2002 Fiscal Year Final Research Report Summary
Examination mechanism of bone absorption by immunosuppressant FK506 and bone graft In molecular biology
| Project/Area Number |
13672094
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Surgical dentistry
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| Research Institution | OKAYAMA UNIVERSITY |
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Principal Investigator |
FUKUNAGA Jyoji Graduate School of Medicine and Dentistry, Assistant, 大学院・医歯学総合研究科, 助手 (10284069)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAAI Yuichiro Graduate School of Medicine and Dentistry, Assistant, 大学院・医歯学総合研究科, 助手 (00158057)
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| Project Period (FY) |
2001 – 2002
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| Keywords | osteoporosis / Immunosuppresant agents / osteoclast / ODF / OCIF / bone graft |
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| Research Abstract |
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.
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