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

Abstract

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.

Cartilage Homeostasis and Osteoarthritis

“…One of the circRNAs that was highly expressed in ISS, circRNA_0079201, functions as an miR-140-3p sponge. Furthermore, the proliferation, hypertrophy, and endochondral ossification of chondrocytes in ISS are regulated by the hsa_circRNA_0079201/miR-140-3p/SMAD2 pathway [ 129 ].…”

Hsa_circ_0008870 suppresses bone formation of growth plate through inhibition of miR-185-3p/ MAPK1 axis in idiopathic short stature

“…To determine the role of circRNAs in the molecular mechanisms of ISS, researchers identified differential expression of circRNAs in the peripheral blood of patients with ISS versus healthy controls. According to the outcomes of the circRNAs microarray, 145 differentially expressed circRNAs were screened (83 upregulated and 62 downregulated) ( Liu et al, 2020 ; Liu et al, 2021 ). In subsequent studies, it was verified that circANAPC2 and hsa_circularRNA_0079201 can serve as potential targets for treatment of ISS ( Liu et al, 2020 ; Liu et al, 2021 ).…”

“…According to the outcomes of the circRNAs microarray, 145 differentially expressed circRNAs were screened (83 upregulated and 62 downregulated) ( Liu et al, 2020 ; Liu et al, 2021 ). In subsequent studies, it was verified that circANAPC2 and hsa_circularRNA_0079201 can serve as potential targets for treatment of ISS ( Liu et al, 2020 ; Liu et al, 2021 ).…”

Identification and characterization of factors associated with short stature and pre-shortness in Chinese preschool-aged children

“…About 20% of short stature is pathological, and 80% is idiopathic due to unknown causes (16). Factors associated with less height gain have been extensively evaluated, yet the results are not often reproducible, especially for modifiable factors (17,18). For example, some studies have showed that high body mass index (BMI) was positively associated with short stature and pre-shortness (13,20), whereas others failed to support this claim (21).…”