Postmenopausal osteoporosis (PMOP) brings a lot of inconvenience to patients and serious economic burden to society. The osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) plays vital role in the process of PMOP treatment. However, the functional mechanism remains unclear. In this study, GATA4, MALAT1 and KHSRP were downregulated in bone tissues of PMOP patients, while NEDD4 was overexpressed. Through functional experiments, GATA4 overexpression strikingly accelerated osteogenic differentiation of BMSCs and promoted bone formation in vitro and in vivo, while these effects were dramatically reversed after MALAT1 silence. Intermolecular interaction experiments confirmed that GATA4 activated the transcription of MALAT1, which could form a ‘RNA-protein’ complex with KHSRP to decay NEDD4 mRNA. NEDD4 promoted the degradation of Runx1 by ubiquitination. Moreover, NEDD4 silencing blocked the inhibitory effects of MALAT1 knockdown on BMSCs osteogenic differentiation. In sum up, GATA4-activated MALAT1 promoted BMSCs osteogenic differentiation via regulating KHSPR/NEDD4 axis-regulated RUNX1 degradation, ultimately improving PMOP.