INVESTIGATION OF MECHANISM OF MATRIX METALLOPROTEINASE ON THE ROLE OF BONE METABOLISM AND CLINICAL APPOACH FOR BONE INVASION AND OSTEOLYTIC LESIONS BY CANCER IN ANIMAL MODEL

• Project/Area Number: 11671988
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: OKAYAMA UNIVERSITY
• Principal Investigator: SASAKI Akira OKAYAMA UNIVERSITY, DENTAL SCHOOL, ASSOCIATE PROFESSOR, 歯学部, 助教授 (00170663)
• Project Period (FY): 1999 – 2000
• Project Status: Completed (Fiscal Year 2000)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2000: ¥1,600,000 (Direct Cost: ¥1,600,000); Fiscal Year 1999: ¥1,900,000 (Direct Cost: ¥1,900,000)
• Keywords: Matrix metalloproteinase / matrix metalloproteinase inhibitor / osteoclast / bone resorption / cancer therapy / bone destruction / human breast cancer / human malignant melanoma

Research Abstract

Matrix Metalloproteinase (MMP) inhibitor, MMI-166 has strong and selective inhibitory activities against MMP-2, -9. Recently, it has been reported that osteoclasts produce MMP-9 which closely related to the bone resorption. Therefore, it is expected MMI-166 may be a beneficial therapy for the osteolytic lesions. In the present study, we investigated the physiological function of MMI-166 for the bone resorption and effectiveness for nude mice bone metastasis model.
1. Mechanism of MMI-166 on bone metabolism : MMI-166 did not inhibit osteoclasts formation in murine bone marrow culture, and did not suppress the resorbing activity against dentin slices. In contrast, MMI-166 dose-dependently inhibited the release of Ca from calvaria stimulated with D3.
2. Effect of MMI-166 on the production of MMPs of osteoclasts : Osteoblastic-cells produced weak MMP-2, -9, and osteoclasts produced weak MMP-9 on gelatin zymogram. The MMP-2, and -9 production was enhanced by the co-culture with the both cells . However, MMI-166 did not affect the both MMP production directly.
3. Effects of MMI-166 for the osteolytic lesions in animal models : MMI-166 statistically inhibited the development of osteolytic area of bone metastasis induced by the intracardiac injection of human breast cancer cell MDA-231 producing little MMP-2, -9, and human malignant melanoma cell A375 with high production of MMP-2. The histomorphometry of metastatic tumor in femur presented that the tumor size in MMI-166-treated groups was lesser than the untreated groups. However, there was no statistical difference between the MMI-166-treated and untreated group. The inhibitory manner by MMI-166 in MDA-231 group was similar to A-375 group, in spite of the difference of the MMPs production. MMI-166 inhibited cancer induced osteolysis, although the inhibition of the metastatic tumor was weak. And, MMPs inhibitors inhibit invasion to extracellular matrices in the initial stage of metastasis steps. Therefore, MMPs inhibitors should be a beneficial drug to be used in the treatment of osteolytic lesion.