Chen Hongyu, Cai Guanhui, Ruan Xiaolei, Lu Yahui, Li Gen, Chen Zhenwei, Guan Zhaolan, Zhang Hengwei, Sun Wen, Wang Hua
Jiangsu Key Laboratory of Oral Diseases, Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
Bone. 2023 Apr;169:116677. doi: 10.1016/j.bone.2023.116677. Epub 2023 Jan 13.
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.
经缝牵引成骨术（TSDO）治疗颅面不协调时复发率高，原因是在缝线间隙未能形成稳定的骨桥。双膦酸盐（BP）极易定位于骨基质中的羟基磷灰石，常用于作为治疗药物局部递送至骨微环境的靶向配体。骨靶向硼替佐米（BP-Btz）是通过将硼替佐米（Btz）与BP残基连接进行化学合成的，可靶向骨组织以促进成骨细胞分化并抑制破骨细胞生成。在此，用Btz和BP-Btz处理缝线来源的间充质干细胞（SuSCs）和破骨细胞。将上述药物局部注射到矢状缝中，以探究它们在TSDO中的作用。此外，通过荧光BP类似物和总泛素化（Ub）蛋白水平评估BP-Btz在缝扩张模型中的药理特性。结果显示，BP-Btz可刺激SuSCs的成骨分化，与骨基质结合并抑制破骨细胞生成。在体外成骨细胞分化和破骨细胞生成抑制方面，BP-Btz的生物学效应与Btz相似。在矢状缝扩张模型中，14天后检测到骨代谢激活。用BP-Btz治疗后，在体内检测到类骨质面积增加、破骨细胞表面显著减少和成骨增强。绿色荧光信号检测和药效学研究显示，BP-Btz与缝边缘结合，在重塑条件下释放Btz，局部浓度更高且比游离Btz持续时间更长。本研究阐述了骨靶向Btz缀合物作为促进经缝牵引成骨的有效策略的临床潜力。
