VDIPEN, a metalloproteinase-generated neoepitope, is induced and immunolocalized in articular cartilage during inflammatory arthritis

The destruction of articular cartilage in immune inflammatory arthritic disease involves the proteolytic degradation of its extracellular matrix. The role of activated matrix metalloproteinases (MMPs) in the chondrodestructive process was studied by identifying a selective cleavage product of aggrec...

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Bibliographic Details
Published in:The Journal of clinical investigation 1995-05, Vol.95 (5), p.2178-2186
Main Authors: Singer, I I, Kawka, D W, Bayne, E K, Donatelli, S A, Weidner, J R, Williams, H R, Ayala, J M, Mumford, R A, Lark, M W, Glant, T T
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Antibodies
Arthritis, Experimental - metabolism
Arthritis, Experimental - pathology
Cartilage, Articular - metabolism
Cartilage, Articular - pathology
Collagen - immunology
Epitopes - analysis
Epitopes - biosynthesis
Female
Glycosaminoglycans - analysis
Glycosaminoglycans - biosynthesis
Hindlimb
Immunoglobulin G
Immunohistochemistry
Inflammation
Metalloendopeptidases - metabolism
Mice
Mice, Inbred BALB C
Mice, Inbred Strains
Molecular Sequence Data
Oligopeptides - analysis
Oligopeptides - biosynthesis
Peptide Fragments - analysis
Peptide Fragments - biosynthesis
Proteoglycans - immunology
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Summary:The destruction of articular cartilage in immune inflammatory arthritic disease involves the proteolytic degradation of its extracellular matrix. The role of activated matrix metalloproteinases (MMPs) in the chondrodestructive process was studied by identifying a selective cleavage product of aggrecan in murine arthritis models initiated by immunization with either type II collagen or proteoglycan. We conducted semiquantitative immunocytochemical studies of VDIPEN341 using a monospecific polyclonal antibody requiring the free COOH group of the COOH-terminal Asn for epitope detection. This antibody recognizes the aggrecan G1 domain fragment generated by MMP [i.e., stromelysin (SLN) or gelatinase A] cleavage of aggrecan between Asn341-Phe342 but does not recognize intact aggrecan. VDIPEN was undetectable in normal mouse cartilage but was observed in the articular cartilage (AC) of mice with collagen-induced arthritis 10 d after immunization, without histological damage and clinical symptoms. This aggrecan neoepitope was colocalized with high levels of glycosaminoglycans (GAGs) in pericellular matrices of AC chondrocytes but was not seen at the articular surface at this early time. Digestion of normal (VDIPEN negative) mouse paw cryosections with SLN also produced heavy pericellular VDIPEN labeling. Computer-based image analysis showed that the amount of VDIPEN expression increased dramatically by 20 d (70% of the SLN maximum) and was correlated with GAG depletion. Both infiltration of inflammatory cells into the synovial cavity and early AC erosion were also very prominent at this time. Analysis of adjacent sections showed that both induction of VDIPEN and GAG depletion were strikingly codistributed within sites of articular cartilage damage. Similar results occurred in proteoglycan-induced arthritis, a more progressive and chronic model of inflammatory arthritis. These studies demonstrate for the first time the MMP-dependent catabolism of aggrecan at sites of chondrodestruction during inflammatory arthritis.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI117907