The osteogenic capacities of bone marrow-derived stromal cells (BMSCs) diminish during replicative senescence, and these changes affect the success of therapeutic application of BMSCs. In this study, we sought to explore the molecular mechanisms underlying the osteogenic differentiation capacities that occur during replicative senescence. It is well known that Oct4 is a key transcription factor essential for maintaining differentiation capacities of the stem cells. In this study, we found that BMSCs at passage 6 (replicative senescent BMSCs) showed marked decreases in the osteogenic differentiation potential and the level of Oct4. These were accompanied by reduced levels of Snf5 and histone H3 lysine-4 trimethylation (H3K4me3) in the Oct4 promoter. In BMSCs at passage 2, knockdown of Snf5 diminished expression of Oct4 and disrupted the up-regulation of alkaline phosphatase (ALP) and runt-related transcription factor 2 (Runx2) after osteogenic differentiation induction, which was accompanied by a reduction in Snf5 and H3K4me3 binding to the Oct4 promoter. These findings indicate that the decreased level of Snf5 binding to the promoter region of the Oct4 gene down-regulated the expression of Oct4, which may be the mechanism underlying the decline in osteogenic capacities in replicative senescent BMSCs.

在复制衰老过程中，骨髓基质细胞（BMSCs）的成骨能力下降，这些变化影响了BMSCs治疗应用的成功。在这项研究中，我们试图探索在复制性衰老过程中发生的成骨分化能力的分子机制。众所周知，Oct4是维持干细胞分化能力所必需的关键转录因子。在这项研究中，我们发现第6代的BMSC（复制性衰老BMSC）显示出成骨分化潜能和Oct4的水平明显降低。这些伴随着Oct4启动子中Snf5和组蛋白H3赖氨酸4三甲基化（H3K4me3）的水平降低。在BMSC，第2通道 Snf5的敲低减少了Oct4的表达并破坏了成骨分化诱导后碱性磷酸酶（ALP）和矮子相关转录因子2（Runx2）的上调，并伴有Snf5和H3K4me3与Oct4启动子结合的减少。这些发现表明，Snf5结合到Oct4基因启动子区域的水平降低，下调了Oct4的表达，这可能是复制性衰老BMSCs成骨能力下降的潜在机制。