Abstract There is growing evidence that IGF-1 and PTH have synergistic actions on bone and that part of the anabolic effects of PTH are mediated by local production of IGF-1. In this study we analyzed the skeletal response to PTH in mouse models with manipulated endocrine or autocrine/paracrine IGF-1. We utilized mice carrying a hepatic IGF-1 transgene (HIT), which results in a 3-fold increase in serum IGF-1 levels and normal tissue IGF-1 expression, and IGF-1 null mice with blunted IGF-1 expression in tissues but 3-fold increases in serum IGF-1 levels (KO-HIT). Evaluation of skeletal growth showed that elevations in serum IGF-1 in mice with igf-1 gene ablation in all tissues except the liver (KO-HIT) resulted in a restoration of skeletal morphology and mechanical properties by adulthood. Intermittent PTH treatment of adult HIT mice resulted in increases in serum osteocalcin levels, femoral total cross-sectional area, cortical bone area and cortical bone thickness, as well as bone mechanical properties. We found that the skeletal response of HIT mice to PTH was significantly higher than that of control mice, suggesting synergy between IGF-1 and PTH on bone. In sharp contrast, although PTH-treated KO-HIT mice demonstrated an anabolic response in cortical and trabecular bone compartments compared to vehicle treated KO-HITs, their response was identical to that of PTH-treated control mice. We conclude that 1) in the presence of elevated serum IGF-1 levels, PTH can exert an anabolic response in bone even in the total absence of tissue IGF-1 and, 2) elevations in serum IGF-1 levels synergize PTH action on bone only if the tissue IGF-1 axis is intact, thus enhancement of PTH anabolic actions is tissue IGF-1-dependent
