Abstract
Deficiencies in either growth hormone (GH) or insulin-like growth factor 1 (IGF-1) are associated with reductions in bone size during growth in humans and animal models. Liver-specific IGF-1-deficient (LID) mice, which have 75% reductions in serum IGF-1, were created previously to separate the effects of endocrine (serum) IGF-1 from autocrine/paracrine IGF-1. However, LID mice also have two- to threefold increases in GH, and this may contribute to the observed pubertal skeletal phenotype. To clarify the role of GH in skeletal development under conditions of significantly reduced serum IGF-1 levels (but normal tissue IGF-1 levels), we studied the skeletal response of male LID and control mice to GH inhibition by pegvisomant from 4 to 8 weeks of age. Treatment of LID mice with pegvisomant resulted in significant reductions in body weight, femur length (Le), and femur total area (Tt.Ar), as well as further reductions in serum IGF-1 levels by 8 weeks of age, compared with the mean values of vehicle-treated LID mice. Reductions in both Tt.Ar and Le were proportional after treatment with pegvisomant. On the other hand, the relative amount of cortical tissue formed (RCA) in LID mice treated with pegvisomant was significantly less than that in both vehicle-treated LID and control mice, indicating that antagonizing GH action, either directly (through GH receptor signaling inhibition) or indirectly (through further reductions in serum/tissue IGF-1 levels), results in disproportionate reductions in the amount of cortical bone formed. This resulted in bones with significantly reduced mechanical properties (femoral whole-bone stiffness and work to failure were markedly decreased), suggesting that compensatory increases of GH in states of IGF-1 deficiency (LID mice) act to protect against a severe inhibition of bone modeling during growth, which otherwise would result in bones that are too weak for normal and/or extreme loading conditions. © 2011 American Society for Bone and Mineral Research.
Highlights
Hormonal action through the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis is an important regulator of bone formation during growth
acidlabile subunit (Als) gene expression in liver-specific IGF-1 deficient (LID) mice was reduced significantly (Fig. 1B). These data are in accordance with previously reported reductions in Igf1 mRNA levels after acute treatment of mice with pegvisomant.[17]. As further confirmation of pharmacologic inhibition, we found that treatment of control mice with pegvisomant resulted in significant reductions in serum IGF-1 levels by 8 weeks of age
Our data indicate a role for GH in establishing pubertal skeletal and body size that is independent of hepatic IGF-1 production
Summary
Hormonal action through the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis is an important regulator of bone formation during growth. Animal models have shown that gene ablation of IGF-1 results in reduced bone size and decreased bone mineral density (BMD).(1–3) In order to separate the effects of circulating (endocrine) IGF-1 from tissue (autocrine/paracrine) IGF-1, we previously created a liver-specific IGF-1 deficient (LID) mouse model that has 75% reductions in serum IGF-1 levels. The possibility exists that GH may regulate skeletal development independent of hepatic IGF-1 (serum) via its binding to the growth hormone receptor (GHR) in bone. Growth hormone receptor knockout (GHRKO) mice have decreased femoral length, as well as decreased BMD, resulting from reduced cortical bone area.[5] in human acromegaly, excessive GH secretion has been linked to increased BMD[6] and is associated with a decrease risk of fracture.[7] The proper regulation of GH action has implications for growth and for aging and fracture risk. GH-deficient patients were found to have up to threefold increases in fracture frequency compared with controls.[8,9] In addition, there is
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