

Insulin-like growth factor 1 (IGF-1) is a crucial mediator of body size and bone mass during growth and development. In serum, IGF-1 is stabilized by several IGF-1-binding proteins (IGFBPs) and the acid labile subunit (ALS). Previous research using ALS knockout (ALSKO) mice indicated a growth retardation phenotype, and clinical reports of humans have indicated short stature and low bone mineral density (BMD) in patients with ALS deficiency. To determine the temporal and sex-specific effects of ALS deficiency on body size and skeletal development during growth, we characterized control and ALSKO mice from 4 to 16 weeks of age. We found that female ALSKO mice had an earlier-onset reduction in body size (4 weeks) but that both female and male ALSKO mice were consistently smaller than control mice. Interestingly, skeletal analyses at multiple ages showed increased slenderness of ALSKO femurs that was more severe in females than in males. Both male and female ALSKO mice appeared to compensate for their more slender bones through increased bone formation on their endosteal surfaces during growth, but ALSKO females had increased endosteal bone formation compared with ALSKO males. This study revealed age- and sex-specific dependencies of body size and bone size on the ALS. These findings may explain the heterogeneity in growth and BMD measurements reported in human ALS-deficient patients.