Abstract：
Loss of p21 leads to increased bone formation post-injury; however, the mechanism(s) by which this occurs remains undetermined. E2f1 is downstream of p21 and as a transcription factor can act directly on gene expression; yet it is unknown if E2f1 plays a role in the osteogenic effects observed when p21 is differentially regulated. In this study we aimed to investigate the interplay between p21 and E2f1 and determine if the pro-regenerative osteogenic effects observed with the loss of p21 are E2f1 dependent. To accomplish this, we employed knockout p21 and E2f1 mice and additionally generated a p21/E2f1 double knockout. These mice underwent burr-hole injuries to their proximal tibiae and healing was assessed over 7 days via microCT imaging. We found that p21 and E2f1 play distinct roles in bone regeneration where the loss of p21 increased trabecular bone formation and loss of E2f1 increased cortical bone formation, yet loss of E2f1 led to poorer bone repair overall. Furthermore, when E2f1 was absent, either individually or simultaneously with p21, there was a dramatic decrease of the number of osteoblasts, osteoclasts, and chondrocytes at the site of injury compared to p21-/- and C57BL/6 mice. Together, these results suggest that E2f1 regulates the cell populations required for bone repair and has a distinct role in bone formation/repair compared to p21-/-E2f1-/-. These results highlight the possibility of cell cycle and/or p21/E2f1 being potential druggable targets that could be leveraged in clinical therapies to improve bone healing in pathologies such as osteoporosis.
摘要：
p21的缺失导致损伤后骨形成增加；然而，发生这种情况的机制仍未确定。E2f1位于p21的下游，作为转录因子可以直接作用于基因表达；然而，当p21受到差异调节时，E2f1是否在成骨效应中起作用尚不清楚。在这项研究中，我们旨在研究p21和E2f1之间的相互作用，并确定p21丢失时观察到的促再生成骨作用是否依赖于E2f1。要做到这一点，我们使用敲除p21和E2f1小鼠，并另外产生p21/E2f1双敲除。这些小鼠的胫骨近端经历了毛刺孔损伤，并通过microCT成像评估了7天的愈合情况。我们发现p21和E2f1在骨再生中起着不同的作用，其中p21的丢失增加了小梁骨形成，而E2f1的丢失增加了皮质骨形成。然而，E2f1的丢失导致骨修复整体较差。此外，当E2f1缺失时，无论是单独或同时p21，成骨细胞的数量急剧减少，破骨细胞,与p21-/-和C57BL/6小鼠相比，损伤部位的软骨细胞。一起,这些结果表明，与p21-/-E2f1-/-相比，E2f1调节骨修复所需的细胞群，并且在骨形成/修复中具有独特的作用。这些结果强调了细胞周期和/或p21/E2f1是潜在的药物靶标的可能性，可以在临床治疗中利用这些靶标来改善诸如骨质疏松症等病理中的骨愈合。
