期刊
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
卷 478, 期 1, 页码 43-51出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2008.07.012
关键词
aggrecanase; ADAMTS; PACE4; proprotein convertase; cartilage; osteoarthritis; metalloproteases; post-translational activation
Proteolytic degradation of the major cartilage macromolecules, aggrecan and type 11 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. (c) 2008 Elsevier Inc. All rights reserved.
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