Skeletal unloading induces biphasic changes in insulin-like growth factor-I mRNA levels and osteoblast activity

To determine the local mechanisms involved in the effects of skeletal unloa ding on bone formation, we studied the temporal pattern of mRNA levels for insulin-like growth factor-I (IGF-I), IGF-I receptor type I (IGF-LR), and t ransforming growth factor beta receptor type II (TGF-beta RII) in relation to osteoblast phenotypic markers and osteoblast activity in hindlimb suspen ded rats. Skeletal unloading decreased bone volume and the mineralizing and osteoblastic surfaces at 4, 7, and 14 days in the tibial metaphysis, where as the mineral appositional rate returned to normal at 14 days of suspensio n. RT-PCR analysis showed that skeletal unloading decreased type 1 collagen (Col 1) and osteocalcin (OC) mRNA levels in metaphyseal bone at days 4 and 7, and the levels returned to normal at 14 days of suspension. Unloading a lso decreased mRNA levels for IGF-I, IGF-IR, and TGF-beta RII at 4-7 days i n the metaphyseal bone. However, IGF-I and IGF-IR levels rose above normal at 14 days of suspension. The biphasic changes in IGF-I mRNA levels were st rongly correlated with Col 1 and OC mRNA levels. The associated biphasic pa ttern of IGF-I/IGF-IR expression, osteoblast markers, and osteoblast activi ty strongly suggests an important role for IGF-I signaling in the local eff ect of skeletal unloading on metaphyseal bone formation, (C) 1999 Academic Press.