Background:Bone morphogenetic protein 2 (BMP2) is an appealing osteogenic and chondrogenic growth factor for promoting tendon-bone healing. Recently, it has been reported that soluble vascular endothelial growth factor (VEGF) receptor 1 (sVEGFR1) (a VEGF receptor antagonist) could enhance BMP2-induced bone repair and cartilage regeneration; thus, their combined application may represent a promising treatment to improve tendon-bone healing. Moreover, BMP2 could stimulate skeletal stem cell (SSC) expansion and formation, which is responsible for wounded tendon-bone interface repair. However, whether the codelivery of BMP2 and sVEGFR1 increases tendon enthesis injury–activated SSCs better than does BMP2 alone needs further research.Purpose:To study the effect of BMP2 combined with sVEGFR1 on tendon-bone healing and injury-activated SSC lineage.Study Design:Controlled laboratory study.Methods:A total of 128 C57BL/6 mice that underwent unilateral supraspinatus tendon detachment and repair were randomly assigned to 4 groups: (1) untreated control group; (2) hydrogel group, which received a local injection of the blank hydrogel at the injured site; (3) BMP2 group, which received an injection of hydrogel with BMP2; and (4) BMP2 with sVEGFR1 group, which received an injection of hydrogel with BMP2 and sVEGFR1. Histology, micro–computed tomography, and biomechanical tests were conducted to evaluate tendon-bone healing at 4 and 8 weeks after surgery. In addition, flow cytometry was performed to detect the proportion of SSCs and their downstream differentiated subtypes, including bone, cartilage, and stromal progenitors; osteoprogenitors; and pro-chondrogenic progenitors within supraspinatus tendon enthesis at 1 week postoperatively.Results:The repaired interface in BMP2 with sVEGFR1 group showed a significantly improved collagen fiber continuity, increased fibrocartilage, greater newly formed bone, and elevated mechanical properties compared with the other 3 groups. There were more SSCs; bone, cartilage, and stromal progenitors; osteoprogenitors; and pro-chondrogenic progenitors in the BMP2 with sVEGFR1 group than that in the other groups.Conclusion:Our study suggests that the combined delivery of BMP2 and sVEGFR1 could promote tendon-bone healing and stimulate the expansion of SSCs and their downstream progeny within the injured tendon-bone interface.Clinical Relevance:Combining BMP2 with sVEGFR1 may be a good clinical treatment for wounded tendon enthesis healing.

中文翻译：

---

BMP2 和可溶性 VEGFR1 联合治疗通过调节损伤激活的骨骼干细胞谱系来增强腱骨愈合

背景：骨形态发生蛋白2（BMP2）是一种有吸引力的成骨和软骨生长因子，可促进腱骨愈合。最近有报道称，可溶性血管内皮生长因子（VEGF）受体1（sVEGFR1）（一种VEGF受体拮抗剂）可以增强BMP2诱导的骨修复和软骨再生；因此，它们的联合应用可能代表一种有希望的改善腱骨愈合的治疗方法。此外，BMP2可以刺激骨骼干细胞（SSC）的扩增和形成，从而负责修复受伤的肌腱-骨界面。然而，BMP2和sVEGFR1的联合递送是否比单独使用BMP2更好地增加肌腱附着损伤激活的SSCs还需要进一步研究。目的：研究BMP2联合sVEGFR1对腱骨愈合和损伤激活的SSC谱系的影响。研究设计：对照实验室研究。方法：128只接受单侧冈上肌腱脱离修复的C57BL/6小鼠随机分为4组：（1）未治疗对照组；（2）对照组。(2)水凝胶组，在受伤部位局部注射空白水凝胶；(3)BMP2组，注射BMP2水凝胶；(4)BMP2+sVEGFR1组，注射BMP2+sVEGFR1水凝胶。术后 4 周和 8 周进行组织学、微型计算机断层扫描和生物力学测试来评估肌腱骨愈合情况。此外，还进行流式细胞术检测SSC及其下游分化亚型的比例，包括骨、软骨和基质祖细胞；骨祖细胞；术后 1 周冈上肌腱附着点内的前软骨祖细胞。结果：与其他 3 组相比，BMP2 与 sVEGFR1 组修复的界面显示出明显改善的胶原纤维连续性、增加的纤维软骨、更多的新形成骨和更高的机械性能。有更多的SSC；骨、软骨和基质祖细胞；骨祖细胞；BMP2 与 sVEGFR1 组中的促软骨祖细胞数量高于其他组。 结论：我们的研究表明，BMP2 和 sVEGFR1 的联合递送可以促进腱骨愈合并刺激受伤部位内 SSC 及其下游子代的扩张临床意义：BMP2 与 sVEGFR1 联合可能是治疗受伤肌腱附着点愈合的良好临床治疗方法。