An arthritogenic monoclonal antibody to type II collagen, CII-C1, impairs cartilage formation by cultured chondrocytes.
Antibodies to type II collagen (CII) cause articular damage in collagen-induced arthritis (CIA) in mice as judged by passive transfer to naive animals of mAb to CII. We tested the hypothesis that mAb degrade cartilage structure by reacting with functionally important regions of the collagen molecule by examining the effects of an arthritogenic mAb to CII, CII-C1, on cultured bovine chondrocytes at high density, at days 7 and 14. The effects were compared of CII-C1, an isotype-matched control mAb, or medium alone, on chondrocyte proliferation and viability, cell morphology, matrix structure by light and electron microscopy, and matrix synthesis by metabolic labelling with 3H-proline for collagen or 35SO4 for proteoglycans. Chondrocytes in culture remained viable, proliferated, and produced an extracellular matrix in which CII was the major collagen. The addition of CII-C1, but not a control mAb, increased the synthesis of CII and proteoglycan, and caused disorganization of the extracellular matrix and thin collagen fibrils ultrastructurally. Moreover, using a cell-free assay, CII-C1 inhibited the normal self-assembly of collagen fibrils from CII in solution. The finding that the mAb to CII, CII-C1 has striking degradative effects in vitro on cartilage synthesis suggests that antibodies to collagen perpetuate the chronic phase of CIA and that, in mice at least, such antibodies are an important component of pathogenesis.
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic 3800, Australia.
S Fatemah
SF
Amirahmadi
Minh Hue
MH
Pho
Robyn E
RE
Gray
Duncan E
DE
Crombie
Senga F
SF
Whittingham
Beltzane Biurrun
BB
Zuasti
Marie-Paule
MP
Van Damme
Merrill J
MJ
Rowley
D000818:Animals; D000911:Antibodies, Monoclonal / Q000633:toxicity*; D001169:Arthritis, Experimental / Q000276:immunology; D002356:Cartilage / Q000166:cytology* / Q000276:immunology; D002417:Cattle; D018929:Cell Culture Techniques; D002474:Cell-Free System; D019902:Chondrocytes / Q000166:cytology* / Q000187:drug effects / Q000648:ultrastructure; D024043:Collagen Type II / Q000276:immunology* / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D011509:Proteoglycans / Q000378:metabolism; D011961:Receptors, Fc / Q000378:metabolism
D000911:Antibodies, Monoclonal; D024043:Collagen Type II; D011509:Proteoglycans; D011961:Receptors, Fc; D020778:Matrix Metalloproteinase 2