INSULIN-LIKE GROWTH-FACTOR-I MEDIATES OSTEOCLAST-LIKE CELL-FORMATION STIMULATED BY PARATHYROID-HORMONE

There have been several lines of evidence that parathyroid hormone (PT H) stimulates production of insulinlike growth factor I (IGF-I) in bon e and that IGF-I stimulates osteoclast formation. Thus, the present st udy was performed to clarify the possible role of IGF-I in PTH-stimula ted osteoclastlike cell formation and the role of PTH-responsive dual signal transduction systems (cyclic [c] AMP-dependent protein kinase [ PKA] and calcium/protein kinase C [PKC]) in its mechanism. Treatment w ith anti-IGF-I antibody (1-10 mu g/ml) partially but significantly blo cked hPTH-(1-34)-stimulated osteoclastlike cell formation in unfractio nated mouse bone cell cultures, although it did not affect osteoclastl ike cell formation stimulated by 1,25-dihydroxyvitamin D-3. Rp-cAMPS ( 10(-4) M), a direct PKA inhibitor, as well as two types of PKC inhibit ors, H-7 (10 mu M) and staurosporine (3 nM), and dantrolene (10(-5) M) , an inhibitor of calcium mobilization from intracellular calcium stor es, all significantly blocked PTH-stimulated osteoclastlike cell forma tion. Anti-IGF-I antibody (3 mu g/ml) significantly blocked osteoclast like cell formation stimulated by 10(-4) M dbcAMP, 10(-4) M Sp-cAMPS, a direct PKA activator, and 10(-5) M forskolin in mouse bone cell cult ures. Dibutyryl cAMP, forskolin, and hPTH-(1-34) significantly stimula ted mRNA expression of both IGF-I and IGF-binding protein 5 (IGFBP-5) in these cultures, but neither 10(-7) M PMA, a PKC activator, nor 10(- 7) M A23187 did. Moreover, anti-IGF-I antibody significantly blocked o steoclastlike cell formation stimulated by the conditioned medium from MC3T3-E1 cells pretreated with 10(-8) PTH-(1-34), which induced IGF-I and IGFBP-5 mRNA expression in these cells. In conclusion, the presen t study indicates that IGF-I mediates osteoclastlike cell formation st imulated by PTH and that the PKA pathway is involved in its mechanism. However, IGF-I does not seem to be the sole effector molecule to be a ctive in this system. (C) 1997 Wiley-Liss, Inc.