Abstract
miR-214 is known to play a role in mammalian skeletal development through inhibition of osteogenesis and stimulation of osteoclastogenesis, but data regarding other vertebrates, as well as a possible role in chondrogenesis, remain unknown. Here, we show that miR-214 expression is detected in bone and cartilage of zebrafish skeleton, and is downregulated during murine ATDC5 chondrocyte differentiation. Additionally, we observed a conservation of the transcriptional regulation of miR-214 primary transcript Dnm3os in vertebrates, being regulated by Ets1 in ATDC5 chondrogenic cells. Moreover, overexpression of miR-214 in vitro and in vivo mitigated chondrocyte differentiation probably by targeting activating transcription factor 4 (Atf4). Indeed, miR-214 overexpression in vivo hampered cranial cartilage formation of zebrafish and coincided with downregulation of atf4 and of the key chondrogenic players sox9 and col2a1. We show that miR-214 overexpression exerts a negative role in chondrogenesis by impacting on chondrocyte differentiation possibly through conserved mechanisms.
Highlights
Most of the elements of the vertebrate skeleton are built through endochondral bone formation from a cartilage anlage
The pattern of expression of miR-214 during zebrafish development and ATDC5 chondrogenic differentiation suggested that this miRNA was most likely associated to chondrogenesis
This was evidenced by the high levels of miR-214 expression found during early stages of cartilage formation in zebrafish and in undifferentiated ATDC5 cells
Summary
Most of the elements of the vertebrate skeleton are built through endochondral bone formation from a cartilage anlage. MiR-214 was shown to inhibit bone formation by regulating Atf[410], and to promote osteoclastogenesis by targeting Pten[11]. Upon miR-214 overexpression, Atf[4] expression concomitantly decreased, suggesting that this gene could be a target of miR-214 in chondrogenesis. Supporting this notion, miR-214 gain-of-function in zebrafish was shown to impair cranial cartilage formation, and this was accompanied by a downregulation of atf[4] and of crucial cartilage markers, unveiling a negative impact of miR-214 on chondrogenesis
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