Proprotein convertase activation of aggrecanases in cartilage in situ

被引：58

作者：

Malfait, Anne-Marie ^{[1
]}

Arner, Elizabeth C. ^{[1
]}

Song, Ruo-Hua ^{[1
]}

Alston, James T. ^{[2
]}

Markosyan, Stella ^{[3
]}

Staten, Nicholas ^{[1
]}

Yang, Zhiyong ^{[4
]}

Griggs, David W. ^{[1
]}

Tortorella, Micky D. ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, St Louis, MO 63017 USA

[2] Eli Lilly & Co, Indianapolis, IN 46285 USA

[3] Abbott Labs, Libertyville, IL 60048 USA

[4] Wyeth Ayerst Res, Cambridge, MA 02140 USA

来源：

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS | 2008年 / 478卷 / 01期

关键词：

aggrecanase; ADAMTS; PACE4; proprotein convertase; cartilage; osteoarthritis; metalloproteases; post-translational activation;

D O I：

10.1016/j.abb.2008.07.012

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 [生物化学与分子生物学]; 081704 [应用化学];

摘要：

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.

引用

页码：43 / 51

页数：9

共 42 条

[1]

Cloning and characterization of ADAMTS11, an aggrecanase from the ADAMTS family [J].