Differential toxicity profile of secreted and processed α-Klotho expression over mineral metabolism and bone microstructure
Roig-Soriano, Joan (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Sánchez-de-Diego, Cristina (Hospital Universitari de Bellvitge)
Esandi-Jauregui, Jon (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Verdés, Sergi (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Abraham, Carmela R (Boston University School of Medicine)
Bosch i Merino, Assumpció (Hospital Universitari Vall d'Hebron)
Ventura, Francesc (Hospital Universitari de Bellvitge)
Chillón Rodríguez, Miguel (Hospital Universitari Vall d'Hebron)

Date:	2023
Abstract:	The aging-protective gene α-Klotho (KL) produces two main transcripts. The full-length mRNA generates a transmembrane protein that after proteolytic ectodomain shedding can be detected in serum as processed Klotho (p-KL), and a shorter transcript which codes for a putatively secreted protein (s-KL). Both isoforms exhibit potent pleiotropic beneficial properties, although previous reports showed negative side effects on mineral homeostasis after increasing p-KL concentration exogenously. Here, we expressed independently both isoforms using gene transfer vectors, to assess s-KL effects on mineral metabolism. While mice treated with p-KL presented altered expression of several kidney ion channels, as well as altered levels of P and Ca 2+ in blood, s-KL treated mice had levels comparable to Null-treated control mice. Besides, bone gene expression of Fgf23 showed a fourfold increase after p-KL treatment, effects not observed with the s-KL isoform. Similarly, bone microstructure parameters of p-KL-treated mice were significantly worse than in control animals, while this was not observed for s-KL, which showed an unexpected increase in trabecular thickness and cortical mineral density. As a conclusion, s-KL (but not p-KL) is a safe therapeutic strategy to exploit KL anti-aging protective effects, presenting no apparent negative effects over mineral metabolism and bone microstructure.
Grants:	Agencia Estatal de Investigación PID2019-104034RB-I00 Agencia Estatal de Investigación PID2020-116735RB-I00
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Biochemistry ; Drug discovery ; Genetics ; Medical research ; Molecular biology ; Molecular medicine
Published in:	Scientific reports, Vol. 13 (march 2023) , ISSN 2045-2322

DOI: 10.1038/s41598-023-31117-6
PMID: 36918615

10 p, 3.2 MB

The record appears in these collections:
Articles > Research articles
Articles > Published articles