Yamato H, Nagai Y, Inoue D, Ohnishi Y, Ueyama Y, Ohno H, Matsumoto T, Ogata E, Ikeda K
Fourth Department of Internal Medicine, University of Tokyo School of Medicine, Japan.
J Bone Miner Res. 1995 Jan;10(1):36-44. doi: 10.1002/jbmr.5650100108.
The present study was undertaken to clarify in vivo the temporal profile of parathyroid hormone-related peptide (PTHRP) gene expression as well as bone histomorphometric features as a function of tumor growth, using an athymic rat model associated with humoral hypercalcemia of malignancy (HHM). Tumor-bearing animals exhibited hypercalcemia, hypophosphatemia, and increased circulating levels of PTHRP, and died within 3 weeks. Steady-state PTHRP mRNA levels and the transcription rate of PTHRP gene in the tumors were markedly increased with tumor growth. RNAse mapping analysis revealed that both upstream and downstream promoters of the human PTHRP gene were utilized in the tumors and became progressively activated with time. Bone histomorphometric analysis showed that osteoclastic bone resorption was progressively increased throughout the course, whereas osteoblastic bone formation was stimulated more than 2-fold at a very early stage (day 6 after tumor implantation) and then markedly suppressed thereafter on day 12 and day 18 compared with age-matched control animals. These results provide in vivo evidence that PTHRP gene transcription is progressively activated with tumor growth and that activation of osteoblasts does occur at a very early phase of HHM syndrome in contrast to the marked suppression of bone formation at later stages.
本研究旨在利用与恶性肿瘤体液性高钙血症（HHM）相关的无胸腺大鼠模型，在体内阐明甲状旁腺激素相关肽（PTHRP）基因表达的时间变化情况以及作为肿瘤生长函数的骨组织形态计量学特征。荷瘤动物出现高钙血症、低磷血症，循环中PTHRP水平升高，并在3周内死亡。随着肿瘤生长，肿瘤中PTHRP mRNA的稳态水平和PTHRP基因的转录率显著增加。核糖核酸酶图谱分析显示，人PTHRP基因的上游和下游启动子在肿瘤中均被利用，并随时间逐渐激活。骨组织形态计量学分析表明，在整个过程中破骨细胞性骨吸收逐渐增加，而成骨细胞性骨形成在非常早期（肿瘤植入后第6天）被刺激超过2倍，然后在第12天和第18天与年龄匹配的对照动物相比明显受到抑制。这些结果提供了体内证据，表明PTHRP基因转录随肿瘤生长而逐渐激活，并且与后期骨形成的明显抑制相反，成骨细胞的激活确实发生在HHM综合征的非常早期阶段。
