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Evidence for a novel parathyroid-specific signaling pathway in calcium homeostasis
DOI:10.1038/bonekey.2014.33
Olauson et al. generated transgenic mice with a Klotho deletion just in parathyroid tissue to observe the interaction between type I membrane-bound α-Klotho, a permissive co-receptor of phosphaturic hormone fibroblast growth factor-23 (FGF23) and calcium homeostasis.
The PTH-KL knockout (KO) mice appeared normal and had typical lifespans. Their expression of parathyroid hormone (PTH) was equivalent to wild-type mice and they demonstrated the same responses to imposed changes in serum calcium levels. So was their response to renal failure or the alteration in PTH production after iv delivery of FGF23, although FGF23 activation of the MAPK/ERK pathway was disrupted.
Some important differences were observed. The Klotho KO mice showed serum levels of 1,25-dihydroxy vitamin D3 (1,25(OH)2D) that were approximately double that of the wild-type mice. Klotho KO mice demonstrated constitutively activated calcineurin-NFAT signaling. Wild-type mice given FGF23 showed PTH suppression even after cyclosporine A treatment but Klotho KO mice became unresponsive.
Editor’s comment: These elegant experiments provide further insights into the complex relationship between FGF23, Klotho, and PTH. Although serum levels of PTH, calcium and phosphate remained unaltered in parathyroid-deficient Klotho mice, pleading for an alternative (Klotho-independent, calcineurin-dependent) regulatory pathway, levels of (1,25(OH)2D) were indeed elevated, which remains unexplained.
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