OSTEOBLASTS MEDIATE INSULIN-LIKE GROWTH-FACTOR-I AND GROWTH-FACTOR-IISTIMULATION OF OSTEOCLAST FORMATION AND FUNCTION

Insulin-like growth factor-I (IGF-I) and IGF-II have powerful, well de fined effects on osteoblastic cells, stimulating their proliferation a nd inducing collagen synthesis, but the role of IGF-I and -II in modul ating osteoclast differentiation and activity remains unclear. We firs t examined the bone-resorptive effects of IGF-I and IGF-II by assessin g Ca-45(2+) release from neonatal mouse calvarial bones. Both IGFs dos e dependently stimulated bone resorption, with an EC(50) of 8 x 10(-9) M for IGF-I and 2 x 10(-8) M for IGF-II. We then tested the effects o f the IGFs on bone resorption by rat isolated osteoclasts cultured on ivory slices. Neither IGF-I nor IGF-II stimulated isolated osteoclast activity. However, in the presence of either primary mouse osteoblasts or human osteosarcoma MG 63 cells, both IGFs enhanced osteoclast reso rptive activity, with an EC(50) of 5 x 10(-10) M for IGF-I and 10(-9) M for IGF-II. Stimulation was not mediated by BALB/c/3T3 cells, a nono steoblastic cell line. The effects of the IGFs were blocked by alpha I R-3, an antibody to the type I IGF receptor, but not by beta-galactosi dase, a lysosomal enzyme that competes with IGF-II for the type II IGF receptor. We then examined the effects of the IGFs on the formation o f osteoclast-like multinucleate cells (MNCs) in mouse bone marrow cult ures. IGF-I and -II dose dependently increased the number of tartrate- resistant acid phosphatase (TRAP)-positive MNCs, although their effect s were less than that of 1,25-dihydroxyvitamin D-3 (a hormone that ind uces osteoclast differentiation). No TRAP-positive MNCs appeared in th e absence of these hormones. Like authentic osteoclasts, the TRAP-posi tive MNCs formed in response to IGF-I and -II bound [I-125]salmon calc itonin. When mouse bone marrow cells were cultured on ivory slices in the presence of either IGF-I or IGF-II for 10 days, numerous resorptio n lacunae were formed. beta-Galactosidase had no effect on IGF-mediate d osteoclast formation. These results are strong evidence that both IG F-I and IGF-II stimulate bone resorption in vitro by enhancing osteocl ast formation and function. Our data also suggest that the IGFs act th rough the intermediary of osteoblastic cells to stimulate osteoclast a ctivity and that the type I, but not the type II, IGF receptor is invo lved in their responses. We propose that the local production of IGF-I and IGF-II may modulate both osteoblast-osteoclast interactions and o steoclast formation and play an important role in bone remodeling.