Insulin-like growth factor-I inhibits parathyroid hormone-stimulated and enhances prostaglandin E2-stimulated adenosine 3',5'-monophosphate production by human osteoblast-like SaOS-2 cells.

Insulin-like growth factor-1 (IGF-I), an endocrine and autocrine/paracrine factor that enhances collagen synthesis and bone matrix formation by osteoblasts, has been implicated in the coupling of bone formation with bone resorption. We have found, using SaOS-2 osteoblastic cells, that IGF-I inhibits PTH-stimulated cAMP production. Pretreatment of SaOS-2 cells with IGF-I for 24 h inhibited cAMP production stimulated by PTH with an IC50 of 1 nM and maximal inhibition to 10-20% of control values at an IGF-I concentration of 10 nM. Pretreatment with IGF-I had no effect on vasoactive intestinal peptide-stimulated cAMP production, but it enhanced cAMP production stimulated by prostaglandin E2 (PGE2) by as much as 5-fold at a concentration of 10 nM and with an EC50 of 1 nM. Pretreatment of SaOS-2 cells with IGF-I did not affect cholera toxin- or forskolin-stimulated cAMP accumulation. Taken together, these findings indicated that IGF-I did not affect Gs alpha, coupling of Gs alpha to adenylate cyclase, or adenylate cyclase itself. Binding experiments using [125I] chicken PTH-related peptide (PTHrP)-(1-36)-[Tyr36]NH2 demonstrated that IGF-I reduced PTH/PTHrP receptor number to 25% of the control value without affecting receptor affinity. IGF-I and the related growth factors, insulin and IGF-II, inhibited PTH-stimulated cAMP production with a rank order of potency of IGF-I > or = IGF-II > insulin, indicating that the actions of IGF-I on SaOS-2 cells were probably mediated by the IGF-I receptor. We conclude that physiologically relevant concentrations of IGF-I specifically inhibited PTH-stimulated and enhanced PGE2-stimulated production of cAMP by an action at the level of PTH and PGE2 receptors and/or coupling of the receptors to Gs alpha.