INSULIN-LIKE GROWTH FACTOR-I INCREASES TRABECULAR BONE-FORMATION AND OSTEOBLASTIC CELL-PROLIFERATION IN UNLOADED RATS

We previously found that the inhibition of bone formation and trabecul ar osteopenia induced by skeletal unloading in rats are associated wit h reduced proliferation of osteoblastic cells lining the bone surface. In this study, we examined the effects of insulin-like growth factor- I (IGF-I) on trabecular bone formation, bone mineral density, and prol iferation of marrow-derived osteoblastic cells in unloaded rats. Skele tal unloading of hind limbs was induced by tail suspension, and recomb inant human IGF-I was administered at two different doses (1.3 or 2.0 mg/kg day) in control and unloaded rats by continuous infusion for 14 days. Treatment with IGF-I had no effect on plasma glucose levels, bod y weight, or longitudinal bone growth. The double calcein-labeled surf ace, bone formation rate, and trabecular number measured at the tibial metaphysis were lower in unloaded rats compared to controls and were increased after IGF-I treatment. The increased number of bone-forming sites induced by IGF-I was associated with to the beneficial effects o f IGF-I on bone formation and bone mineral content in unloaded rats, I GF-I had no effect in control rats. To evaluate the cellular mechanism s of action of IGF-I, marrow stromal cells were derived from the tibia of unloaded and control rats and studied in vitro. Unloading was asso ciated with a decreased proliferation of alkaline phosphatase-positive (ALP+) marrow stromal cells. Treatment with IGF-I increased the numbe r of ALP+ cells in unloaded rats, but not in control rats. IGF-I treat ment increased ALP activity and osteocalcin production by marrow-deriv ed cells in suspended and control rats, suggesting that IGF-I stimulat ed the proliferation and differentiation of osteoblast precursor cells . These results indicate that IGF-I infusion enhanced the recruitment of osteoblastic cells, increased trabecular bone formation, and partia lly prevented trabecular bone loss in unloaded rats, which supports th e hypothesis that IGF-I may mediate in part the effects of loading on bone formation.