Speaker: Dr Kazuhiro Yamamoto, Kennedy Institute of Rheumatology, University of Oxford
Newcastle University Research Fellowship Candidate
Venue: L.2.2 2nd Floor William Leech Building
Date and time: Monday 8th December 2014 10.30-11.30am
‘’Regulation of Cartilage Homeostatis by Endocytic Pathways in Health and Disease’’
Cartilage degradation in osteoarthritis (OA) is now well established to be the result of elevated proteinase activities, with the key enzymes being aggrecanases and collagenases. Their activities are not readily detected in normal cartilage, but they are greatly upregulated under pathological conditions, such as rheumatoid arthritis (RA) and OA, at the levels of transcription, epigenetic modification, posttranscriptional regulation by microRNAs, activation of pro-enzymes and inhibition by endogenous inhibitors. Recently, I have discovered an additional regulatory mechanism in that many of the key matrix-degrading metalloproteinases are rapidly endocytosed and degraded by chondrocytes in healthy cartilage, and this process is mediated by the endocytic receptor, low-density lipoprotein receptor-related protein 1 (LRP1) on the cell surface. However, under inflammatory conditions, or in OA cartilage, the LRP1 is proteolytically shed from the cell surface, which impairs the endocytic pathway. This introduces further complexity to extracellular matrix (ECM) catabolism in health and disease. I’m currently investigating how alterations in endocytosis affects cartilage homeostasis and what are the molecular events associated with it. A clearer understanding of this important mechanism will reveal novel biomarkers and generate new therapeutic approaches for OA, a disease that currently has no disease-modifying drugs. This unmet clinical need represents the major area of research to identify treatable therapeutic targets as our population ages.
In this seminar, I will talk about my current and future approaches to investigate how normal adult cartilage maintains homeostasis by regulating its ECM turnover and how this balance is lost upon ageing and in pathological conditions. I will also talk about a potential of my entirely novel approach to understand tissue catabolism in other tissue contexts and diseases.
Key words: Tissue catabolism; Osteoarthrits; Endocytosis; Extracellular trafficking; Metalloproteinases.