Serum IGF-1 Determines Skeletal Strength by Regulating Subperiosteal Expansion and Trait Interactions

Abstract

Strong correlations between serum IGF-1 levels and fracture risk indicate that IGF-1 plays a critical role in regulating bone strength. However, the mechanism by which serum IGF-1 regulates bone structure and fracture resistance remains obscure and cannot be determined using conventional approaches. Previous analysis of adult liver-specific IGF-1-deficient (LID) mice, which exhibit 75% reductions in serum IGF-1 levels, showed reductions in periosteal circumference, femoral cross-sectional area, cortical thickness, and total volumetric BMD. Understanding the developmental sequences and the resultant anatomical changes that led to this adult phenotype is the key for understanding the complex relationship between serum IGF-1 levels and fracture risk. Here, we identified a unique developmental pattern of morphological and compositional traits that contribute to bone strength. We show that reduced bone strength associated with low levels of IGF-1 in serum (LID mice) result in impaired subperiosteal expansion combined with impaired endosteal apposition and lack of compensatory changes in mineralization throughout growth and aging. We show that serum IGF-1 affects cellular activity differently depending on the cortical surface. Last, we show that chronic reductions in serum IGF-1 indirectly affect bone strength through its effect on the marrow myeloid progenitor cell population. We conclude that serum IGF-1 not only regulates bone size, shape, and composition during ontogeny, but it plays a more fundamental role-that of regulating an individual's ability to adapt its bone structure to mechanical loads during growth and development.

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

“…Genetic models in mice indicate that endogenous IGF1 increases bone formation and bone mass, which is more significant at the cortical than at the trabecular bone level (103,104). Consistently, reduction in serum IGF1 levels results in decreased subperiosteal expansion and bone strength (105). In vivo treatment with IGF1 stimulates bone formation (106).…”

Autocrine and Paracrine Actions of IGF-I Signaling in Skeletal Development

“…Similarly, ablation of IGF-IR in mature osteoblasts prevents the anabolic effects of intermittent PTH in OCN IGF-IR -/-mice (59). Interestingly, ablating IGF-I in the liver does not affect PTH-induced anabolism in bone (85).…”

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

“…These changes were concurrent with a significant increase in the amount of intracortical porosity at 104 weeks of age. It should be noted that some increase in Tt.Ar with age is expected since periosteal bone formation does continue at low levels throughout adulthood Price et al 2005;Yakar et al 2009a) and male mice are likely to add greater amounts of bone periosteally than females, if they follow their human counterparts (Szulc et al 2006). However, in this study, the increases in Tt.Ar are sizeable and statistically significant from 80 to 104 weeks.…”