Differential toxicity profile of secreted and processed α-Klotho expression over mineral metabolism and bone microstructure

Assumpció Bosch i Merino, Miguel Chillón Rodríguez, Joan Roig-Soriano, Cristina Sánchez-de-Diego, Jon Esandi-Jauregui, Sergi Verdés, Carmela R Abraham, Francesc Ventura

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)


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.
Original languageEnglish
Article number4211
Number of pages10
JournalScientific Reports
Publication statusPublished - 14 Mar 2023


  • Biochemistry
  • Drug discovery
  • Genetics
  • Medical research
  • Molecular biology
  • Molecular medicine
  • Bone and Bones/metabolism
  • Protein Isoforms/metabolism
  • Minerals/metabolism
  • Klotho Proteins/metabolism
  • Kidney/metabolism
  • Mice, Knockout
  • Animals
  • Glucuronidase/genetics
  • Mice


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