Anti-ADAMTS5 monoclonal antibodies: implications for aggrecanase inhibition in osteoarthritis

被引:31
作者
Apte, Suneel S. [1 ,2 ]
机构
[1] Cleveland Clin, Lerner Res Inst, Dept Biomed Engn ND20, 9500 Euclid Ave, Cleveland, OH 44195 USA
[2] Cleveland Clin, Orthopaed & Rheumatol Res Ctr, 9500 Euclid Ave, Cleveland, OH 44195 USA
关键词
ADAMTS proteinase; aggrecan; arthritis; articular cartilage; metalloproteinase; osteoarthritis; MATRIX-METALLOPROTEINASE; CARTILAGE EXPLANTS; MURINE MODEL; CLEAVAGE; ADAMTS-5; DEGRADATION; FRAGMENTS; VERSICAN; DOMAIN; CATABOLISM;
D O I
10.1042/BJ20151072
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The extracellular matrix of articular cartilage is structurally specialized for efficient absorption of mechanical impact. In particular, giant aggregates of the large chondroitin sulfate proteoglycan, aggrecan, with the glycosaminoglycan, hyaluronan, allow cartilage to resist compressive load. Proteolysis of aggrecan by members of the proteinase family ADAMTS (A disintegrin-like and metalloproteinase domain with thrombospondin type 1 motif), was identified as an early step in the inexorable destruction of cartilage in osteoarthritis (OA). Of the investigated proteinases, ADAMTS5 has emerged as a principal mediator of aggrecan loss in OA, convincingly so in mouse models, and with high probability in humans. ADAMTS5 has a bipartite organization, comprising a proteinase domain and an ancillary domain containing exosites for interaction with aggrecan and other substrates. In a recent issue of this journal, Santamaria et al. characterized anti-ADAMTS5 monoclonal antibodies isolated from a phage display library. By blocking the catalytic site of the ADAMTS5 immunogen with a synthetic inhibitor, the authors of the paper biased selection of antibodies to the ancillary domain. This work, together with other antibodies targeting ADAMTS5, offers diverse, high-affinity and, as far as can be determined, selective aggrecanase inhibitors. Mapping of their epitopes provided novel insights into ADAMTS5 interactions with aggrecan. These monoclonal antibodies deserve continued investigation for potential arthritis therapy, although their successful use will require a comprehensive understanding of the physiological roles of ADAMTS5, and its regulation, intrinsic properties and intermolecular interactions.
引用
收藏
页码:E1 / E4
页数:4
相关论文
共 44 条
[1]   Cloning and characterization of ADAMTS11, an aggrecanase from the ADAMTS family [J].
Abbaszade, I ;
Liu, RQ ;
Yang, F ;
Rosenfeld, SA ;
Ross, OH ;
Link, JR ;
Ellis, DM ;
Tortorella, MD ;
Pratta, MA ;
Hollis, JM ;
Wynn, R ;
Duke, JL ;
George, HJ ;
Hillman, MC ;
Murphy, K ;
Wiswall, BH ;
Copeland, RA ;
Decicco, CP ;
Bruckner, R ;
Nagase, H ;
Itoh, Y ;
Newton, RC ;
Magolda, RL ;
Trzaskos, JM ;
Hollis, GF ;
Arner, EC ;
Burn, TC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (33) :23443-23450
[2]   A Disintegrin-like and Metalloprotease (Reprolysin-type) with Thrombospondin Type 1 Motif (ADAMTS) Superfamily: Functions and Mechanisms [J].
Apte, Suneel S. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (46) :31493-31497
[3]   Generation and characterization of aggrecanase - A soluble, cartilage-derived aggrecan-degrading activity [J].
Arner, EC ;
Pratta, MA ;
Trzaskos, JM ;
Decicco, CP ;
Tortorella, MD .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (10) :6594-6601
[4]   The Different Roles of Aggrecan Interaction Domains [J].
Aspberg, Anders .
JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY, 2012, 60 (12) :987-996
[5]   Targeting of ADAMTS5's ancillary domain with the recombinant mAb CRB0017 ameliorates disease progression in a spontaneous murine model of osteoarthritis [J].
Chiusaroli, R. ;
Visentini, M. ;
Galimberti, C. ;
Casseler, C. ;
Mennuni, L. ;
Covaceuszach, S. ;
Lanza, M. ;
Ugolini, G. ;
Caselli, G. ;
Rovati, L. C. ;
Visintin, M. .
OSTEOARTHRITIS AND CARTILAGE, 2013, 21 (11) :1807-1810
[6]   Domains and maturation processes that regulate the activity of ADAMTS-2, a metalloproteinase cleaving the aminopropeptide of fibrillar procollagens types I-III and V [J].
Colige, A ;
Ruggiero, F ;
Vandenberghe, I ;
Dubail, J ;
Kesteloot, F ;
Van Beeumen, J ;
Beschin, A ;
Brys, L ;
Lapière, CM ;
Nusgens, B .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (41) :34397-34408
[7]   Current and emerging therapeutic strategies for preventing inflammation and aggrecanase-mediated cartilage destruction in arthritis [J].
Dancevic, Carolyn M. ;
McCulloch, Daniel R. .
ARTHRITIS RESEARCH & THERAPY, 2014, 16 (05)
[8]   Altered versican cleavage in ADAMTS5 deficient mice; A novel etiology of myxomatous valve disease [J].
Dupuis, Loren E. ;
McCulloch, Daniel R. ;
McGarity, Jessica D. ;
Bahan, Alexandria ;
Wessels, Andy ;
Weber, Deidra ;
Diminich, A. Megan ;
Nelson, Courtney M. ;
Apte, Suneel S. ;
Kern, Christine B. .
DEVELOPMENTAL BIOLOGY, 2011, 357 (01) :152-164
[9]   Functional differences of the catalytic and non-catalytic domains in human ADAMTS-4 and ADAMTS-5 in aggrecanolytic activity [J].
Fushimi, Kazunari ;
Troeberg, Linda ;
Nakamura, Hiroyuki ;
Lim, Ngee Han ;
Nagase, Hideaki .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (11) :6706-6716
[10]   Proteolytic activities of human ADAMTS-5 - Comparative studies with ADAMTS-4 [J].
Gendron, Christi ;
Kashiwagi, Masahide ;
Lim, Ngee Han ;
Enghild, Jan J. ;
Thogersen, Ida B. ;
Hughes, Clare ;
Caterson, Bruce ;
Nagase, Hideaki .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (25) :18294-18306