Skeletal unloading induces resistance to insulin-like growth factor I on bone formation

Skeletal unloading results in an inhibition of bone formation associated with a decrease in osteoblast number, impaired mineralization of bone, and altered proliferation and differentiation of osteoprogenitor cells. Although such changes are likely to be mediated by multiple factors, resistance to the growth-promoting action of insulin-like growth factor I (IGF-I) has been hypothesized to play an important role. To determine whether skeletal unloading induces resistance to IGF-I on bone formation, we examined the response of unloaded (hindlimb elevation) and normally loaded tibia and femur to IGF-I administration. To eliminate the variable of endogenous growth hormone production and secretion during exogenous IGF-I administration, we used growth hormone-deficient dwarf rats (dw-4). The rats were given IGF-I (2.5 mg/kg/day) or vehicle during 7 and 14 days of unloading or normal loading. This significantly increased the serum level of IGF-I in both the normally loaded and unloaded rats. Unloading did not affect the serum level of IGF-I in the vehicle-treated rats. IGF-I markedly increased periosteal bone formation at the tibiofibular junction of normally loaded rats. Unloading decreased bone formation in the vehicle-treated rats, and blocked the ability of IGF-I to increase bone formation. On the other hand, IGF-I increased periosteal bone formation at the midpoint of the humerus (normally loaded in this model) in both hindlimb-elevated and normally loaded rats. IGF-I significantly increased osteogenic colony number, total ALP activity, and total mineralization in bone marrow osteoprogenitor (BMOp) cells of normally loaded rats. Unloading reduced these parameters in the vehicle-treated rats, and blocked the stimulation by IGF-I. Furthermore, IGF-I administration (10 ng/ml) in vitro significantly increased cell proliferation of the BMOp cells isolated from normally loaded bone, but not that of cells from unloaded bone. These results indicate that skeletal unloading induces resistance to IGF-I on bone formation.