Biological Activity of Different Forms of Oxidized Parathyroid Hormone

Hasan, Ahmed A.; Hocher, Carl-Friedrich; Kleuser, Burkhard; Krämer, Bernhard K.; Hocher, Berthold

doi:10.3390/ijms232012228

Cited by 3 publications

(2 citation statements)

References 51 publications

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“…Regarding PTH determination, we also acknowledge that currently used assays are unable to distinguish between the vast majority of oxidized forms of PTH and its non-oxidized form. Therefore, we cannot exclude the possibility that high levels of PTH in our cohort might only reflect a higher level of oxidative stress, which is also harmful to CKD patients [ 59 , 60 ]. Another important limitation was the absence of ionized calcium, which more precisely represents the amount of calcium exerting a biological effect.…”

Section: Discussionmentioning

confidence: 99%

Association between CKD-MBD and mortality in older patients with advanced CKD—results from the EQUAL study

Magagnoli

Cozzolino

Caskey

et al. 2023

Nephrology Dialysis Transplantation

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Background Chronic Kidney Disease—Mineral and Bone Disorder (CKD-MBD) is a common complication of CKD, associated with higher mortality in dialysis patients, while its impact in non-dialysis patients remains mostly unknown. We investigated the associations between parathyroid hormone (PTH), phosphate, and calcium (and their interactions) and all-cause, cardiovascular (CV), and non-CV mortality in older non-dialysis patients with advanced CKD. Methods We used data from the European Quality study, which includes patients aged ≥65 with eGFR ≤20 ml/min/1.73 m2 from six European countries. Sequentially adjusted Cox models were used to assess the association between baseline and time-dependent CKD-MBD biomarkers and all-cause, CV, and non-CV mortality. Effect modification between biomarkers was also assessed. Results In 1294 patients, the prevalence of CKD-MBD at baseline was 94%. Both PTH (aHR 1.12, 95%CI 1.03–1.23, p 0.01) and phosphate (aHR 1.35, 95%CI 1.00–1.84, p 0.05), but not calcium (aHR 1.11, 95%CI 0.57–2.17, p 0.76), were associated with all-cause mortality. Calcium was not independently associated with mortality, but modified the effect of phosphate, with the highest mortality risk found in patients with both hypercalcemia and hyperphosphatemia. PTH level was associated with CV mortality, but not with non-CV mortality, whereas phosphate was associated with both CV and non-CV mortality in most models. Conclusions CKD-MBD is very common in older non-dialysis patients with advanced CKD. PTH and phosphate are independently associated with all-cause mortality in this population. While PTH level is only associated with CV mortality, phosphate seems to be associated with both CV and non-CV mortality.

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Section: Discussionmentioning

confidence: 99%

Association between CKD-MBD and mortality in older patients with advanced CKD—results from the EQUAL study

Magagnoli

Cozzolino

Caskey

et al. 2023

Nephrology Dialysis Transplantation

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“…The clinical assay used to measure oxPTH and n-oxPTH is only able to differentiate non-oxidized PTH from all forms oxidized PTH (Met8-oxPTH, Met18-oxPTH and Met8, Met18-di-oxPTH). Since Met18-oxPTH is partially bioactive ( 73 ), it would have been of interest to measure the oxidized forms of PTH separately. However, this is currently not possible with the methods available for clinical research so far.…”

Section: Discussionmentioning

confidence: 99%

Inverse correlation of intact PTH, oxidized PTH as well as non-oxidized PTH with 25-hydroxyvitamin D3 in kidney transplant recipients

et al. 2023

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Background25-hydroxyvitamin D (25(OH)D) and potentially also 1,25-dihydroxyvitamin D (1,25(OH)2D) inhibits the synthesis of parathyroid hormone (PTH) in the chief cells of the parathyroid gland. Clinical studies showing a negative correlation between (25(OH)D and PTH are in good agreement with these findings in basic science studies. However, PTH was measured in these studies with the currently clinically used 2nd or 3rd generation intact PTH (iPTH) assay systems. iPTH assays cannot distinguish between oxidized forms of PTH and non-oxidized PTH. Oxidized forms of PTH are the by far most abundant form of PTH in the circulation of patients with impaired kidney function. Oxidation of PTH causes a loss of function of PTH. Given that the clinical studies done so far were performed with an PTH assay systems that mainly detect oxidized forms of PTH, the real relationship between bioactive non-oxidized PTH and 25(OH)D as well as 1,25(OH)2D is still unknown.MethodsTo address this topic, we compared for the first time the relationship between 25(OH)D as well as 1,25(OH)2D and iPTH, oxPTH as well as fully bioactive n-oxPTH in 531 stable kidney transplant recipients in the central clinical laboratories of the Charité. Samples were assessed either directly (iPTH) or after oxPTH (n-oxPTH) was removed using a column that used anti-human oxPTH monoclonal antibodies, a monoclonal rat/mouse parathyroid hormone antibody (MAB) was immobilized onto a column with 500 liters of plasma samples. Spearman correlation analysis and Multivariate linear regression were used to evaluate the correlations between the variables.ResultsThere was an inverse correlation between 25(OH)D and all forms of PTH, including oxPTH (iPTH: r=-0.197, p<0.0001; oxPTH: r=-0.203, p<0.0001; n-oxPTH: r=-0.146, p=0.001). No significant correlation was observed between 1,25(OH)2D and all forms of PTH. Multiple linear regression analysis considering age, PTH (iPTH, oxPTH and n-oxPTH), serum calcium, serum phosphor, serum creatinine, fibroblast growth factor 23 (FGF23), osteoprotegerin (OPG), albumin, and sclerostin as confounding factors confirmed these findings. Subgroup analysis showed that our results are not affected by sex and age.ConclusionIn our study, all forms of PTH are inversely correlated with 25-hydroxyvitamin D (25(OH)D). This finding would be in line with an inhibition of the synthesis of all forms of PTH (bioactive n-oxPTH and oxidized forms of PTH with minor or no bioactivity) in the chief cells of the parathyroid glad.

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Only bioactive forms of PTH (n-oxPTH and Met18(ox)-PTH) inhibit synthesis of sclerostin – evidence from in vitro and human studies

Li,

Hasan,

Chu

et al. 2024

Pflugers Arch - Eur J Physiol

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Sclerostin (SOST) is produced by osteocytes and is known as a negative regulator of bone homeostasis. Parathyroid hormone (PTH) regulates calcium, phosphate as well as vitamin D metabolism, and is a strong inhibitor of SOST synthesis in vitro and in vivo. PTH has two methionine amino acids (positions 8 and 18) which can be oxidized. PTH oxidized at Met18 (Met18(ox)-PTH) continues to be bioactive, whereas PTH oxidized at Met8 (Met8(ox)-PTH) or PTH oxidized at Met8 and Met18 (Met8, Met18(di-ox)-PTH) has minor bioactivity. How non-oxidized PTH (n-oxPTH) and oxidized forms of PTH act on sclerostin synthesis is unknown. The effects of n-oxPTH and oxidized forms of PTH on SOST gene expression were evaluated in UMR106 osteoblast-like cells. Moreover, we analyzed the relationship of SOST with n-oxPTH and all forms of oxPTH in 516 stable kidney transplant recipients using an assay system that can distinguish in clinical samples between n-oxPTH and the sum of all oxidized PTH forms (Met8(ox)-PTH, Met18(ox)-PTH, and Met8, Met18(di-ox)-PTH). We found that both n-oxPTH and Met18(ox)-PTH at doses of 1, 3, 20, and 30 nmol/L significantly inhibit SOST gene expression in vitro, whereas Met8(ox)-PTH and Met8, Met18(di-ox)-PTH only have a weak inhibitory effect on SOST gene expression. In the clinical cohort, multivariate linear regression showed that only n-oxPTH, but not intact PTH (iPTH) nor oxPTH, is independently associated with circulating SOST after adjusting for known confounding factors. In conclusion, only bioactive PTH forms such as n-oxPTH and Met18(ox)-PTH, inhibit SOST synthesis.

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Biological Activity of Different Forms of Oxidized Parathyroid Hormone

Cited by 3 publications

References 51 publications

Association between CKD-MBD and mortality in older patients with advanced CKD—results from the EQUAL study

Association between CKD-MBD and mortality in older patients with advanced CKD—results from the EQUAL study

Inverse correlation of intact PTH, oxidized PTH as well as non-oxidized PTH with 25-hydroxyvitamin D3 in kidney transplant recipients

Only bioactive forms of PTH (n-oxPTH and Met18(ox)-PTH) inhibit synthesis of sclerostin – evidence from in vitro and human studies

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