González E A, Martin K J
Division of Nephrology, St. Louis University Health Sciences Center, 3635 Vista Avenue at Grand Boulevard, St. Louis, Missouri 63110-0250, USA.
Calcif Tissue Int. 1996 Jun;58(6):429-34. doi: 10.1007/BF02509443.
Although osteoblast proliferation is a prominent feature of osteitis fibrosa, studies in vitro using osteoblast-like cells have shown that parathyroid hormone (PTH) impairs cell growth. Recent studies in our laboratory have shown that PTH increases epidermal growth factor (EGF) receptor expression in UMR 106-01 osteoblast-like cells, and thus, osteoblast proliferation may occur as a result of an enhanced response of the osteoblast to EGF. In the present studies we investigated the effect of calcitriol and the influence of retinoids on the regulation of EGF receptors. Calcitriol increased 125I-EGF binding 2.5-3-fold after 72 hours of incubation and was maximal at a calcitriol dose of 100 nM. Scatchard analysis showed that this effect was due to increased receptor number. In contrast, all-trans retinoic acid or 9-cis retinoic acid alone, even at 10 microM, caused less than a 50% increase in 125I-EGF binding. However, the effect of calcitriol was totally abolished in the presence of all-trans retinoic acid. 9-cis retinoic acid was equivalent with all-trans retinoic acid in this regard. In the presence of either retinoid, the stimulatory effect of PTH was totally eliminated and EGF binding was actually decreased below control values. Additional studies revealed that retinoic acid decreased PTH-stimulated cAMP generation in a dose-dependent manner. These data are consistent with our previous studies which showed that the effect of PTH on the induction of EGF receptors was mediated by a cAMP-dependent mechanism. The inhibition of the calcitriol effect by retinoids is consistent with the requirement of the retinoid-X-receptor (RXR) for binding of the vitamin D receptor (VDR) to its target sequences in DNA. These data indicate that EGF receptors in UMR 106-01 cells are up-regulated by PTH and calcitriol and that this process can be modulated by retinoids. Retinoids, therefore, may play a major role in the regulation of osteoblast function by PTH and calcitriol.
尽管成骨细胞增殖是纤维性骨炎的一个显著特征，但使用成骨样细胞进行的体外研究表明，甲状旁腺激素（PTH）会损害细胞生长。我们实验室最近的研究表明，PTH会增加UMR 106 - 01成骨样细胞中表皮生长因子（EGF）受体的表达，因此，成骨细胞增殖可能是由于成骨细胞对EGF的反应增强所致。在本研究中，我们调查了骨化三醇的作用以及类维生素A对EGF受体调节的影响。孵育72小时后，骨化三醇使125I - EGF结合增加了2.5至3倍，在骨化三醇剂量为100 nM时达到最大值。Scatchard分析表明，这种效应是由于受体数量增加所致。相比之下，单独使用全反式维甲酸或9 - 顺式维甲酸，即使浓度为10 microM，也只会使125I - EGF结合增加不到50%。然而，在全反式维甲酸存在的情况下，骨化三醇的作用完全被消除。在这方面，9 -顺式维甲酸与全反式维甲酸相当。在任何一种类维生素A存在的情况下，PTH 的刺激作用都完全被消除，并且EGF结合实际上降至对照值以下。进一步的研究表明，维甲酸以剂量依赖的方式降低PTH刺激的cAMP生成。这些数据与我们之前表明PTH对EGF受体诱导作用是由cAMP依赖性机制介导的研究一致。类维生素A对骨化三醇作用的抑制与类维生素X受体（RXR）对于维生素D受体（VDR）与DNA中其靶序列结合的必要性一致。这些数据表明，UMR 106 - 01细胞中的EGF受体被PTH和骨化三醇上调，并且这个过程可以被类维生素A调节。因此，类维生素A可能在PTH和骨化三醇对成骨细胞功能的调节中起主要作用。
