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Examination mechanism of bone absorption by immunosuppressant FK506 and bone graft In molecular biology

免疫抑制剂FK506骨吸收及骨移植的分子生物学研究机制

基本信息

批准号：
13672094
负责人：
FUKUNAGA Jyoji
金额：
$ 2.3万
依托单位：
OKAYAMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672094/
关键词：
osteoporosis Immunosuppresant agents osteoclast ODF OCIF bone graft 破骨細胞分子因子

项目摘要

Immunosuppressant drugs are currently required by transplant recipients for the remainder of their lives, despite the many adverse effects associated with these therapies. Acute osteoporosis is one such effect, and a reproducible osteoporosis model has been established through the administration of the immunosuppressant drug FK506 in rats. It has been demonstrated that this osteoporosis was caused by abnormal osteoclast proliferation, altering the process of bone remodeling. However, it has been unclear why FK506 induces osteoclast proliferation and whether this process is mediated by cytokine changes or an increase in bone resorption factors. An investigation was therefore conducted focusing on the recent discoveries of osteoclast differentiation factor (ODF) and osteoclastogenesis inhibitory factor (OCIF). These factors led to elucidation of the osteoclast differentiation/maturation mechanism. An osteoporosis model was produced in rats utilizing intramuscular FK506 injection (1 mg/kg) for 28 consecutive days. Trabecular bone resorption was observed inferior to enchondral ossification in the FK506 group, and tartrate resistant acid phosphatase (TRAP) staining revealed a clear increase in osteoclasts at the site of enchondral ossification, relative to the control group. Reverse transcriptase polymerase chain reaction (RT-PCR) and in situ hybridization (ISH) demonstrated minimal differences in OCIF expression between control and the treatment groups. However, RT-PCR revealed clearly increased ODF expression in the treatment group. ODF expression was also shown to be increased in the treatment group using ISH. This was histologically consistent with a region of osteoclast proliferation inferior to enchondral ossification. The results of this study support the hypothesis that FK506-mediated osteoporosis occurs by action of the drug on osteoclasts, promoting expression of ODF mRNA and thus prompting osteoclast differentiation and maturation.

免疫抑制药物目前是移植受者在其剩余生命中所需要的，尽管与这些疗法相关的许多副作用。急性骨质疏松症就是这样一种效应，通过给予免疫抑制药物FK506，在大鼠身上建立了可重复的骨质疏松症模型。已经证明，这种骨质疏松症是由异常破骨细胞增殖引起的，改变了骨重塑的过程。然而，FK506诱导破骨细胞增殖的原因以及这一过程是由细胞因子变化还是骨吸收因子增加介导的，目前尚不清楚。因此，我们对最近发现的破骨细胞分化因子（ODF）和破骨细胞生成抑制因子（OCIF）进行了调查。这些因素导致破骨细胞分化/成熟机制的阐明。采用FK506肌内注射（1 mg/kg），连续28天建立大鼠骨质疏松模型。FK506组骨小梁骨吸收低于软骨成骨，抗酒石酸酸性磷酸酶（TRAP）染色显示，与对照组相比，软骨成骨部位破骨细胞明显增加。逆转录聚合酶链反应（RT-PCR）和原位杂交（ISH）显示对照组和治疗组之间OCIF表达差异极小。然而，RT-PCR显示治疗组ODF表达明显升高。使用ISH治疗组的ODF表达也有所增加。这在组织学上与破骨细胞增殖区域一致，低于软骨成骨。本研究结果支持fk506介导的骨质疏松是通过药物作用于破骨细胞，促进ODF mRNA的表达，从而促进破骨细胞分化成熟而发生的假说。