Sequential application of small molecule therapy enhances chondrogenesis and angiogenesis in murine segmental defect bone repair.
Sequential application of small molecule therapy enhances chondrogenesis and angiogenesis in murine segmental defect bone repair.
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小分子治疗的连续应用可增强小鼠节段缺损骨修复中的软骨生成和血管生成。
DOI：
10.1002/jor.25493
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Mohan,Subburaman
中科院分区：
文献类型：
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作者：
Rundle,CharlesH;Gomez,GustavoA;Pourteymoor,Sheila;Mohan,Subburaman
影响软骨内骨折常规愈合的生理/病理条件的发生率不断增加，严重骨损伤的发生需要新的方法来加强临床上具有挑战性的骨折修复。为了促进骨不连骨折的愈合，我们在小鼠股骨节段性缺损骨不连模型的骨痂中测试了一种方法，该方法使用两个小分子依次促进软骨的发育和向骨的转化。全身注射平滑激动剂21k-2(SAG21k)通过激活sonic hedgehog(SHH)途径在骨修复早期刺激软骨形成，同时注射Pro-羟基酶结构域(PhD)2抑制剂IOX2刺激低氧信号介导的软骨内成骨。SAG21k和IOX2分别刺激软骨细胞系SHH通路基因和Phd2靶基因的表达。节段性缺损区对连续全身应用这些小分子作出反应，软骨细胞ptch1、GLI1和SOX9的表达增加对SAG的反应，缺损区组织中缺氧诱导因子-1α和血管内皮生长因子A的表达增加。术后6周，联合应用SAG-IOX2治疗可增加骨缺损处的骨形成。临床意义：这种治疗方法成功地促进了临界大小的节段性缺损区的软骨和骨形成，并确立了序贯小分子疗法在临床挑战性骨损伤中促进骨折骨痂发育的有效性。
The increasing incidence of physiologic/pathologic conditions that impair the otherwise routine healing of endochondral bone fractures and the occurrence of severe bone injuries necessitate novel approaches to enhance clinically challenging bone fracture repair. To promote the healing of nonunion fractures, we tested an approach that used two small molecules to sequentially enhance cartilage development and conversion to the bone in the callus of a murine femoral segmental defect nonunion model of bone injury. Systemic injections of smoothened agonist 21k (SAG21k) were used to stimulate chondrogenesis through the activation of the sonic hedgehog (SHH) pathway early in bone repair, while injections of the prolyl hydroxylase domain (PHD)2 inhibitor, IOX2, were used to stimulate hypoxia signaling‐mediated endochondral bone formation. The expression of SHH pathway genes andPhd2target genes was increased in chondrocyte cell lines in response to SAG21k and IOX2 treatment, respectively. The segmental defect responded to sequential systemic administration of these small molecules with increased chondrocyte expression of PTCH1, GLI1, and SOX9 in response to SAG and increased expression of hypoxia‐induced factor‐1α and vascular endothelial growth factor‐A in the defect tissues in response to IOX2. At 6 weeks postsurgery, the combined SAG–IOX2 therapy produced increased bone formation in the defect with the bony union over the injury. Clinical significance: This therapeutic approach was successful in promoting cartilage and bone formation within a critical‐size segmental defect and established the utility of a sequential small molecule therapy for the enhancement of fracture callus development in clinically challenging bone injuries.