The Effects of Retinoic Acid on the Insulin-like Growth Factor Axis in Primary Tissue Culture from Hyperparathyroidism

Background The importance of the IGF system in HPT has been previously demonstrated. Additionally, the role of vitamin A in HPT has been reported. Retinoic acid (RA), a derivative of vitamin A, is a ligand for the IGF II receptor (IGF2R). We have evaluated the interactions of RA with the IGF system in a primary parathyroid cell culture model. Materials and Methods Primary cell cultures were prepared from nine patients. Following adhesion, the cells were transferred to serum-free medium and dosed once with growth factors ± RA for 96 hours. Proliferation was assessed by measuring tritiated thymidine incorporation. Results Compared with the control group (100%), both IGF I and II increased DNA synthesis significantly. Retinoic acid significantly reduced the basal DNA synthesis to 82.2% ± 4.2% compared with control ( P < 0.05). Retinoic acid ×10 −5 M completely abrogated the proliferative actions of IGF II (70.2% ± 9.7%, P < 0.05) but had no significant effect on the IGF I response ( P > 0.05). To evaluate the role of IGF2R or IGFBPs in mediating the actions of RA, the IGF II analogs [Leu27]IGF II (10–20-fold reduced IGF I receptor affinity) and des(1–6) IGF II (lower IGFBP binding affinity) were used. The IGF II inhibitory effect of RA was enhanced in the presence of analogs [Leu27]IGF II ( P = 0.052) but not with des(1–6)IGF II ( P > 0.05), compared with wild-type IGF II. Conclusions These data implicate a novel antiproliferative role for RA in enhancing the pericellular clearance of IGF II via the IGF2R preventing ligand activation of the IGF I receptor. This may have broader implications for RA effects in other tumors.