Bone-targeted bortezomib increases bone formation within Calvarial trans-sutural distraction osteogenesis.
Bone-targeted bortezomib increases bone formation within Calvarial trans-sutural distraction osteogenesis.
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DOI：
10.1016/j.bone.2023.116677
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发表时间：
2023-01
期刊：
影响因子：
4.1
通讯作者：
Hongyu Chen;Guanhui Cai;Xiaorui Ruan;Yahui Lu;Gen Li;Zhenwei Chen;Zhaolan Guan;Hengwei Zhang;Wen-jian Sun;Hua Wang
中科院分区：
文献类型：
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作者：
Hongyu Chen;Guanhui Cai;Xiaorui Ruan;Yahui Lu;Gen Li;Zhenwei Chen;Zhaolan Guan;Hengwei Zhang;Wen-jian Sun;Hua Wang
经缝牵张成骨(TSDO)治疗颅面部不协调复发率高是由于未能在缝隙内形成稳定的骨桥。双膦酸盐(BP)具有很高的定位于骨基质中的羟基磷灰石的倾向，通常被用作局部给药的靶向配体。骨靶向硼替佐米(BP-BTZ)是通过将BTZ(Bortezomib)连接到BP残基上而化学合成的，可以靶向骨组织，促进成骨细胞分化，抑制破骨细胞的生成。在这里，缝线来源的间充质干细胞(SuSCs)和破骨细胞用BTZ和BP-BTZ处理。将上述药物局部注入矢状缝，探讨其在TSDO中的作用。进一步，通过荧光BP类似物和总泛素化(Ub)蛋白水平来评价BP-BTZ在缝合扩张模型中的药理性质。结果表明，BP-BTZ能促进SuSCs向成骨细胞分化，与骨基质结合，抑制破骨细胞生成。BP-BTZ在成骨细胞分化和体外抑制破骨细胞生成方面的生物学作用与BTZ相似。矢状缝扩张模型14天后检测到活性骨代谢。经BP-BTZ处理后，体内类骨质面积增加，破骨细胞表面积显著减少，成骨能力增强。绿色荧光信号检测和药效学研究表明，BP-BTZ结合在缝合边缘，在重塑条件下释放BTZ，具有更高的局部浓度和持续时间比游离BTZ。这项研究描述了骨靶向BTZ结合物作为促进跨缝牵张成骨的有效策略的临床潜力。
The high rate of relapse in craniofacial disharmony treatment via trans-sutural distraction osteogenesis (TSDO) is due to the failure to form a stable bone bridge in the suture gap. Bisphosphonates (BP) have a high propensity to localize to hydroxyapatite in the bone matrix and are commonly used as targeting ligands for local delivery of therapeutics into bone microenvironment. Bone-targeted Bortezomib (BP-Btz) is chemosynthetic by linking Btz (Bortezomib) to a BP residue and could target bone tissue to promote osteoblast differentiation and inhibit osteoclastogenesis. Here, suture-derived mesenchymal stem cells (SuSCs) and osteoclasts were treated with Btz and BP-Btz. Aforesaid drugs were injected locally into the sagittal sutures to explore their effects in TSDO. Further, pharmacological properties of BP-Btz in the suture expansion model were assessed by fluorescent BP analogs and levels of total ubiquitinated (Ub)-proteins. The results showed that BP-Btz could stimulate osteogenic differentiation of SuSCs, bind to bone matrix and inhibit osteoclastogenesis. Biological effects of BP-Btz were similar with those of Btz in osteoblast differentiation and osteoclastogenesis inhibition in vitro. Activated bone metabolism were detected after 14 days in the sagittal suture expansion model. Increased osteoid area, remarkably decreased osteoclast surface and enhanced osteogenesis were detected in vivo after treatment with BP-Btz. Green fluorescence signal detection and pharmacodynamic studies revealed that BP-Btz bound to suture edge, released Btz in remodeling conditions, had a higher local concentration and sustained longer than free Btz. This study delineated the clinical potential of bone-targeted Btz conjugate as an efficacious strategy to promote trans-sutural distraction osteogenesis.