Abstract: Objective To investigate the role of a novel human-specific long noncoding RNA (lncRNA), MEK6-AS1, and its potential molecular mechanism in improving the osteogenic differentiation of senescent mesenchymal stem cells (MSCs). Methods An in vitro human MSCs replicative senescence model was established by sequential passaging, and then senescence was identified by β staining and senescence-related gene expression. RT-qPCR was used to detect the expression of MEK6-AS1 during senescence and osteogenic differentiation of human MSCs (hMSCs); Lentiviral knockdown technology was used to regulate the expression of MEK6-AS1 in the MSCs replicative senescence model. Transcriptome sequencing technology was utilized to analyze the effects of MEK6-AS1 on the transcriptome of hMSCs especially on genes and pathways related to osteogenic differentiation. The effect of MEK6-AS1 as an intervention target at osteogenic differentiation of human senescent hMSCs was evaluated with alkaline phosphatase staining microscopy. PCR technology was used to detect osteogenic gene expression levels in cells. Results With aging process, the osteogenic differentiation ability of hMSCs decreased significantly while the expression level of MEK6-AS1 was enhanced(P＜0.000 1). Knockdown of MEK6-AS1 significantly enhanced the osteogenic differentiation of MSCs by the up-regulating expression of osteogenic markers and increasing mineralization capacity(P＜0.001). Conclusions Knockdown of human-specific lncRNA MEK6-AS1 improves osteogenic differentiation of senescent MSCs, providing a new target and theoretical basis for the treatment of senescence-associated osteoporosis.

Key words: mesenchymal stem cells (MSCs), senescence, osteogenic differentiation, long noncoding RNA (lncRNA), MEK6-AS1