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OBJECTIVE To illustrate the role of micro ribonucleic acid (miR)-330-5p in regulating osteogenesis through biglycan (Bgn)-mediated bone morphogenetic protein (BMP)/Smad pathway. MATERIALS AND METHODS A mouse model of osteoporosis (OP) was established by ovariectomy (OVX). BMD and miR-330-5p levels in mice undergoing sham operation or OVX were determined. BMD and BV/TV in OP mice with in vivo knockdown of miR-330-5p were measured by Micro-CT. After silencing of miR-330-5p in mouse primary bone marrow stromal cells (BMSCs), expression changes in osteogenesis-associated genes, ALP activity, and mineralization ability were assessed. Subsequently, the interaction between miR-330-5p and Bgn was examined by Dual-Luciferase reporter gene assay and Western blotting. Then, Bgn levels in BMSCs undergoing osteogenesis at different time points were measured. At last, the regulatory effects of miR-330-5p/Bgn axis on the BMP/Smad pathway, ALP activity, and mineralization ability in BMSCs were evaluated. RESULTS BMD was decreased and miR-330-5p was upregulated in OP mice. OP mice with in vivo knockdown of miNA-330-5p presented higher BMD and BV/TV than controls. Transfection with miR-330-5p inhibitor upregulated osteogenesis-associated genes, ALP activity, and mineralization ability in BMSCs. Bgn was time-dependently upregulated in BMSCs undergoing osteogenesis, which was indicated to be the target gene of miR-330-5p. Besides, Bgn level was negatively regulated by miR-330-5p. Importantly, Bgn was able to reverse the regulatory effects of miR-330-5p on the BMP/Smad pathway, ALP activity, and mineralization ability in BMSCs. CONCLUSIONS Knockdown of miR-330-5p facilitates osteogenesis in BMSCs through the Bgn-induced BMP/Smad pathway, thus alleviating the progression of OP.