A novel mechanism for skeletal resistance in uremia
A novel mechanism for skeletal resistance in uremia
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DOI：
10.1016/s0085-2538(15)47156-x
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发表时间：
2000-08-01
影响因子：
19.6
通讯作者：
Dusso, A
中科院分区：
文献类型：
--
作者：
Slatopolsky, E;Finch, J;Dusso, A
背景在治疗继发性甲状旁腺功能亢进症时，血清全段甲状旁腺激素（I-PTH）的目标水平应是正常值的3至5倍，以预防粘连性骨病。在循环中，有一个非（1-84）PTH截短片段，可能是7-84，除了PTH 1-84外，大多数I-PTH免疫放射测定（IRMA）测定也可测量该片段，从而错误地给出高I-PTH值。我们已经开发了一种新的IRMA测定法，其中标记的抗体仅识别PTH分子的前六个氨基酸。因此，这种新的IRMA测定（全PTH）仅测量生物活性1-84 PTH分子。使用这种新的IRMA检测（全PTH）和Nichols“完整”PTH检测，我们比较了每种检测识别人PTH（hPTH）1-84和hPTH 7-84的能力，并检查了循环和甲状旁腺中非1-84 PTH的百分比。结果：7-84 PTH片段对1-84 PTH的生物学活性有拮抗作用。在28例尿毒症患者中，用Nichols测定法（代表hPTH 1-84和hPTH 7-84的组合测量）测量的PTH值比全测定法（仅hPTH 1-84）高34%;中位PTH为523 vs 318 pg/mL（P < 0.001）。在14例肾移植患者中发现了类似的结果。在成骨细胞样细胞中，ROS 17.2，1-84 PTH（10（-8）mol/L）使cAMP从18.1 +/- 1.25增加到738 +/- 4.13 mmol/孔。相反，相同浓度的7-84 PTH没有影响。在甲状旁腺切除大鼠喂养钙缺乏的饮食中，7-84 PTH不仅是生物学上没有活性，但对骨中的1-84 PTH有拮抗作用。1-84 PTH治疗后2小时血浆钙升高（0.65 mg/dL），而7-84 PTH无影响。当1-84 PTH和7-84 PTH以1：1的摩尔比同时给予时，对1-84 PTH的钙离子反应降低了94%。在正常大鼠中，给予1-84 PTH可增加肾磷排泄分数（11.9 - 27.7%，P < 0.001）。而1-84 PTH和7-84 PTH同时给药时，7-84 PTH使尿磷反应降低50.2%（P < 0.005）。最后，在6例尿毒症患者手术切除的甲状旁腺中，我们发现细胞内总PTH的44.1%是非PTH（1-84），最可能是PTH 7- 84。在慢性肾衰竭患者中，通过“完整”测定检测到的非1-84 PTH片段（最可能是7-84 PTH）的高循环水平的存在以及7-84 PTH对1-84 PTH的生物活性的拮抗作用解释了需要更高水平的“完整”PTH来预防粘连性骨病。
Background. In treating secondary hyperparathyroidism, the target level of serum intact parathyroid hormone (I-PTH) should be three to five times normal to prevent adynamic bone disease. In circulation, there is a non-(1-84) PTH-truncated fragment, likely 7-84, which, in addition to PTH 1-84, is measured by most I-PTH immunoradiometric (IRMA) assays, giving erroneously high I-PTH values. We have developed a new IRMA assay in which the labeled antibody recognizes only the first six amino acids of the PTH molecule. Thus, this new IRMA assay (Whole PTH) measures only the biologically active 1-84 PTH molecule.Methods. Using this new IRMA assay (Whole PTH) and the Nichols "intact" PTH assay, we compared the ability of each assay to recognize human PTH (hPTH) 1-84 and hPTH 7-84 and examined the percentage of non-1-84 PTH in circulation and in parathyroid glands. Possible antagonistic effects of the 7-84 PTH fragment on the biological activity of 1-84 PTH in rats were also tested.Results. In 28 uremic patients, PTH values measured with the Nichols assay, representing a combined measurement of both hPTH 1-84 and hPTH 7-84, were 34% higher than with the Whole assay (hPTH 1-84 only); the median PTH was 523 versus 318 pg/mL (P < 0.001). Similar results were found in 14 renal transplant patients. In osteoblast-like cells, ROS 17.2, 1-84 PTH (10(-8) mol/L) increased cAMP from 18.1 +/- 1.25 to 738 +/- 4.13 mmol/well. Conversely, the same concentration of 7-84 PTH had no effect. In parathyroidectomized rats fed a calcium-deficient diet, 7-84 PTH was not only biologically inactive, but had antagonistic effects on 1-84 PTH in bone. Plasma calcium was increased (0.65 mg/dL) two hours after 1-84 PTH treatment, while 7-84 PTH had no effect. When 1-84 PTH and 7-84 PTH were given simultaneously in a 1:1 molar ratio, the calcemic response to 1-84 PTH was decreased by 94%. In normal rats, the administration of 1-84 PTH increased renal fractional excretion of phosphate (11.9 to 27.7%, P < 0.001). However, when 1-84 PTH and 7-84 PTH were given simultaneously, the 7-84 PTH decreased the phosphaturic response by 50.2% (P < 0.005). Finally, in surgically excised parathyroid glands from six uremic patients, we found that 44.1% of the total intracellular PTH was the non-PTH (1-84), most likely PTH 7-84.Conclusion. In patients with chronic renal failure, the presence of high circulating levels of non-1-84 PTH fragments (most likely 7-84 PTH) detected by the "intact" assay and the antagonistic effects of 7-84 PTH on the biological activity of 1-84 PTH explain the need of higher levels of "intact" PTH to prevent adynamic bone disease.