Soluble Klotho causes hypomineralization in Klotho-deficient mice

Area of Science:

• Endocrinology
• Bone Biology
• Molecular Signaling

Background:

• Klotho protein functions as a coreceptor for FGF23 in the kidney.
• Soluble Klotho (sKL) exhibits hormone-like activities, but its precise mechanisms in various organs are not fully understood.
• Aberrantly high FGF23 levels contribute to phosphate wasting and osteomalacia.

Purpose of the Study:

• To investigate the effects of exogenous soluble Klotho (sKL) on bone and osteoblasts.
• To elucidate the role of sKL in fibroblast growth factor 23 (FGF23) signaling within bone tissue.
• To identify downstream effectors of the sKL-FGF23-FGFR axis in bone.

Main Methods:

• Utilized Klotho-deficient (kl/kl) mice for in vivo studies.
• Employed cell and organ cultures for in vitro experiments.
• Analyzed FGF23 signaling, mineral deposition, and gene expression (including Phex).

Main Results:

• Exogenous sKL induced FGF23 signaling in bone and worsened hypomineralization in kl/kl mice.
• In vitro studies confirmed sKL-FGF23-FGFR complex formation and decreased Phex expression.
• Soluble PHEX treatment rescued sKL-FGF23-dependent hypomineralization in vitro.

Conclusions:

• Exogenously administered sKL directly participates in FGF23 signaling within bone.
• PHEX is identified as a downstream effector of the sKL-FGF23-FGFR signaling pathway in bone.
• These findings shed light on the complex interplay between Klotho, FGF23, and bone mineralization.