ATF6-dependent expression of an BMP2-inducible XBP1S protein is required for chondrocyte differentiation

Our previous research testified that XBP1S is a significant downstream mediator of BMP2 and is involved in BMP2-stimulated chondrocyte differentiation. Herein we report that ATF6 and ATF6a are expressed in growth plate chondrocytes. There are differentially induced during BMP2-triggered chondrocyte differentiation. This differential expression is probably resulted from the activation of the ATF6 gene by Runx2 and repression by Sox6 transcription factor. Runx2 and Sox6 combine with their respective binding elements of ATF6 gene. When overexpressed, ATF6 and ATF6a intensify chondrogenesis; our studies demonstrate that under the stimulation of ATF6 and ATF6a, chondrocytes tend to be hypertrophied and mineralized, a process leading to bone formation. Additionally, lowing expression of ATF6a using its specific siRNA suppresses chondrocyte differentiation. Moreover, ATF6a interacts with Runx2 and augments Runx2-mediated hypertrophied chondrocyte. Importantly, overexpression and knockdown of ATF6a in chondrocyte hypertrophy also lead to altered expressions of IHH and PTHrP. Taken together, these findings indicate that ATF6a favorably controls chondrogenesis and bone formation via a) acting as a co-factor of Runx2 and enhancing Runx2-incited hypertrophic chondrocyte differentiation, and b) affecting IHH/PTHrP signaling.