Soluble Klotho regulates bone differentiation by upregulating expression of the transcription factor EGR-1

FEBS Lett. 2020 Jan;594(2):290-300. doi: 10.1002/1873-3468.13613. Epub 2019 Oct 6.


Klotho is a transmembrane protein known to regulate aging and lifespan. Soluble Klotho (sKL), a truncated form of Klotho, regulates various cell signaling pathways, including bone development. Here, we investigated the relationship between sKL and the zinc finger transcription factor early growth response protein 1 (EGR-1) on bone formation. We find that sKL induces the expression of EGR-1 mRNA and protein. Through mutational analysis, we identify the 130 bp region on the EGR-1 promoter that is responsive to sKL overexpression. Additionally, sKL induces the expression of markers of bone differentiation (BMP2, RUNX2, ALP, COL1A, and osteocalcin) in osteoblast MC3T3 cells. EGR-1 siRNA decreases the bone mineralization induced by sKL or ascorbic acid/glycerol 2-phosphate in MC3T3 cells. Our results suggest that sKL may regulate bone development through EGR-1 expression.

Keywords: EGR-1; osteogenic differentiation; soluble Klotho.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Bone Morphogenetic Protein 2 / genetics
  • Calcification, Physiologic / genetics
  • Cell Differentiation / genetics*
  • Collagen Type I / genetics
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Early Growth Response Protein 1 / genetics*
  • Gene Expression Regulation, Developmental / genetics
  • Glucuronidase / genetics*
  • HEK293 Cells
  • Humans
  • Mice
  • Osteoblasts / metabolism
  • Osteogenesis / genetics*
  • RNA, Small Interfering / genetics
  • Signal Transduction / genetics


  • BMP2 protein, human
  • Bone Morphogenetic Protein 2
  • Collagen Type I
  • Core Binding Factor Alpha 1 Subunit
  • EGR1 protein, human
  • Early Growth Response Protein 1
  • RNA, Small Interfering
  • collagen type I, alpha 1 chain
  • Glucuronidase
  • klotho protein