[Bone and Calcium Research Update 2015. The regulation of proliferation and differentiation by the ER stress transducer in chondrocytes]

BBF2H7 is an ER-resident transmembrane transcription factor which is structurally similar to ATF6, one of the canonical ER stress transducers, and preferentially expresses in chondrocytes. This molecule is processed at the transmembrane region in response to ER stress or differentiation stimuli. The cleaved amino (N) -terminal cytoplasmic domain promotes transcription of the ER-Golgi trafficking protein Sec23a, and plays a crucial role in secretion of extracellular matrix proteins from chondrocytes during cartilage formation. On the contrary, the cleaved C-terminal luminal domain of BBF2H7 is secreted from chondrocytes. The secreted BBF2H7 C-terminus directly binds to both Indian Hedgehog and its receptor Patched-1, and facilitates complex formation of the ligand-receptor followed by activation of Hedgehog signaling to promote proliferation in neighbouring chondrocytes. The dual N- and C-terminal functions of BBF2H7 triggered by physiological ER stress could allow chondrocytes to promote simultaneously distinct cellular events for differentiation and proliferation in developing cartilage.