Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, United States of America.
Key Laboratory of Ethnomedicine, Minzu University of China, Beijing, China.
PLoS One. 2022 Feb 25;17(2):e0263839. doi: 10.1371/journal.pone.0263839. eCollection 2022.
The ubiquitin/proteasome system controls the stability of Runx2 and JunB, proteins essential for differentiation of mesenchymal progenitor/stem cells (MPCs) to osteoblasts. Local administration of proteasome inhibitor enhances bone fracture healing by accelerating endochondral ossification. However, if a short-term administration of proteasome inhibitor enhances fracture repair and potential mechanisms involved have yet to be exploited. We hypothesize that injury activates the ubiquitin/proteasome system in callus, leading to elevated protein ubiquitination and degradation, decreased MPCs, and impaired fracture healing, which can be prevented by a short-term of proteasome inhibition. We used a tibial fracture model in Nestin-GFP reporter mice, in which a subgroup of MPCs are labeled by Nestin-GFP, to test our hypothesis. We found increased expression of ubiquitin E3 ligases and ubiquitinated proteins in callus tissues at the early phase of fracture repair. Proteasome inhibitor Bortezomib, given soon after fracture, enhanced fracture repair, which is accompanied by increased callus Nestin-GFP+ cells and their proliferation, and the expression of osteoblast-associated genes and Runx2 and JunB proteins. Thus, early treatment of fractures with Bortezomib could enhance the fracture repair by increasing the number and proliferation of MPCs.
泛素-蛋白酶体系统控制着 Runx2 和 JunB 的稳定性，这两种蛋白对于间充质祖细胞（MPCs）向成骨细胞分化至关重要。局部给予蛋白酶体抑制剂可通过加速软骨内骨化来增强骨骨折愈合。然而，蛋白酶体抑制剂的短期给药是否能增强骨折修复，以及涉及的潜在机制尚未得到利用。我们假设损伤会激活骨痂中的泛素-蛋白酶体系统，导致蛋白质泛素化和降解增加，MPCs 减少，骨折愈合受损，而短期的蛋白酶体抑制可以预防这种情况。我们使用 Nestin-GFP 报告小鼠的胫骨骨折模型来检验我们的假设，其中一小部分 MPCs 被 Nestin-GFP 标记。我们发现，在骨折修复的早期阶段，骨痂组织中泛素 E3 连接酶和泛素化蛋白的表达增加。在骨折后不久给予蛋白酶体抑制剂硼替佐米可增强骨折修复，这伴随着骨痂 Nestin-GFP+细胞及其增殖的增加，以及成骨细胞相关基因和 Runx2 和 JunB 蛋白的表达。因此，早期用硼替佐米治疗骨折可通过增加 MPC 的数量和增殖来增强骨折修复。
