ATF6a, a Runx2-activable transcription factor, is a novel regulator of chondrocyte hypertrophy

Abstract

Our previous research has shown that the spliced isoform of XBP1 (XBP1s) is an important downstream mediator of BMP2 and is involved in BMP2-stimulated chondrocyte differentiation. Herein, we report that ATF6 and its cleaved N-terminal cytoplasmic domain (known as ATF6a) are expressed in growth plate chondrocytes. We find that these proteins are differentially induced during BMP2-triggered chondrocyte differentiation. This differential expression probably results from the activation of the ATF6 gene by Runx2 and its repression by the Sox6 transcription factor. Runx2 and Sox6 act through their respective binding elements on the 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. By contrast, lowering expression of ATF6a by use of its specific siRNA suppresses chondrocyte differentiation. Moreover, ATF6a interacts with Runx2 and augments the Runx2-mediated hypertrophication of chondrocytes. Importantly, overexpression and knockdown of ATF6a during the chondrocyte hypertrophy process also led to altered expressions of IHH and PTHrP (also known as PTHLH). Taken together, these findings indicate that ATF6a favorably controls chondrogenesis and bone formation (1) by acting as a co-factor of Runx2 and enhancing Runx2-incited hypertrophic chondrocyte differentiation, and (2) by affecting IHH and PTHrP signaling.

Transcriptional control of chondrocyte specification and differentiation

“…The factor, however, exacerbates post-traumatic osteoarthritis downstream of inflammatory cytokines. Other studies have suggested that ATF2 and CREB could promote GPC cell cycle progression, and that ATF6 could promote chondrocyte hypertrophy by interacting with RUNX2 [149]. BBF2H7 (encoded by CREB3L2 ) is a membrane-bound TF most highly expressed in CCs [150].…”

Establishment and validation of an endoplasmic reticulum stress reporter to monitor zebrafish ATF6 activity in development and disease

“…Recently, ATF6 has been implicated in the development of multiple tissue types, and dysregulation of ATF6 expression is related to disease (Hillary and FitzGerald, 2018). Developmental roles of ATF6 include mesoderm differentiation (Kroeger et al, 2018), osteogenesis and chondrogenesis (Guo et al, 2016;Jang et al, 2012;Kim et al, 2014;Maeda et al, 2015;Xiong et al, 2015), neurodevelopment (Cho et al, 2009;Naughton et al, 2015;Saito et al, 2012;Zhang et al, 2007), adipogenesis and lipogenesis (Lowe et al, 2012), and formation of female reproductive structures (Lin et al, 2012;Park et al, 2013;Xiong et al, 2016;Yang et al, 2015). Most relevant to our work is the role of ATF6 in ocular and muscular embryology, because these tissues had the highest ATF6 reporter expression during zebrafish development.…”

Hypertrophic differentiation of mesenchymal stem cells is suppressed by xanthotoxin via the p38-MAPK/HDAC4 pathway

“…Then we draw a conclusion that XAT suppresses chondrocyte hypertrophic differentiation of MSCs. The transcription factor Runx2 is crucial for regulating chondrocyte hypertrophy ( 21 , 22 ). Overexpression of Runx2 in all chondrocytes resulted in premature chondrocyte hypertrophy ( 23 ).…”