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“Can we prevent osteoarthritis?” This was the question Dr. Hideaki Nagase recalled asking himself fifteen years ago when he joined the Kennedy Institute of Rheumatology at the University of Oxford. 250 million people across the world suffer from knee-related osteoarthritis, making it one of the major causes of mobility disability. As of now, there is no legitimate cure- only joint replacement, anti-inflammatory drugs, and pain management. As the Professor and Head of Matrix Biology at the Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences at Oxford, Dr. Nagase is a trailblazer in the research towards understanding the mechanisms of osteoarthritis and for discovering anti-arthritic agents against this crippling condition.
At the Amrita School of Biotechnology this week, Dr. Nagase addressed the students and faculty on his work concerning matrix metalloproteinases (MMPs). Many MMPs play major roles in cartilage matrix breakdown during progression of various types of arthritis. Dr. Nagase also spoke on the structural and functional studies of their inhibitors which can help us achieve a method of preventing the further exacerbation of osteoarthritis in patients. In his seminar titled as “LRP-1 Mediated Endocytosis of Metalloproteinases and Extra Cellular Matrix Turnover: Implications in Osteoarthritis”, Dr. Nagase referred to two sets of MMPs: collagenases and aggrecanases. As the extra cellular matrix is mostly made up of collagen and aggrecan, proteases that can cleave these proteins are responsible for the common extracellular matrix remodeling that is required for normal processes such as morphogenesis and wound healing, but also for the irreversible tissue damage that occurs in cartilage as seen in osteoarthritis.
Collagen, in its triple-helical form, is not an easy protein to cleave. Collagenases, such as MMP-1, utilize both a catalytic and hemopexin domain to unwind and successfully cleave the strands. Aggrecanases, such as ADAMTS-4 and ADAMTS-5, contain a few more domains in comparison to MMP-1, including a disintegrin, cysteine-rich, spacer, and thrombospondin domain. The trick in developing an inhibitor of these metalloproteinases is to not target the active site, but to instead target the more specific ancillary domains.
Another point of interest for Dr. Nagase was the fact that both collagenases and aggrecanases can be inhibited by tissue inhibitors of metalloproteinases (TIMPs), most specifically TIMP-3, thus providing a possible anti-arthritis agent. TIMP-3 is highly regulated by Low-density lipoprotein receptor-related protein (LRP-1). This regulation is based on the endocytosis of TIMP-3 by means of membrane bound LRP-1. By using LRP-1 antagonists, like RAP, Dr. Nagase was able to understand the mechanism of this regulation and further investigate the effects of aggrecanases and collagenases in osteoarthritis.
Dr. Nagase has been here at Amrita for the past three weeks, a stay which he emphasized as being thoroughly enjoyable. While concluding his talk he even spoke about his newly acquired aptitude for meditation and joked that it may lead him towards new discoveries in the realm of MMPs and arthritis when he returns to the UK. Overall, it was an honor to have Dr. Nagase with us at ASBT for such an extended visit and as a newly appointed international adjunct faculty at Amrita we all hope to hear much more from him in the future.
February 21, 2015
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