Category: endocrine_axis
Klotho (αKlotho) is a single-pass transmembrane protein discovered as a longevity gene — Klotho-deficient mice show premature aging (vascular calcification, osteopenia, infertility, atrophy). αKlotho acts as the obligate co-receptor for FGF23, converting promiscuous FGFRs (1c, 3c, 4) into FGF23-specific high-affinity receptors in target tissues (kidney proximal tubule + parathyroid). Phosphate axis: FGF23 is secreted by osteocytes/osteoblasts in response to ↑serum Pi + ↑calcitriol + ↑PTH. FGF23-Klotho-FGFR1c on kidney → ↓NaPi-2a/2c (PT brush border) → phosphaturia; FGF23 also ↓CYP27B1 + ↑CYP24A1 → ↓calcitriol (counter-regulating Pi absorption). In parathyroid: FGF23 → ↓PTH (acute). Three-hormone interplay: PTH ↑Pi excretion + ↑calcitriol + ↑bone resorption; FGF23 ↑Pi excretion + ↓calcitriol; calcitriol ↑Ca + Pi absorption + ↑FGF23 secretion. CKD-MBD: declining GFR → Pi retention → ↑FGF23 (compensatory) → ↓calcitriol → secondary hyperparathyroidism → tertiary HPT; ↑FGF23 also independently associated with CV mortality + LVH. Klotho also has hormonal soluble form (shed by ADAM10/17 + γ-secretase) — circulates as anti-aging factor (regulates Ca channels, oxidative stress, Wnt, IGF-1). Loss of soluble Klotho in CKD → contributes to vascular calcification + cognitive decline. Therapeutics: phosphate binders (sevelamer, lanthanum, calcium carbonate, sucroferric oxyhydroxide) lower dietary Pi load; calcimimetics (cinacalcet, etelcalcetide) — CaSR agonists → ↓PTH; calcitriol/paricalcitol for CKD-MBD with monitoring; burosumab (anti-FGF23 mAb) for X-linked hypophosphatemic rickets + tumor-induced osteomalacia. Cross-links: [[calcium_phosphate_pth_axis]] (PTH + Ca arm), [[vitamin_d_metabolism]] (calcitriol), [[bone_remodeling_rank_rankl]] (osteocyte source).