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C-terminal fragment of BBF2H7, an ER stress transducer, regulates chondrocyte proliferation

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DOI:10.1038/bonekey.2014.50

Dysfunction of the endoplasmic reticulum (ER) releases an abundance of unfolded proteins. This study reveals that the unfolded portion of BBF2H7, the product of a gene located on chromosome 7, plays a crucial role in cartilage development.

BBF2H7 knockout mice exhibit severe chondrodysplasia due to inhibition of chondrocyte function and also chondrocyte number. In this model, transfecting mouse embryonic fibroblasts with full length BBF2H7 provided a complete rescue, as did the BBF2H7 C-terminal luminal domain alone. The BBF2H7 N-terminal fragment had no effect. Further studies showed that the C-terminal fragment was secreted into the extracellular space, and this increased with physiological stress on the ER.

The C terminus was shown to enhance expression of targets of Hedgehog signaling and to promote chondrocyte proliferation by acting as a cofactor of Indian hedgehog (Ihh). Binding of BBF2H7 C terminus to Patched-1 and Ihh led to the formation of a ligand-receptor complex. Experiments also showed that the BBF2H7 C terminus acted as a suppressor of hypertrophic differentiation through its activity within the Ihh-parathyroid hormone-related protein pathway.

Editor’s comment: BBF2H7 N terminus functions as a transcription factor and plays a role in chondrocyte differentiation. This study demonstrates that BBF2H7 C terminus is secreted extracellularly by physiological ER stress, activates hedgehog signaling and promotes chondrocyte proliferation by binding to both Indian hedgehog and its receptor Patched-1. Thus, ER stress triggers both differentiation and proliferation of chondrocytes by producing N and C terminus of BBF2H7.

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