Circulating exosomal circRNA_0063476 impairs expression of markers of bone growth via the miR-518c-3p/DDX6 axis in ISS

Endocrinology. 2022 Aug 17;bqac138. doi: 10.1210/endocr/bqac138. Online ahead of print.

Abstract

Objectives: Idiopathic short stature (ISS), a disorder of unknown cause, accounts for approximately 80% of the clinical diagnoses of children with short stature. Exosomal circular RNA in plasma has been implicated in various disease processes. However, the role of exosome-derived circRNA in ISS has not been elucidated yet.

Methods: Plasma exosomes of ISS and normal children were cocultured with human chondrocytes. Microarray analysis and RT-PCR identified the differential expression of circRNA in exosomes between ISS and normal children. Hsa_circ_0063476 was upregulated or downregulated in human chondrocytes. Subsequently, overexpression rats of hsa_circ_0063476 was constructed via adenovirial vector to further validate the role of hsa_circ_0063476 on longitudinal bone growth via in vivo experiment.

Results: The plasma exosome of ISS children suppressed the expression of markers of chondrocyte hypertrophy and endochondral ossification. Subsequently, upregulation of hsa_circ_0063476 in ISS exosome was identified. In vitro experiment demonstrated that chondrocyte proliferation, cell cycle and endochondral ossification were suppressed, and apoptosis was increased following hsa_circ_0063476 overexpression in human chondrocyte. Conversely, silencing hsa_circ_0063476 in human chondrocyte can show opposite outcomes. Our study further revealed hsa_circ_0063476 overexpression in vitro can enhance chondrocyte apoptosis and inhibit the expression of markers of chondrocyte proliferation and endochondral ossification via miR-518c-3p/DDX6 axis. Additionally, the rats of hsa_circ_0063476 overexpression showed a short stature phenotype.

Conclusions: The authors identified a novel pathogenesis in ISS that exosome-derived hsa_circ_ 0063476 retards the expression of markers of endochondral ossification and impairs longitudinal bone growth via miR-518c-3p/DDX6 axis, which may provide a unique therapeutic avenue for ISS.

Keywords: circular RNA; endochondral ossification; exosome; idiopathic short stature.