Tørring O, Turner R T, Carter W B, Firek A F, Jacobs C A, Heath H
Endocrine Research Unit, Mayo Clinic Rochester, Minnesota 55905.
Endocrinology. 1992 Jul;131(1):5-13. doi: 10.1210/endo.131.1.1319327.
Humoral hypercalcemia of malignancy (HHM) is at least partly caused by tumor secretion of PTH-related peptide (PTHrP), but there is growing evidence for cosecretion with PTHrP of other bone-resorbing peptides, such as the cytokine interleukin-1 alpha (IL-1 alpha). Administration of PTHrP in vivo and in vitro generally mimics the actions of PTH itself, with increases in both resorption and formation of bone. However, bone in HHM is characterized by uncoupling of bone turnover, with increased resorption and decreased formation. We performed experiments to determine whether IL-1 alpha might alter the effects of PTHrP and produce uncoupling. Thus, we administered to 100-g male rats by sc osmotic minipumps synthetic PTHrP-(1-34) alone (2 micrograms/100 g/day), recombinant IL-1 alpha alone (1.5 micrograms/100 g/day), both peptides together at the previous doses, or vehicle only. We infused 5 groups of 12 rats each (PTHrP, IL-1 alpha, PTHrP plus IL-1 alpha, ad libitum fed control, and controls pair-fed to the PTHrP plus IL-1 alpha group) for 14 days. At the end of the study, blood and urine were taken for chemical measurements, and tibias and femurs were harvested for histomorphometry and extraction of RNA from periosteal cells. As expected, PTHrP induced hypercalcemia, relative hypophosphatemia, phosphaturia, and reduced bone mass. Osteoblast number was increased, but osteoclast number was not. Indices of bone formation were unchanged or reduced. The dose of IL-1 alpha chosen had no statistically significant effect, except for reduced longitudinal bone growth, but when combined with PTHrP, IL-1 alpha reduced hypercalcemia, hypophosphatemia, and phosphaturia. In contrast to the blood and urine effects, IL-1 alpha did not interact significantly with PTHrP's effect on bone measurements. Northern analysis of periosteal cell mRNA showed that PTHrP reduced expression of osteocalcin, but not glyceraldehyde-3-phosphate dehydrogenase; IL-1 alpha had no additional effect. These data suggest that 1) continuously administered PTHrP alone may induce uncoupled bone turnover with decreased cortical bone formation; 2) IL-1 alpha appears to inhibit strongly the renal effects of PTHrP and weakly (if at all) its actions on bone and, thus, to decrease its hypercalcemic, phosphaturic, and hypophosphatemic actions; and 3) cosecretion of IL-1 alpha, and possibly other peptide cytokines, with PTHrP may modify the clinical expression of HHM.
恶性肿瘤体液性高钙血症（HHM）至少部分是由肿瘤分泌甲状旁腺激素相关肽（PTHrP）引起的，但越来越多的证据表明，其他骨吸收肽如细胞因子白细胞介素-1α（IL-1α）也与PTHrP共同分泌。体内和体外给予PTHrP通常会模拟PTH本身的作用，导致骨吸收和骨形成增加。然而，HHM中的骨具有骨转换解偶联的特征，即骨吸收增加而骨形成减少。我们进行了实验，以确定IL-1α是否可能改变PTHrP的作用并导致解偶联。因此，我们通过皮下渗透微型泵给100 g雄性大鼠单独注射合成的PTHrP-(1-34)（2微克/100克/天）、单独注射重组IL-1α（1.5微克/100克/天）、以先前剂量同时注射两种肽或仅注射载体。我们将每组12只大鼠分为5组（PTHrP组、IL-1α组、PTHrP加IL-1α组、自由进食对照组和与PTHrP加IL-1α组配对喂养的对照组），持续输注14天。在研究结束时，采集血液和尿液进行化学测量，并收获胫骨和股骨进行组织形态计量学分析以及从骨膜细胞中提取RNA。正如预期的那样，PTHrP诱导了高钙血症、相对低磷血症、磷尿症和骨量减少。成骨细胞数量增加，但破骨细胞数量未增加。骨形成指标未改变或降低。所选剂量的IL-1α除了减少纵向骨生长外，没有统计学上的显著影响，但与PTHrP联合使用时，IL-1α可减轻高钙血症、低磷血症和磷尿症。与对血液和尿液的影响相反，IL-1α与PTHrP对骨测量的影响没有显著相互作用。骨膜细胞mRNA的Northern分析表明，PTHrP降低了骨钙素的表达，但不影响甘油醛-3-磷酸脱氢酶的表达；IL-1α没有额外影响。这些数据表明：1）单独持续给予PTHrP可能会诱导骨转换解偶联，皮质骨形成减少；2）IL-1α似乎强烈抑制PTHrP的肾脏作用，对其骨作用的抑制作用较弱（如果有），从而降低其高钙血症、磷尿症和低磷血症作用；3）IL-1α以及可能的其他肽细胞因子与PTHrP共同分泌可能会改变HHM的临床表现。
