Unexpected action of lanthanum carbonate

Takenaka, Tsuneo; Yamanaka, T.; Yoshida, Masashi; Suzuki, Hiromichi

doi:10.1007/s00198-015-3155-5

Cited by 5 publications

(2 citation statements)

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“…However, potential adverse actions of klotho, such as rickets, should be taken into account. (28) The present findings suggest the safety of supplemental but not pharmacological doses of klotho for chronic kidney diseases. Finally, klotho may have more interaction partners than was previously anticipated.…”

Section: Discussionmentioning

confidence: 56%

Xeno-Klotho Inhibits Parathyroid Hormone Signaling

Takenaka

Inoue

Miyazaki

et al. 2015

Journal of Bone and Mineral Research

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Although fibroblast growth factor (FGF) 23 was recently identified as a phosphatonin that influences vitamin D metabolism, the underlying signaling mechanisms remain unclear. FGF23 elevates the renal levels of membrane-associated klotho as well as soluble klotho. Klotho is expressed on distal tubules. Upon enzymatic cleavage, soluble klotho is released into the renal interstitial space and then into the systemic circulation. The expression of 25-hydroxyvitamin D 3 1a-hydroxylase (1-OH) on proximal tubular cells is controlled by parathyroid hormone (PTH). Klotho binds to various membrane proteins to alter their function. Here, the interaction between the PTH receptor and klotho was studied using various approaches, including immunoprecipitation, in vitro cell culture, and in vivo animal experiments. Immunoprecipitation studies demonstrate, for the first time, that recombinant human klotho protein interacts with human PTH receptors to inhibit the binding of human PTH. Furthermore, when applied to human proximal tubular cells, recombinant human klotho suppresses PTH-stimulated generation of inositol trisphosphate in vitro. Moreover, PTHinduced increase of cyclic AMP secretion and 1a,25-dihydroxyvitamin D 3 (1,25VD) was attenuated by recombinant human klotho in vivo. In addition, recombinant human klotho inhibits the expression of 1-OH by PTH both in vitro and in vivo. These results suggest that free klotho mediates the FGF23-induced inhibition of 1,25VD synthesis.

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Section: Discussionmentioning

confidence: 56%

Xeno-Klotho Inhibits Parathyroid Hormone Signaling

Takenaka

Inoue

Miyazaki

et al. 2015

Journal of Bone and Mineral Research

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“…Various studies over the past 15 years have suggested that, at certain concentrations within bone, La 3+ (which bears a number of chemical similarities to Ca 2+ including ionic radius, preferred coordination number, and preference for hard donor ligands) can invoke a cellular response that enhances bone building, signifying a potential for La 3+ to counter the effects of osteoporosis. − As a carbonate salt (known as Fosrenol), La 3+ is an approved orally administered treatment for hyperphosphatemia, and the drug owes its effectiveness to its very low intestinal absorbance (estimated to be less than 0.002%) . It was in this form that an effect of the metal ion on bone histology was first noted; however, with such low bioavailability, vastly elevated quantities would need to be administered in order to generate an effective oral dose.…”

Section: Introductionmentioning

confidence: 99%

Dipicolinate Complexes of Gallium(III) and Lanthanum(III)

et al. 2016

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Three dipicolinic acid amine-derived compounds functionalized with a carboxylate (Hdpaa), phosphonate (Hdppa), and bisphosphonate (Hdpbpa), as well as their nonfunctionalized analogue (Hdpa), were successfully synthesized and characterized. The 1:1 lanthanum(III) complexes of Hdpa, Hdpaa, and Hdppa, the 1:2 lanthanum(III) complex of Hdpa, and the 1:1 gallium(III) complex of Hdpaa were characterized, including via X-ray crystallography for [La(dppa)(HO)] and [Ga(dpaa)(HO)]. Hdpa, Hdpaa, and Hdppa were evaluated for their thermodynamic stability with lanthanum(III) via potentiometric and either UV-vis spectrophotometric (Hdpaa) or NMR spectrometric (Hdpa and Hdppa) titrations, which showed that the carboxylate (Hdpaa) and phosphonate (Hdppa) containing ligands enhanced the lanthanum(III) complex stability by 3-4 orders of magnitude relative to the unfunctionalized ligand (comparing log β and pM values) at physiological pH. In addition, potentiometric titrations with Hdpaa and gallium(III) were performed, which gave significantly (8 orders of magnitude) higher thermodynamic stability constants than with lanthanum(III). This was predicted to be a consequence of better size matching between the dipicolinate cavity and gallium(III), which was also evident in the aforementioned crystal structures. Because of a potential link between lanthanum(III) and osteoporosis, the ligands were tested for their bone-directing properties via a hydroxyapatite (HAP) binding assay, which showed that either a phosphonate or bisphosphonate moiety was necessary in order to elicit a chemical binding interaction with HAP. The oral activity of the ligands and their metal complexes was also assessed by experimentally measuring log P values using the shake-flask method, and these were compared to a currently prescribed osteoporosis drug (alendronate). Because of the potential therapeutic applications of the radionuclides Ga, radiolabeling studies were performed withGa and Hdpaa. Quantitative radiolabeling was achieved at pH 6.5 in 10 min at room temperature with concentrations as low as 10 M, and human serum stability studies were undertaken.

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