1. Intermittent PTH(1-34) signals through protein kinase A to regulate osteoprotegerin production in human periodontal ligament cells in vitro
Dominik Kraus, Andreas Jäger, Nuersailike Abuduwali, James Deschner, Stefan Lossdörfer Clin Oral Investig. 2012 Apr;16(2):611-8. doi: 10.1007/s00784-011-0541-z. Epub 2011 Mar 29.
Periodontal ligament (PDL) cells have been associated with the regulation of periodontal repair processes by the differential expression of osteoprotegerin and RANKL in response to intermittent parathyroid hormone (PTH) resulting in a modified activity of bone-resorbing osteoclasts. Here, we examined the intracellular signaling pathways that PDL cells use to mediate the PTH(1-34) effect on osteoprotegerin production and hypothesized that those would be dependent on the cellular maturation stage. Two stages of confluence served as a model for cellular maturation of 5th passage human PDL cells from six donors. Intermittent PTH(1-34) (10(-12) M) and PTH(1-31), the latter lacking the protein kinase C (PKC) activating domain, induced a significant decrease of osteoprotegerin production in confluent cultures, whereas the signal-specific fragments PTH(3-34) and PTH(7-34), which both are unable to activate protein kinase A (PKA), had no effect. The addition of the PKA inhibitor H8 antagonized the PTH(1-34) effect, whereas the PKC inhibitor RO-32-0432 did not. In pre-confluent, less mature cultures, intermittent PTH(1-34) resulted in a significant increase of osteoprotegerin. Similar results were obtained when PTH(1-31) substituted for PTH(1-34) as opposed to a lack of an effect of PTH(3-34) and PTH(7-34). Likewise, in confluent cultures, H8 inhibited the PTH(1-34) effect in pre-confluent cultures contrasted by RO-32-0432 which had no effect. These findings indicate that PTH(1-34) signaling targeting osteoprotegerin production in PDL cells involves a PKA-dependent pathway. The PTH(1-34) effect is dependent on cell status, whereas intracellular signal transduction is not. Clinical trials will have to prove whether those in vitro data are of physiological relevance for interference strategies.
2. Full-length versus intact PTH concentrations in pseudohypoparathyroidism type 1 and primary hyperparathyroidism: clinical evaluation of immunoassays in individuals from China
Yi Yang, Ailing Song, An Song, Yingying Hu, Yan Jiang, Mei Li, Weibo Xia, Xiaoping Xing, Xinqi Cheng, Ou Wang Endocrine. 2022 Dec;78(3):605-614. doi: 10.1007/s12020-022-03204-7. Epub 2022 Oct 11.
Purpose: The application of the third-generation parathyroid hormone (PTH) assay [PTH(1-84) assay] for evaluating PTH levels in patients with pseudohypoparathyroidism type-1 (PHP1) is less popular than the second-generation assay. Therefore, we aimed at examining the conformity between the PTH(1-84) assay and the intact PTH (iPTH) assay, specifically examining their performance in individuals with PHP1 versus individuals with primary hyperparathyroidism (PHPT), compared to healthy controls. Methods: PTH(1-84) and iPTH assay were performed in patients with PHP1, patients with PHPT, and healthy volunteers. ∆PTH%, PTH(1-84)/iPTH (3rd/2nd ratio), iPTH/upper limit of normal (ULN), and PTH (1-84)/ULN of each group were calculated for comparison. Linear regression, Kappa conformity test, and Bland-Altman analysis of ∆PTH/mean of iPTH and PTH(1-84) (percent bias) plotted against the mean of iPTH and PTH(1-84) were performed to determine the conformance of PTH(1-84) assay with iPTH assay. Results: A total of 54 patients with PHP1, 127 patients with PHPT, and 65 healthy volunteers were enrolled in this study. All the three groups showed strong linear relationship between iPTH and PTH (1-84) (r2 = 0.9661, 0.7733, and 0.9575, respectively). No significant differences were noted in 3rd/2nd ratio (median 0.76 vs. 0.72) between the PHP1 and PHPT groups (p > 0.05). Conformity examination showed the Kappa value was 0.778 and 0.395 for PHP1 and PHPT groups respectively. No difference in the Kappa values was found between PHP1A and PHP1B subgroups. Bland-Altman plot demonstrated that the proportion of data points that were plotted within mean ± 1.96 SD in PHP1, PHPT and normal control groups were 96.3%, 93.7%, and 98.5%, respectively. The mean percent bias of the three groups were 26.1%, 31.2%, and 17.0%, respectively. The range of mean ± 1.96 SD of percent bias of the three groups were 2.2%-50.0%, -14.3%-76.6%, and 6.7%-27.2%, respectively. Conclusion: Although iPTH and PTH(1-84) values were both lower in the present PHP1 cohort than in the PHPT cohort, there appear to be differences in the relative agreement between both immunoassays, and in the relationship between the two values, especially in comparison to healthy controls. Whether these differences are due to differential accumulation of C-terminal fragments or other factors requires further study.
