Institute of Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany.
Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
Int J Mol Sci. 2022 Oct 13;23(20):12228. doi: 10.3390/ijms232012228.
Preclinical studies have shown that parathyroid hormone (PTH) loses its biological effects through oxidation. PTH can be oxidized at methionines 8 and 18. Three possible variations of oxidized PTH (oxPTH) exist: Met8(ox)PTH, Met18(ox)PTH, and Met8, Met18(di-ox)PTH. A recent study showed that Met18(ox)PTH retained biological activity and was able to upregulate gene expression, whereas Met8(ox)PTH and Met8, Met18(di-ox)PTH showed less or no biological activity. An earlier study likewise showed that the oxidation of Met18 has minor effects on the secondary structure of PTH, whereas the oxidation of Met8 causes substantial structural changes, consistent with another study showing that oxidization just at Met8 blocks the generation of the second messenger cAMP, whereas the effect of the oxidation of Met18 is much less potent in inhibiting cAMP formation. A considerable percentage of circulating PTH in chronic kidney disease (CKD) patients is oxidized. However, we do not know the relative amounts of the different forms of oxPTH with agonistic, partial agonistic, or even antagonistic biological actions in different CKD populations. This might explain different clinical findings in the different CKD populations analyzed so far. The currently available method that was used in these clinical studies just distinguishes between oxPTH and noxPTH without being able to differentiate between different forms of oxPTH. Only methods of PTH measurement that are able to differentiate between PTH forms (noxPTH, Met8(ox)PTH, Met18(ox)PTH, and Met8, Met18(di-ox)PTH) have the potential to improve patient care, because only these methods will definitively separate bioactive from non-bioactive PTH forms. Such methods need to be developed, validated, and used in prospective randomized clinical trials to define the potential value of bioactive PTH forms as a predictor of cardiovascular events, mortality, and bone turnover.
临床前研究表明，甲状旁腺激素（PTH）通过氧化失去其生物学效应。PTH 可以在蛋氨酸 8 和 18 处被氧化。存在三种可能的氧化 PTH（oxPTH）变体：Met8（ox）PTH、Met18（ox）PTH 和 Met8、Met18（二氧）PTH。最近的一项研究表明，Met18（ox）PTH 保留了生物活性，能够上调基因表达，而 Met8（ox）PTH 和 Met8、Met18（二氧）PTH 表现出较少或没有生物活性。早期的一项研究同样表明，Met18 的氧化对 PTH 的二级结构影响较小，而 Met8 的氧化会导致结构发生重大变化，这与另一项研究一致，该研究表明，仅在 Met8 处氧化会阻止第二信使 cAMP 的产生，而 Met18 氧化的抑制 cAMP 形成的作用要弱得多。在慢性肾脏病（CKD）患者中，相当大比例的循环 PTH 被氧化。然而，我们不知道在不同的 CKD 人群中，具有激动剂、部分激动剂甚至拮抗剂生物学作用的不同 oxPTH 形式的相对含量。这可能解释了迄今为止在不同的 CKD 人群中分析得到的不同临床发现。目前在这些临床研究中使用的方法只是区分 oxPTH 和 noxPTH，而无法区分不同形式的 oxPTH。只有能够区分 PTH 形式（noxPTH、Met8（ox）PTH、Met18（ox）PTH 和 Met8、Met18（二氧）PTH）的 PTH 测量方法才有潜力改善患者的护理，因为只有这些方法才能将生物活性和非生物活性的 PTH 形式明确区分开来。需要开发、验证和在前瞻性随机临床试验中使用这些方法，以确定生物活性 PTH 形式作为心血管事件、死亡率和骨转换预测因子的潜在价值。
