Proprotein convertase activation of aggrecanases in cartilage in situ |
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Authors: | Malfait Anne-Marie Arner Elizabeth C Song Ruo-Hua Alston James T Markosyan Stella Staten Nicholas Yang Zhiyong Griggs David W Tortorella Micky D |
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Affiliation: | a Pfizer Global Research and Development, 700 Chesterfield Parkway-AA3E, Chesterfield, St. Louis, MO 63017, USA b Eli-Lilly & Company, Indianapolis, IN 46285, USA c Abbott Laboratories, Libertyville, IL 60048, USA d Wyeth Research, Cambridge, MA 02140, USA |
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Abstract: | Proteolytic degradation of the major cartilage macromolecules, aggrecan and type II collagen, is a key pathological event in osteoarthritis (OA). ADAMTS-4 and ADAMTS-5, the primary aggrecanases capable of cartilage aggrecan cleavage, are synthesized as latent enzymes and require prodomain removal for activity. The N-termini of the mature proteases suggest that activation involves a proprotein convertase, but the specific family member responsible for aggrecanase activation in cartilage in situ has not been identified. Here we describe purification of a proprotein convertase activity from human OA cartilage. Through biochemical characterization and the use of siRNA, PACE4 was identified as a proprotein convertase responsible for activation of aggrecanases in osteoarthritic and cytokine-stimulated cartilage. Posttranslational activation of ADAMTS-4 and ADAMTS-5 was observed in the extracellular milieu of cartilage, resulting in aggrecan degradation. These findings suggest that PACE4 represents a novel target for the development of OA therapeutics. |
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Keywords: | Aggrecanase ADAMTS PACE4 Proprotein convertase Cartilage Osteoarthritis Metalloproteases Post-translational activation |
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