Hsa_circularRNA_0079201 suppresses chondrocyte proliferation and endochondral ossification by regulating the microRNA-140-3p/SMAD2 signaling pathway in idiopathic short stature

Circular (circ)RNAs are an important group of non-coding RNAs involved in different pathological and physiological functions, such as longitudinal bone growth. However, the effects of an increase or decrease in circRNA expression on idiopathic short stature (ISS) remain largely unknown. The present study compared the circRNA expression patterns of patients with ISS and healthy individuals to identify differentially expressed circRNAs involved in the regulation of ISS pathogenesis and their target microRNAs (miR). Microarray analysis revealed that 145 circRNAs were differentially expressed in patients with ISS, including 83 up- and 62 downregulated circRNAs. Reverse transcription-quantitative PCR confirmed that hsa_circRNA_0079201 was increased in patients with ISS compared with that in the normal individuals, whilst hsa_circRNA_0079201 overexpression in human chondrocytes was shown to significantly suppress their proliferation, hypertrophy and endochondral ossification abilities. Luciferase reporter assays identified that circRNA_0079201 acted as an miR-140-3p sponge. In situ hybridization confirmed the co-localization of circRNA_0079201 and miR-140-3p in the human chondrocyte and neonatal femur growth plate of C57 mice, while rescue experiments demonstrated that miR-140-3p overexpression reversed the inhibition of human chondrocyte proliferation, hypertrophy and endochondral ossification, caused by circRNA_0079201 overexpression. Bioinformatics analysis and luciferase reporter assays revealed that SMAD2 was a potential target gene of miR-140-3p. Furthermore, overexpressing circRNA_0079201 in human chondrocytes suppressed miR-140-3p and increased SMAD2 protein expression level. Taken together, chondrocyte proliferation, hypertrophy and endochondral ossification in ISS was suppressed by a novel regulatory axis consisting of the hsa_circRNA_0079201/miR-140-3p/SMAD2 pathway. The present study provided evidence that hsa_circRNA_0079201 may be a potential target for ISS therapy.