2000 Fiscal Year Final Research Report Summary
Analysis of substrates for ADAMTS-1 metalloproteinase
| Project/Area Number |
11670316
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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 |
Immunology
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| Research Institution | Kanazawa University |
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Principal Investigator |
KUNO Kouji Cancer Research Institute, Kanazawa University Research Associate, がん研究所, 助手 (40242565)
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| Project Period (FY) |
1999 – 2000
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| Keywords | ADAM / metalloproteinase / aggrecan / adrenal gland / arthritis |
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| Research Abstract |
ADAMTS-1 is an ADAM family protein with thrombospondin (TSP) type I motifs. We previously established that ADAMTS-1 is an extracellular matrix-anchored metalloproteinase. In this study, we found that ADAMTS-1 is able to cleave a major cartilage proteoglycan, aggrecan. N-terminal sequencing analysis of the cleavage product revealed that ADAMTS-1 cleaves the Glu^<1871>-Leu^<1872> bond within the chondroitin sulfate attachment domain of aggrecan. In addition to two proteolytic cleavage sites within the IGD, proteolysis of aggrecan within the CS attachment domain has been reported in cartilage explant cultures and in the synovial fluid of arthritis patients. Since the ADAMTS-1 cleavage site corresponds to one of these in vivo cleavage sites of aggrecan, it is possible that ADAMTS-1 be involved in the turnover of aggrecan in vivo. In addition, deletional analysis demonstrated that the C-terminal spacer region of ADAMTS-1 is necessary for the degradation of aggrecan.
To identify the physiological role of ADAMTS-1, we disrupted the mouse ADAMTS-1 gene. We found that ADAMTS-1 gene knockout mice show enlargement of the calyx, which resembles ureteropelvic junction obstruction in human. In addition to renal anomalies, an abnormal adrenal medullary architecture was observed in ADAMTS-1 (-/-) mice. Moreover, fertilization was impaired in ADAMTS-1 (-/-) females. These findings demonstrate that ADAMTS-1 is a multifunctional metalloproteinase that is necessary for the stucture and function of the ureteropelvic junction and adrenal glands as well as of the female genital organs.
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