Nfatc1 Is a Functional Transcriptional Factor Mediating Nell-1-Induced Runx3 Upregulation in Chondrocytes

Int J Mol Sci. 2018 Jan 6;19(1):168. doi: 10.3390/ijms19010168.

Abstract

Neural EGFL like 1 (Nell-1) is essential for chondrogenic differentiation, maturation, and regeneration. Our previous studies have demonstrated that Nell-1's pro-chondrogenic activities are predominantly reliant upon runt-related transcription factor 3 (Runx3)-mediated Indian hedgehog (Ihh) signaling. Here, we identify the nuclear factor of activated T-cells 1 (Nfatc1) as the key transcriptional factor mediating the Nell-1 → Runx3 signal transduction in chondrocytes. Using chromatin immunoprecipitation assay, we were able to determine that Nfatc1 binds to the -833--810 region of the Runx3-promoter in response to Nell-1 treatment. By revealing the Nell-1 → Nfatc1 → Runx3 → Ihh cascade, we demonstrate the involvement of Nfatc1, a nuclear factor of activated T-cells, in chondrogenesis, while providing innovative insights into developing a novel therapeutic strategy for cartilage regeneration and other chondrogenesis-related conditions.

Keywords: chondrogenesis; neural EGFL like 1 (Nell-1); nuclear factor of activated T-cells 1 (Nfatc1); runt-related transcription factor 3 (Runx3).

MeSH terms

  • Adipose Tissue / cytology
  • Animals
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Calcium-Binding Proteins / pharmacology*
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Chondrocytes / cytology
  • Chondrocytes / metabolism
  • Chondrogenesis / drug effects
  • Core Binding Factor Alpha 1 Subunit / deficiency
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / antagonists & inhibitors
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • Core Binding Factor Alpha 3 Subunit / genetics
  • Core Binding Factor Alpha 3 Subunit / metabolism*
  • Glycoproteins / genetics
  • Glycoproteins / metabolism
  • Glycoproteins / pharmacology*
  • Mice
  • Mice, Knockout
  • NFATC Transcription Factors / antagonists & inhibitors
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / metabolism*
  • Promoter Regions, Genetic
  • Protein Binding
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Signal Transduction / drug effects
  • Up-Regulation / drug effects*

Substances

  • Calcium-Binding Proteins
  • Core Binding Factor Alpha 1 Subunit
  • Core Binding Factor Alpha 2 Subunit
  • Core Binding Factor Alpha 3 Subunit
  • Glycoproteins
  • NFATC Transcription Factors
  • Nell1 protein, mouse
  • RNA, Small Interfering
  • Runx1 protein, mouse
  • Runx2 protein, mouse
  • Runx3 protein, mouse