Regulation of endoplasmic reticulum stress response by a BBF2H7-mediated Sec23a pathway is essential for chondrogenesis

Nat Cell Biol. 2009 Oct;11(10):1197-204. doi: 10.1038/ncb1962. Epub 2009 Sep 20.


Many tissues have a specific signal transduction system for endoplasmic reticulum (ER) dysfunction; however, the mechanisms underlying the ER stress response in cartilage remain unclear. BBF2H7 (BBF2 human homologue on chromosome 7), an ER-resident basic leucine zipper transcription factor, is activated in response to ER stress and is highly expressed in chondrocytes. In this study, we generated Bbf2h7(-/-) mice to assess the in vivo function of BBF2H7. The mice showed severe chondrodysplasia and died by suffocation shortly after birth because of an immature chest cavity. The cartilage showed a lack of typical columnar structure in the proliferating zone and a decrease in the size of the hypertrophic zone, resulting in a significant reduction of extracellular matrix proteins. Interestingly, proliferating chondrocytes showed abnormally expanded ER, containing aggregated type II collagen (Col2) and cartilage oligomeric matrix protein (COMP). We identified Sec23a, which encodes a coat protein complex II component responsible for protein transport from the ER to the Golgi, as a target of BBF2H7, which directly bound to a CRE-like sequence in the promoter region of Sec23a to activate its transcription. When Sec23a was introduced to Bbf2h7(-/-) chondrocytes, the impaired transport and secretion of cartilage matrix proteins was totally restored, indicating that by activating protein secretion the BBF2H7-Sec23a pathway has a crucial role in chondrogenesis. Our findings provide a new link by which ER stress is converted to signalling for the activation of ER-to-Golgi trafficking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Cartilage Oligomeric Matrix Protein
  • Cartilage, Articular / cytology
  • Cells, Cultured
  • Chondrocytes / physiology
  • Chondrocytes / ultrastructure
  • Chondrogenesis*
  • Collagen Type II / metabolism
  • Embryo, Mammalian
  • Endoplasmic Reticulum / physiology*
  • Endoplasmic Reticulum / ultrastructure
  • Extracellular Matrix Proteins / metabolism
  • Gene Expression Regulation, Developmental
  • Glycoproteins / metabolism
  • Golgi Apparatus / metabolism
  • Immunohistochemistry
  • In Situ Hybridization
  • Matrilin Proteins
  • Mice
  • Mice, Knockout
  • Protein Transport
  • Ribs / cytology
  • Vesicular Transport Proteins / biosynthesis
  • Vesicular Transport Proteins / genetics*
  • Vesicular Transport Proteins / metabolism*


  • Basic-Leucine Zipper Transcription Factors
  • Cartilage Oligomeric Matrix Protein
  • Collagen Type II
  • Creb3l2 protein, mouse
  • Extracellular Matrix Proteins
  • Glycoproteins
  • Matn1 protein, mouse
  • Matrilin Proteins
  • Sec23a protein, mouse
  • TSP5 protein, human
  • Vesicular Transport Proteins