Lee Tien-Ching, Chen Hui-Ting, Tai I-Chun, Kao Li-Ting, Hung Ming-Hsin, Chen Chung-Hwan, Fu Yin-Chih, Wang Yan-Hsiung, Kao Chih-Ming, Chang Je-Ken, Ho Mei-Ling
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan.
Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
Biomedicines. 2022 Aug 8;10(8):1915. doi: 10.3390/biomedicines10081915.
Large bone defects may develop fracture nonunion, leading to disability and psychosocial burdens. Bone grafting with anabolic agents is a good autografting alternative. Simvastatin, as a cholesterol-lowering agent worldwide, is proven to enhance osteogenesis. Considering its dose-dependent adverse effects, we developed a simvastatin derivative, named KMUHC-01, which has bone anabolic capacity and lower cytotoxicity than simvastatin. We hypothesize that KMUHC-01 could help bone formation in bone-defect animal models. We used rat models of critical calvarial and long-bone defects to evaluate the effects of KMUHC-01 and simvastatin on biological changes at the bone defect through histology, immunohistology, and mechanical testing using three-point bending and evaluated the new bone formation microstructure through microcomputed tomography analysis. The newly formed bone microstructure at the calvarial defect site showed a significantly improved trabecular bone volume in the KMUHC-01 1-μM group compared with that in the control and simvastatin groups. The biomechanical study revealed a significantly increased maximal strength in the KMUHC-01 1-μM group compared with that in the control group. KUMHC-01, as a simvastatin derivative, showed a great anabolic effect in promoting bone defect healing. However, further studies will be conducted to prove the bioavailability and bone-forming efficacy of KMUHC-01 via systemic administration.
大的骨缺损可能会导致骨折不愈合，从而导致残疾和心理社会负担。使用促合成剂的骨移植是一种很好的自体移植替代方法。辛伐他汀作为一种在全球范围内使用的降胆固醇药物，已被证明可促进骨生成。考虑到其剂量依赖性不良反应，我们开发了一种辛伐他汀衍生物，命名为KMUHC-01，它具有骨合成能力且细胞毒性低于辛伐他汀。我们假设KMUHC-01可以帮助骨缺损动物模型中的骨形成。我们使用大鼠颅骨关键缺损和长骨缺损模型，通过组织学、免疫组织学以及使用三点弯曲的力学测试来评估KMUHC-01和辛伐他汀对骨缺损处生物学变化的影响，并通过微计算机断层扫描分析评估新形成骨的微观结构。与对照组和辛伐他汀组相比，KMUHC-01 1μM组颅骨缺损部位新形成的骨微观结构显示小梁骨体积显著改善。生物力学研究表明，与对照组相比，KMUHC-01 1μM组的最大强度显著增加。作为一种辛伐他汀衍生物，KMUHC-01在促进骨缺损愈合方面显示出巨大的合成代谢作用。然而，将进行进一步研究以证明KMUHC-01通过全身给药的生物利用度和骨形成功效。
