|Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2001: ¥2,200,000 (Direct Cost: ¥2,200,000)
Stroke-prone spontaneously hypertensive rats (SHRSP) are thought to be an animal model of osteonecrosis of the femoral head (ONFH). Studies for human ONFH and animal models have indicated that steroid hormone-induced hyperlipemia causing swollened adipocyts and endothelium dysfunctions is related to the etiology of this necrosis. Human ONFH, complicated by a high dose of steroid hormone-therapy, is a major side effect of organ transplantation. Our previous studies revealed that ONFH was observed in SHRSP at 15 to 20 weeks of age, and chronic ingestion of an NOS inhibitor inhibited the onset of the disease. To clarify the participation of hyperlipemia as an etiological factor in the disease, we examined the onset of ONFH in a new animal model of SHRSP fed a high fat and high cholesterol diet (HFC) containing N^G-nitro-L-arginine (L-NNA), as an NOS inhibitor. SHRSP with an administration of steroid hormone was used for the purpose of comparison.
Male SHRSP/Nagasaki, maintained and bred at
the Laboratory Animal Center for Biomedical Research, Nagasaki University School of Medicine were used. At 15 weeks of age, rats were put at random into groups of 30, 25 and 24. The first group of 30 rats were fed the HFC diet containing L-NNA in a dose of 0.006% (HFC-NNA group). The second group of 25 was fed the SP diet (Funabashi Farm Co., Chiba, Japan), and at 17 weeks of age, 5 or 10 mg of methylpredonisolone was subcuatneously injected into the second group of rats (Steroid group). The third group of 24 rats, given the SP diet with no drug, served as controls. The rats were decapitated at 19 weeks of age.
The incidence of ONFH in the Steroid group was 50%, but it was lower in the HFC-NNA group and the control SHRSP. Numerous adipocytes in the metaphysial bone marrow of the HFC-NNA group and the Steroid group was observed microscopically. In the Steroid group, we noted the epiphysial bone marrow was filled with massive swollen adipocytes. In addition, there was a migration of swollen fatty cells into the necrotic area in the epiphysial bone marrow of the Steroid group. 94.0% of this group also demonstrated osteonecrosis and/or swollen adipocytes.
Epidemiological investigations for human ONFH has suggested that steroid hormone and alcohol intake are etiological factors related to the avascular necrosis of femoral head. We observed here the highest incidence of ONFH in the Steroid group. A hyperlipemia-induced increase in the number and invasion to necrotic areas of adipocytes seems to be an etiological factor, however, a lower incidense was observed in the HFC-NNA group with hypercholesterolemia. We admit that other mechanisms may be operative in the experimental model of femoral head avascular necrosis. Less