Involvement of α-klotho, fibroblast growth factor-, vitamin-D- and calcium-sensing receptor in 53 patients with primary hyperparathyroidism

Latus, Joerg; Lehmann, Renate; Roesel, Meike; Fritz, Péter; Braun, Niko; Ulmer, Christoph; Steurer, Wolfgang; Biegger, Dagmar; Ott, German; Dippon, Juergen; Alscher, Mark Dominik; Kimmel, Martin

doi:10.1007/s12020-013-9881-6

Cited by 18 publications

(20 citation statements)

References 28 publications

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“…Previous studies showed Klotho and CaSR expression were significantly decreased in PTGs of PHTP, SHPT patients, patients after kidney transplantation, and those with end-stage renal disease (55)(56)(57). We could demonstrate a binding interaction between Klotho and CaSR that might play a synergistic effect in controlling PTH synthesis and glandular hyperplasia.…”

Section: Discussionmentioning

confidence: 54%

Interrelated role of Klotho and calcium-sensing receptor in parathyroid hormone synthesis and parathyroid hyperplasia

Fan

Liu

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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The pathogenesis of parathyroid gland hyperplasia is poorly understood, and a better understanding is essential if there is to be improvement over the current strategies for prevention and treatment of secondary hyperparathyroidism. Here we investigate the specific role of Klotho expressed in the parathyroid glands (PTGs) in mediating parathyroid hormone (PTH) and serum calcium homeostasis, as well as the potential interaction between calcium-sensing receptor (CaSR) and Klotho. We generated mouse strains with PTG-specific deletion of Klotho and CaSR and dual deletion of both genes. We show that ablating CaSR in the PTGs increases PTH synthesis, that Klotho has a pivotal role in suppressing PTH in the absence of CaSR, and that CaSR together with Klotho regulates PTH biosynthesis and PTG growth. We utilized the tdTomato gene in our mice to visualize and collect PTGs to reveal an inhibitory function of Klotho on PTG cell proliferation. Chronic hypocalcemia and ex vivo PTG culture demonstrated an independent role for Klotho in mediating PTH secretion. Moreover, we identify an interaction between PTG-expressed CaSR and Klotho. These findings reveal essential and interrelated functions for CaSR and Klotho during parathyroid hyperplasia.

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Section: Discussionmentioning

confidence: 54%

Interrelated role of Klotho and calcium-sensing receptor in parathyroid hormone synthesis and parathyroid hyperplasia

Fan

Liu

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…In a study of primary hyperparathyroid patients, expression of Klotho mRNA and protein was decreased or undetectable in parathyroid adenomas, and the expression was inversely correlated to serum calcium levels [ 44 ]. In another study, the expression of parathyroid Klotho (but not the FGFR) was decreased in patients with primary hyperparathyroidism compared to normal tissue, but there was no correlation between Klotho expression and serum calcium levels [ 45 ]. In uremic patients with secondary hyperparathyroidism, Klotho was detected in nodular parathyroid tissue, but the expression varied in every nodule [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Differential expression and regulation of Klotho by paricalcitol in the kidney, parathyroid, and aorta of uremic rats

Ritter

Zhang

Delmez

et al. 2015

Kidney International

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Klotho plays an important role in the pathogenesis of cardiovascular disease in chronic kidney disease (CKD). Klotho is highly expressed in the kidney and parathyroid glands, but its presence in the vasculature is debated. Renal Klotho is decreased in CKD, but the effect of uremia on Klotho in other tissues is not defined. The effect of vitamin D receptor activator therapy in CKD on expression of Klotho in various tissues is also in debate. In uremic rats (surgical 5/6th nephrectomy model), we compared 3-months of treatment with and without paricalcitol on Klotho immunostaining in the kidney, parathyroid glands and aorta. With uremia, Klotho was unchanged in the parathyroid, significantly decreased in the kidney (66%) and the intimal-medial area of the aorta (69%), and significantly increased in the adventitial area of the aorta (67%) compared with controls. Paricalcitol prevented the decrease in Klotho in the kidney, increased expression in the parathyroid (31%), had no effect in the aortic media, but blunted the increase of Klotho in aortic adventitia. We propose that fibroblasts are responsible for expression of Klotho in the adventitia. In hyperplastic human parathyroid tissue from uremic patients, Klotho was higher in oxyphil compared with chief cells. Thus, under our conditions of moderate CKD and mild-to-moderate hyperphosphatemia in rats, the differential expression of Klotho and its regulation by paricalcitol in uremia is tissue-dependent.

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“…We investigated whether 990G allele affects the interaction of CASR In conclusion, FLNA is variably down-regulated in parathyroid tumors both at mRNA and protein levels. Therefore, parathyroid tumor cells are characterized by receptor and post-receptor defects, namely loss of CASR (Martin-Salvago et al 2003;Yano et al 2003;Haven et al 2004;Kawata et al 2006;Wittenween et al 2011;Latus et al 2013;Varshney et al 2013a), Gq/11 Mingione et al 20 protein (Corbetta et al 2000) Admittedly, our conclusions were limited by the fact that functional experiments were performed in HEK293 cells and could not be replicated in human normal or tumor parathyroid cells.…”

Section: Discussionmentioning

confidence: 90%

“…carcinomas (Haven et al 2004, Wittenveen et al 2011 and primary and secondary hyperplasia (Martin-Salvago et al 2003;Latus et al 2013;Varshney et al 2013a). CASR gene mutations have been rarely identified in sporadic parathyroid tumors (Frank-Raue et al 2011;Guarnieri et al 2010) and CASR gene deregulation is not sustained by promoter hypermethylation (Varshney et al 2013b).…”

Section: Discussionmentioning

confidence: 99%

Filamin A is Reduced and Contributes to CASR Sensitivity in Human Parathyroid Tumors

Terranegra

Mingione

Verdelli

et al. 2016

Qatar Foundation Annual Research Conference Proceedings Volume 2016 Issue 1

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Parathyroid tumors display reduced sensitivity to extracellular calcium ([Ca 2+ ] o). [Ca 2+ ] o activates calcium-sensing receptor (CASR), which interacts with the scaffold protein filamin A (FLNA). The study aimed to investigate: 1) the FLNA expression in human parathyroid tumors, 2) its effects on the CASR mRNA and protein expression, and 3) on ERK signaling activation, 4) the effect of the carboxy-terminal CASR variants and 5) of the treatment with the CASR agonist R568 on FLNA-mediated ERK phosphorylation in HEK293 cells. Full-length FLNA immunostaining was variably reduced in parathyroid tumors. Immunofluorescence showed that FLNA localized in membrane and cytoplasm and co-localized with CASR in parathyroid adenomas (PAds)-derived cells. Cleaved C-terminus FLNA fragment could also be detected in PAds nuclear protein fractions. In HEK293 cells transfected with 990R-CASR or 990G-CASR variants, silencing of endogenous FLNA reduced CASR mRNA levels and total and membrane-associated CASR proteins. In agreement, FLNA mRNA levels positively correlated with CASR expression in a series of 74 PAds; however, any significant correlation with primary hyperparathyroidism severity could be detected and FLNA transcript levels did not differ between PAds harboring 990R or 990G CASR variants. R568 treatment was efficient in restoring 990R-CASR and 990G-CASR sensitivity to [Ca 2+ ] o in absence of FLNA. In conclusion, FLNA is down-regulated in parathyroid tumors and parallels the CASR expression levels. Loss of FLNA reduces CASR mRNA and protein expression levels and the CASR-induced ERK phosphorylation. FLNA is involved in receptor expression, membrane localization and ERK signaling activation of both 990R and 990G CASR variants.

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Involvement of α-klotho, fibroblast growth factor-, vitamin-D- and calcium-sensing receptor in 53 patients with primary hyperparathyroidism

Cited by 18 publications

References 28 publications

Interrelated role of Klotho and calcium-sensing receptor in parathyroid hormone synthesis and parathyroid hyperplasia

Interrelated role of Klotho and calcium-sensing receptor in parathyroid hormone synthesis and parathyroid hyperplasia

Differential expression and regulation of Klotho by paricalcitol in the kidney, parathyroid, and aorta of uremic rats

Filamin A is Reduced and Contributes to CASR Sensitivity in Human Parathyroid Tumors

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