Neural EGFL-Like 1 Is a Downstream Regulator of Runt-Related Transcription Factor 2 in Chondrogenic Differentiation and Maturation

Am J Pathol. 2017 May;187(5):963-972. doi: 10.1016/j.ajpath.2016.12.026. Epub 2017 Mar 14.


Recent studies indicate that neural EGFL-like 1 (Nell-1), a secretive extracellular matrix molecule, is involved in chondrogenic differentiation. Herein, we demonstrated that Nell-1 serves as a key downstream target of runt-related transcription factor 2 (Runx2), a central regulator of chondrogenesis. Unlike in osteoblast lineage cells where Nell-1 and Runx2 demonstrate mutual regulation, further studies in chondrocytes revealed that Runx2 tightly regulates the expression of Nell-1; however, Nell-1 does not alter the expression of Runx2. More important, Nell-1 administration partially restored Runx2 deficiency-induced impairment of chondrocyte differentiation and maturation in vitro, ex vivo, and in vivo. Mechanistically, although the expression of Nell-1 is highly reliant on Runx2, the prochondrogenic function of Nell-1 persisted in Runx2-/- scenarios. The biopotency of Nell-1 is independent of the nuclear import and DNA binding functions of Runx2 during chondrogenesis. Nell-1 is a key functional mediator of chondrogenesis, thus opening up new possibilities for the application of Nell-1 in cartilage regeneration.

MeSH terms

  • Animals
  • Calcium-Binding Proteins / physiology*
  • Cartilage / physiology*
  • Cell Differentiation / physiology
  • Cell Proliferation / physiology
  • Chondrocytes / physiology
  • Chondrogenesis / physiology*
  • Core Binding Factor Alpha 1 Subunit / physiology*
  • Femur / embryology
  • Femur / growth & development
  • Glycoproteins / physiology*
  • Hindlimb / physiology
  • Mice, Inbred C57BL
  • Regeneration


  • Calcium-Binding Proteins
  • Core Binding Factor Alpha 1 Subunit
  • Glycoproteins
  • Nell1 protein, mouse
  • Runx2 protein, mouse