title: Anti-ADAMTS5 monoclonal antibodies: implications for aggrecanase inhibition in osteoarthritis.
abstract: 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.
authors.affiliation: Department of Biomedical Engineering (ND20), Cleveland Clinic Lerner Research Institute and the Orthopaedic and Rheumatologic Research Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, U.S.A. aptes@ccf.org.
authors.forename: Suneel S
authors.initials: SS
authors.lastname: Apte
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology*; D000071116:ADAMTS5 Protein; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D010450:Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D010003:Osteoarthritis / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D010450:Endopeptidases; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; C083641:aggrecanase
keywords: ADAMTS proteinase; aggrecan; arthritis; articular cartilage; metalloproteinase; osteoarthritis