British Endocrine Societies Joint Meeting 2002
Harrogate, UK
08 April 2002 - 11 April 2002
British Endocrine Societies
The biology of matrix metalloproteinases and their inhibitors
The Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, UK.
Matrix metalloproteinases (MMPs) play critical roles in embryonic development, morphogenesis, blastocyst implantation, ovulation, post-partum uterine involution, endometrial cycling, bone remodelling and wound healing, and in diseases such as arthritis, cancer, cardiovascular diseases, tissue ulceration and fibrosis. Currently, twenty-four vertebrate MMPs have been reported. An important feature of the MMPs is that many of these genes are inducible by growth factors, cytokines, physical stress, oncogenic transformation, cell-cell and cell-matrix interactions. Our studies on mouse uterus during peri-implantation period indicated striking changes in expression of MMP-2, MMP-9, MT2-MMP and TIMP-3 mRNAs during days 1-8 of pregnancy, suggesting their involvement in early phase of decidualization through ECM modelling.
Once synthesised MMPs are either secreted from the cell or bound to the plasma membrane. A few members are activated intracellularly by furin, but most are secreted from the cell as in active zymogens. The activation of proMMP-2 (progelatinase A) by MT-MMPs on the cell surface is implicated to cell migration and angiogenesis. Recent studies suggest that MMP does not only remove ECM, but also reveals cryptic biological functions of ECM macromolecules.
The activities of MMPs are regulated by the endogenous inhibitors, TIMPs and α2-macroglobulin. The 3D structure of TIMP-1 and TIMP-3 complex revealed the inhibition mechanism of TIMPs. TIMPs exhibit additional biological activities. TIMP-1 and TIMP-2 have mitogenic activity and anti-apoptotic activity. TIMP-3 exhibits apoptotic activity. Most of those cellular activities are independent of the MMP-inhibitory activity.
Endocrine Abstracts 3 S22