Atrophic fracture nonunion poses a significant clinical problem with limited therapeutic interventions. In this study, we developed a unique nonunion model with high clinical relevance using serum transfer-induced rheumatoid arthritis (RA). Arthritic mice displayed fracture nonunion with the absence of fracture callus, diminished angiogenesis and fibrotic scar tissue formation leading to the failure of biomechanical properties, representing the major manifestations of atrophic nonunion in the clinic. Mechanistically, we demonstrated that the angiogenesis defect observed in RA mice was due to the downregulation of SPP1 and CXCL12 in chondrocytes, as evidenced by the restoration of angiogenesis upon SPP1 and CXCL12 treatment in vitro. In this regard, we developed a biodegradable scaffold loaded with SPP1 and CXCL12, which displayed a beneficial effect on angiogenesis and fracture repair in mice despite the presence of inflammation. Hence, these findings strongly suggest that the sustained release of SPP1 and CXCL12 represents an effective therapeutic approach to treat impaired angiogenesis and fracture nonunion under inflammatory conditions.

萎缩性骨折骨不连是一个重大的临床问题，治疗干预有限。在这项研究中，我们使用血清转移诱导的类风湿性关节炎 (RA) 开发了一种具有高度临床相关性的独特骨不连模型。关节炎小鼠骨折不愈合，骨折骨痂缺失，血管生成减少，纤维化瘢痕组织形成导致生物力学性能下降，是临床萎缩性骨不连的主要表现。从机制上讲，我们证明在 RA 小鼠中观察到的血管生成缺陷是由于软骨细胞中 SPP1 和 CXCL12 的下调，正如体外 SPP1 和 CXCL12 治疗后血管生成恢复所证明的那样。在这方面，我们开发了一种载有 SPP1 和 CXCL12 的可生物降解支架，尽管存在炎症，但它对小鼠的血管生成和骨折修复显示出有益作用。因此，这些发现有力地表明，SPP1 和 CXCL12 的持续释放代表了一种有效的治疗方法，可以在炎症条件下治疗受损的血管生成和骨折不愈合。