Treatment of glucocorticoid-induced osteonecrosis with nano-fullerenes

描述（由申请人提供）：该项目的长期目标是建立一种治疗糖皮质激素诱导的股骨头骨坏死（ONFH）的创新方法，使用纳米富勒烯作为出色的活性氧（ROS）清除剂。糖皮质激素用于治疗各种炎症和自身免疫性疾病是ONFH最常见的非创伤性原因。ONFH是一种使人衰弱的疾病，影响到30岁以上的年轻人。因此，大多数患者在其一生中经常需要多次越来越困难的手术。由于早期诊断困难、病因复杂以及对其发病机制的了解有限，成功治疗ONFH仍然是科学家和临床医生面临的一大挑战。假设纳米富勒烯可能非常有效地治疗ONFH，并且具有更好溶解度的多羟基富勒烯富勒醇可能比原始的C60产生更大的活性。具体目标包括：1。探讨纳米富勒烯对地塞米松诱导的兔骨髓基质细胞脂肪生成和凋亡的拮抗作用。2. 探讨纳米富勒烯对兔股骨头骨坏死（ONFH）模型的体内预防作用。水纳米颗粒悬浮液将由原始的C60和富勒醇制备。将给予这两种纳米富勒烯和谷胱甘肽，并在体外细胞培养和体内动物模型中确定其预防和治疗ONFH的有效性。各种实验方法，如组织学，实时PCR， western blot，流式细胞术，血液生化，股骨组织病理学和单光子发射计算机断层扫描（SPECT）将被采用。预计这三种抗氧化剂均能抑制ONFH的发展，但富勒醇的抑制作用最强。这些结果将支持一个创新的概念，纳米富勒烯可以有效地治疗糖皮质激素诱导的ONFH。该研究将为新的治疗策略提供科学依据，并为治疗ONFH提供新的药物开发。

DESCRIPTION (provided by applicant): The long-term objective of this project is to establish an innovative therapeutic approach toward glucocorticoid-induced osteonecrosis of the femoral head (ONFH), using nano-fullerenes which function as outstanding reactive oxygen species (ROS) scavengers. Glucocorticoid administration for treatment of various inflammatory and autoimmune diseases is the most common non-traumatic cause of ONFH. ONFH is a debilitating disease affecting young adults from the third decade of life. Consequently most patients often need multiple increasingly difficult surgeries over the course of their lifetime. Successful treatment of ONFH still remains a big challenge to both scientists and clinicians, due to the difficulties in its early diagnose, the complexity in its etiology and the limited knowledgein its pathogenesis. The hypothesis is that nano-fullerenes might be very effective in treatment of ONFH, and a polyhydroxylated fullerene fullerol with better solubility might elicit a greater activity than the pristine C60. The following specific aims are included: 1. To determine the antagonizing activity of nano-fullerenes against dexamethasone (DEX)- induced adipogenesis and apoptosis in rabbit bone marrow stromal cells in vitro. 2. To evaluate in vivo preventive effects of nano-fullerenes on the development of osteonecrosis of the femoral head (ONFH) in a rabbit model. Aqueous nanoparticle suspension will be prepared from the pristine C60 and fullerol. These two nano-fullerenes and glutathione will be administered and their effectiveness in prevention and treatment of ONFH will be determined in vitro in cell culture and in vivo in an animal model. Various experimental approaches such as histology, real-time PCR, western blot, flow cytometry, blood biochemistry, femur histopathology and single photon emission computed tomography (SPECT) will be employed. It is expected that all three antioxidants can inhibit ONFH development but the activity of fullerol is the strongest. These outcomes would support an innovative concept that nano-fullerenes can effectively treat glucocorticoid-induced ONFH. The study will provide scientific basis for a new therapeutic strategy and lead to novel development of pharmaceutical drugs for ONFH treatment.