RETINOIDS MODULATE THE EFFECT OF PTH AND CALCITRIOL ON EGF RECEPTOR EXPRESSION IN UMR-106-01 CELLS

Although osteoblast proliferation is a prominent feature of osteitis f ibrosa, studies in vitro using osteoblastlike cells have shown that pa rathyroid hormone (PTH) impairs cell growth. Recent studies in our lab oratory have shown that PTH increases epidermal growth factor (EGF) re ceptor expression in UMR 106-01 osteoblast-like cells, and thus, osteo blast proliferation may occur as a result of an enhanced response of t he osteoblast to EGF. In the present studies we investigated the effec t of calcitriol and the influence of retinoids on the regulation of EG F receptors. Calcitriol increased I-125-EGF binding 2.5-3-fold after 7 2 hours of incubation and was maximal at a calcitriol dose of 100 nM. Scatchard analysis showed that this effect was due to increased recept or number. In contrast, all-bans retinoic acid or 9-cis retinoic acid alone, even at 10 mu M, caused less than a 50% increase in I-125-EGF b inding. However, the effect of calcitriol was totally abolished in the presence of all-trans retinoic acid. 9-cis retinoic acid was equivale nt with all-trans retinoic acid in this regard. In the presence of eit her retinoid, the stimulatory effect of PTH was totally eliminated and EGF binding was actually decreased below control values. Additional s tudies revealed that retinoic acid decreased PTH-stimulated cAMP gener ation in a dose dependent manner. These data are consistent with our p revious studies which showed that the effect of PTH on the induction o f EGF receptors was mediated by a cAMP-dependent mechanism. The inhibi tion of the calcitriol effect by retinoids is consistent with the requ irement of the retinoid-X-receptor (RXR) for binding of the vitamin D receptor (VDR) to its target sequences in DNA. These data indicate tha t EGF receptors in UMR 106-01 cells are upregulated by PTH and calcitr iol and that this process can be modulated by retinoids. Retinoids, th erefore, may play a major role in the regulation of osteoblast functio n by PTH and calcitriol.