Teriparatide facilitates osteogenic differentiation of bone mesenchymal stem cells to alleviate idiopathic osteoporosis via the circFNDC3B-miR-125a-5p-GLS axis

Osteoporosis (OP), a systemic bone disease, is characterized by degeneration of bone microstructure and susceptibility to fracture. Teriparatide (TPD) is an active fragment of human endogenous parathyroid hormone which has been revealed to promote osteogenesis of mesenchymal stem cells (hMSCs) to alleviate osteoporosis. Currently, the underlying cellular and molecular mechanisms of TPD in treating OP were not fully understood. This study aimed to investigate the roles of non-coding RNA-regulated osteogenic differentiation of hMSCs under TPD treatments. Circular RNA FNDC3B was significantly downregulated, and miRNA-125a-5p was upregulated in primary hMSCs of osteoporosis patients. Moreover, during osteogenesis, expression of circFNDC3B and glutamine metabolism were gradually elevated and miR-125a-5p was suppressed. Silencing circFNDC3B or overexpression of miR-125a-5p remarkedly suppressed the TPD-induced osteogenic differentiation-related genes (ALP, RUNX2, osteocalcin, osteonectin) activity or expression and calcium deposition of hMSCs. Results from RNA pull-down, RNA IP and luciferase assays demonstrated that circFNDC3B sponged miR-125a-5p, which further targeted 3'UTR of glutaminase (GLS), a key enzyme in glutamine metabolism to form a ceRNA regulator network. Rescue experiments demonstrated under TPD treatment, silencing of circFNDC3B significantly upregulated miR-125a-5p expression, blocked GLS expression and inhibited osteogenic differentiation evidenced by the suppressed ALP activity and expressions of osteocalcin, osteonectin and RUNX2. These regulatory phenotypes were further overridden by miR-125a-5p inhibition. In summary, our study demonstrated that TPD treatment promoted osteogenic differentiation of hMSCs by regulating the circFNDC3B-miR-125a-5p-GLS pathway.