Circular RNA circSTX12 regulates osteo-adipogenic balance and proliferation of BMSCs in senile osteoporosis

Increased adipogenic differentiation and decreased osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) along with slow self-renewal are pivotal causes for decreased bone formation in senile osteoporosis. Circular RNAs (circRNAs) play important roles in cell proliferation and differentiation, and are closely related to osteoporosis. Whether circRNAs orchestrate the adipo-osteogenic balance and the proliferation of BMSCs in osteoporosis remains unclear. We found in this study that circSTX12 was abnormally upregulated in bone sections from osteoporosis patients and in BMSCs from aged mice, as well as in later-generation human BMSCs in culture. Knockdown of circSTX12 in BMSCs resulted in enhanced osteogenesis, decreased adipogenesis, and increased proliferation capacity; circSTX12 overexpression had the opposite effect. RNA pull-down and mass spectrometry revealed the interactions between circSTX12 with CBL and LMO7. At the molecular level, circSTX12 regulated cell fate in BMSCs by competitively binding to CBL, reducing the ubiquitination-mediated degradation of MST1 and thereby activating the Hippo pathway, a key regulator of adipo-osteogenic balance. Knockdown of circSTX12 promoted the nuclear localization of YAP. In addition, our findings suggest that LMO7 mediates circSTX12-induced BMSCs proliferation by regulating the transcription of CCNA2, CCNH, and CCND1. In vivo, injection of antisense oligonucleotides (ASOs) to knockdown circSTX12 promoted bone formation in aged mice. Our results provide evidence for circSTX12 as a regulator of adipo-osteogenic differentiation and proliferation of BMSCs through binding to CBL and LMO7, respectively. Targeting circSTX12 may be a novel approach for osteoporosis treatment.