In 1973 I went to the USA to pursue my PhD in Biochemistry in Fred Woessner’s laboratory at the University of Miami. The project was to purify a protease in bovine nasal cartilage that digests aggrecan. The enzyme was characterized a zinc metalloproteinase. Since then I have been attracted by extracellular matrix (ECM)-degrading metalloproteinases, as they were thought to play key roles in both biology and pathology. Only a handful mammalian metalloendopeptidases were known then.
From mid 1980’s cDNA cloning techniques advanced the field rapidly and identified 23 MMPs and 4 tissue inhibitors of metalloproteinases (TIMPs) in humans. I was fortunate to be involved in discovery of a collagenase activator (MMP-3) in Ted Harris’ lab in Dartmouth in early 1980’s. From 1986 to 1999 I was in Kansas City, where I continued to study activation mechanisms of proMMPs and demonstrated the stepwise activation mechanism. Structural functional studies with Keth Brew in Florida and Wolfram Bode in Munich let us elucidate how TIMPs inhibit MMPs. We also obtained biochemical evidence that collagenase (MMP-1) unfolds triple helical collagen before it cuts peptide bonds. After moving to London in 1999 , a success in getting crystal structure of the MMP-1-collagen peptide with Erhard Hohenester (Imperial College) and Richard Farndale (Cambridge) let us propose how collagenase may unwinds collagen.
In London I started a project on osteoarthritis, the most prevalent age-related arthritis. We recently found that ADAMTS-4 and ADAMTS-5, two major aggrecanases, and MMP-13 (collagenase 3) and their inhibitor TIMP-3 are rapidly endocytosed via low-density lipoprotein receptor-related protein 1 (LRP1) in healthy cartilage. This endocytic pathway is impaired in osteoarthritic cartilage due to an increased shedding of LRP1. LRP1 is expressed in many cell types. We propose that the control of extracellular trafficking of matrix-degrading systems is an important component in ECM turnover in health and disease.