REGULATION OF INSULIN-LIKE GROWTH FACTOR-II SYNTHESIS IN BONE CELL-CULTURES BY SKELETAL GROWTH-FACTORS

Insulin-like growth factor-II (IGF-II) is a growth factor secreted by bone cells and presumed to act as an autocrine regulator of bone forma tion. Although hormones and growth factors regulate the synthesis of s keletal IGF-I, hormones do not seem to modify the synthesis of skeleta l IGF-II. We postulated that skeletal IGF-II is regulated by growth fa ctors, and we tested the effects of basic fibroblast growth factor (bF GF), transforming growth factor-beta l (TGF beta 1), and platelet-deri ved growth factor-BB (PDGF-BB) on IGF-II messenger RNA (mRNA) expressi on and polypeptide concentrations in cultures of osteoblast-enriched ( Ob) cells from 22-day-old fetal rat calvariae. Steady state IGF-II mRN A levels were determined by Northern blot analysis, and IGF-II concent rations were determined in acidified and fractionated culture medium b y a specific RIA. Treatment of Ob cells with bFGF, TGF beta 1, and PDG F-BB decreased IGF-II mRNA levels after 24-48 h. A continuous 48-h tre atment with bFGF at 0.6-6 nM, TGF beta 1 at 0.04-1.2 nM, and PDGF-BB a t 0.3-3.3 nM caused a dose-dependent decrease in steady state IGF-II m RNA. The effects of bFGF, TGF beta 1, and PDGF-BB on IGF-II mRNA were dependent on protein synthesis and decreased in the presence of cycloh eximide at 3.6 mu M, but were independent of cell division, because th ey were observed in the presence and absence of 1 mM hydroxyurea. Trea tment with bFGF, TGF beta 1, and PDGF-BB for 24 h did not cause a chan ge in IGF-II polypeptide levels. PDGF-BB at 3.3 nM and TGF beta 1 at 0 .04-0.4 nM for 48 h decreased IGF-II polypeptide levels by about 50%, although bFGF had no effect.In conclusion, bFGF, TGF beta 1, and PDGF decrease skeletal IGF-II transcript levels, and this effect may contri bute to their actions on selected aspects of Ob cell function.