Low levels of plasma IGF-1 inhibit intracortical bone remodeling during aging

Abstract

Studies linking insulin-like growth factor-1 (IGF-1) to age-related bone loss in humans have been reported but remain only correlative. In this investigation, we characterized the bone phenotype of aged WT C57BL/6J male mice in comparison to that of C57BL/ 6J mice with reduced serum IGF-1 levels arising from an igfals gene deletion (ALS knockout (ALSKO)). During the aging process, WT mice showed an increase in fat mass and decrease lean mass while ALSKO mice had stable lean and fat mass values. Skeletal analyses of femora from WT mice revealed an expansion of the marrow area and a significant accumulation of intracortical porosity associated with increased intracortical remodeling. In contrast, ALSKO mice showed only small age-related declines in the amount of cortical bone tissue and minimal intracortical porosity, at 2 years of age. Accordingly, mechanical tests of femora from 2-year-old WT mice revealed reduced stiffness and maximal load when compared to bones from ALSKO mice. We show here that lifelong reductions in serum IGF-1 compromise skeletal size in development leading to slender bones; they are also associated with decreased intracortical bone remodeling and preservation of bone strength during aging.

IGF-1 Regulates Vertebral Bone Aging Through Sex-Specific and Time-Dependent Mechanisms

“…Because the rate and extent of age-related bone loss has been shown to be site-specific (65–67) , it may be interesting to examine whether our early-life IGF-1 deficient females exhibit similar protection within their long bones. As mentioned, previous studies have shown both protective and deleterious effects of IGF-1 deficiency on femoral aging (29,30) . These two studies used very different mouse models and the time points in which IGF-1 deficiency began in these two studies was markedly different, which may contribute to the divergence in results.…”

“…For example, early-life knockout of acid-labile subunit (ALS), an important stabilizing protein for IGF-1 in the circulation, has been shown to reduce IGF-1 levels by 60–75% but increase femur cortical thickness in aged male mice (29) . These results suggest that an early and prolonged loss of IGF-1 may be beneficial for long bone aging.…”

Age- and gender-associated changes in the concentrations of serum TGF-1β, DHEA-S and IGF-1 in healthy captive baboons (Papio hamadryas anubis)

“…It has implications in age-related diseases like Alzheimer's and atherosclerosis [10, 15, 40]. Furthermore, low concentrations of serum IGF-1 are associated with reduced bone remodeling and preservation of bone strength during aging [9]. …”

Development, validation and characterization of a novel mouse model of Adynamic Bone Disease (ABD)

“…We suspect that the effect of bisphosphonate-induced reductions in cortical bone energy absorption and toughness was not observed in our ABD mice for several reasons: the dogs in the study by Tang et al [48] were treated for a year while our mice were only treated for 6 weeks; the rats in the study by Smith and Allen [49] were treated with zoledronate, which is 100-fold more potent than pamidronate used in our study; and a slower basal bone turnover rate in cortical bone may not have allowed sufficient time for our adynamic bone condition to be established in the cortical compartment during the 6-week treatment period. Although the murine skeleton continues to grow slowly after puberty and lacks osteonal remodeling of the cortical bone [50]; it still exhibits cortical porosity and increased cortical bone remodeling with advancing age [51,52]. In our current study, the young ABD mice (4 months of age at the onset of treatment) may not have had enough time to accumulate microdamage [53], nor increased secondary mineralization in their cortical bone during the 6-week treatment period to result in a decrease in bone toughness.…”