α-Klotho/FGF23システム：電解質代謝，老化関連疾患，腎不全を結ぶ新たな視点

Bone Metabolism and Cardiovascular Function Update. α-Klotho/FGF23 system；A new insight into the field of mineral homeostasis and the pathogeneses of aging-associated syndromes and the complications of chronic kidney disease.

　α-klotho（α-kl）は多彩な早期老化類似症状を呈する挿入突然変異マウスの原因遺伝子として同定されたが，その後の分子機能の解析により電解質代謝を統合制御する分子であると結論された。α-klノックアウトマウスは血管の石灰化，軟部組織の異所性の石灰化，骨密度の低下，皮膚の老人性萎縮，肺気腫などの病理組織所見，ならびにカルシウム，リン濃度の亢進，ビタミンＤの機能亢進などの変異表現型を示し，その石灰化を中心とする病理組織所見は腎不全，特に血液透析患者の病理所見と酷似している。また，α-klノックアウトマウスの変異表現型の主要な要因である顕著な高リン血症が慢性腎臓病（CKD）の心血管障害による死亡に強く相関しており，α-kl mRNA，α-KlタンパクはCKD患者で著しく低下している。これらの事実はα-Kl，FGF23は加齢に関わる疾患のみならずCKDの合併症に深く関わっていることを示唆している。 　本稿ではα-KlとFGF23による電解質代謝の制御について概説し，α-kl変異マウスの解析を基盤に腎不全との関わりについて述べる。

　α-klotho（α-kl）was first identified as an aging gene and was later shown to be a regulator of mineral homeostasis. α-kl－/－ mice display multiple aging related phenotypes including atherosclerosis, cardiovascular/soft tissue calcifications, pulmonary emphysema, osteopenia, and senile atrophy of skin；such age-related organ pathologies are associated with biochemical changes in blood, including severe hyperphosphatemia, elevated serum FGF23 and1,25（OH）2 Vitamin D levels. Of significance, advanced stage patients suffering chronic kidney disease（CKD）develop multiple complications quite resembling phenotypes observed in α-kl－/－ mice, and high serum phosphate, the major cause of abnormalities of α-kl－/－ mice, has been reported to be closely associated with high levels of cardiovascular disease morbidity and mortality in patients with CKD, particularly in patients with end-stage renal disease. In addition, the expressions of α-kl mRNA and α-Kl protein were severely reduced in these patients. These results suggest the involvement of α-Kl and FGF23 in the pathogeneses of not only aging-associated syndromes but also the complications of CKD. Here, the unveiling of the molecular functions of α-Klotho and FGF23 has recently given new insight into the field of mineral homeostasis and the pathogeneses of aging-associated syndromes and the complications of CKD.