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

Singer, Irwin; Kawka, Douglas W.; Bayne, Ellen K.; Donatelli, Susan; Weidner, Jeffrey R.; Williams, Hollis R.; Ayala, Julia M.; Mumford, Richard A.; Lark, Michael W.; Glant, Tibor T.

doi:10.1172/jci117907

Cited by 116 publications

(86 citation statements)

References 52 publications

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“…This is supported by the finding that the MMP-generated G1 fragment terminating in VDIPEN-341 and aggrecanase-generated G1 fragments terminating in NITEGE-373 are both detected in cartilage from joints with osteoarthritis and rheumatoid arthritis [40]. The generation and/or turnover of these specific aggrecan fragments is not necessarily co-ordinated, since both the NITEGE-373 and VDIPEN-341 neoepitopes can be non-coincident within a single joint [38]. Turnover of aggrecan in cultured rat chondrosarcoma cells and primary bovine chondrocytes can be mediated exclusively by aggrecanase [52].…”

Section: The Inter-globular Domain (Igd)mentioning

confidence: 85%

“…The first major cleavage site generates a G1-containing fragment with the C-terminus neoepitope VDIPEN-341 and a larger GAG-bearing fragment with the N-terminus neoepitope 342-FFGVGGE [34], [38][39][40]. The results of many studies support the contention that MMPs are involved in the breakdown of aggrecan molecules in vivo.…”

Section: The Inter-globular Domain (Igd)mentioning

confidence: 96%

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Structure and function of aggrecan

et al. 2002

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Aggrecan is the major proteoglycan in the articular cartilage. This molecule is important in the proper functioning of articular cartilage because it provides a hydrated gel structure (via its interaction with hyaluronan and link protein) that endows the cartilage with load-bearing properties. It is also crucial in chondroskeletal morphogenesis during development. Aggrecan is a multimodular molecule expressed by chondrocytes. Its core protein is composed of three globular domains (G1, G2, and G3) and a large extended region (CS) between G2 and G3 for glycosaminoglycan chain attachment. G1 comprises the amino terminus of the core protein. This domain has the same structural motif as link protein. Functionally, the G1 domain interacts with hyaluronan acid and link protein, forming stable ternary complexes in the extracellular matrix. G2 is homologous to the tandem repeats of G1 and of link protein and is involved in product processing. G3 makes up the carboxyl terminus of the core protein. It enhances glycosaminoglycan modification and product secretion. Aggrecan plays an important role in mediating chondrocyte-chondrocyte and chondrocyte-matrix interactions through its ability to bind hyaluronan.

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Section: The Inter-globular Domain (Igd)mentioning

confidence: 85%

Section: The Inter-globular Domain (Igd)mentioning

confidence: 96%

Structure and function of aggrecan

et al. 2002

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“…In MS, the demyelination process has been proposed to be the consequence of immune cell infiltration in white matter (56), and part of the deleterious effect of invading cells may involve a myelin proteolysis by MMPs (57) and a subsequent alteration of oligodendrocytes forming myelin. On the other hand, by generating encephalitogen peptides and neoepitopes (58,59), MMP-9 and MMP-3 may be involved in the immune-mediated destruction of oligodendrocytes, in particular by the so-called "epitope spreading" mechanism (60). Finally, MMPs and TIMPs may play a critical role in the intricate cellular interaction within the CNS (40) by remodeling the ECM, which constitutes the interface between neural cells (38,61).…”

Section: Discussionmentioning

confidence: 99%

T Lymphocytes Activated by Persistent Viral Infection Differentially Modify the Expression of Metalloproteinases and Their Endogenous Inhibitors, TIMPs, in Human Astrocytes: Relevance to HTLV-I-Induced Neurological Disease

Giraudon

Szymocha

Buart

et al. 2000

The Journal of Immunology

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Activation of T lymphocytes by human pathogens is a key step in the development of immune-mediated neurologic diseases. Because of their ability to invade the CNS and their increased secretion of proinflammatory cytokines, activated CD4+ T cells are thought to play a crucial role in pathogenesis. In the present study, we examined the expression of inflammatory mediators the cytokine-induced metalloproteinases (MMP-2, -3, and -9) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMP-1, -2, and -3), in human astrocytes in response to activated T cells. We used a model system of CD4+ T lymphocytes activated by persistent viral infection (human T lymphotropic virus, HTLV-I) in transient contact with human astrocytes. Interaction with T cells resulted in increased production of MMP-3 and active MMP-9 in astrocytes despite increased expression of endogenous inhibitors, TIMP-1 and TIMP-3. These data suggest perturbation of the MMP/TIMP balance. These changes in MMP and TIMP expression were mediated, in part, by soluble factors (presumably cytokines) secreted by activated T cells. Integrin-mediated cell adhesion is also involved in the change in MMP level, since blockade of integrin subunits (α1, α3, α5, and β1) on T cells resulted in less astrocytic MMP-9-induced expression. Interestingly, in CNS tissues from neurological HTLV-I-infected patients, MMP-9 was detected in neural cells within the perivascular space, which is infiltrated by mononuclear cells. Altogether, these data emphasize the importance of the MMP-TIMP axis in the complex interaction between the CNS and invading immune cells in the context of virally mediated T cell activation.

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“…VDIPEN expression indicates the presence of active MMPs, which also degrade collagen fibers, resulting in severe cartilage damage. To detect VDIPEN, sections were digested with proteinase-free chondroitinase ABC (0.25 units/ml in 0.1M Tris HCl, pH 8.0; Sigma, Zwijndrecht, The Netherlands) to remove the side chains of proteoglycans, followed by incubation with affinity-purified rabbit anti-VDIPEN IgG (23). The primary antibody was detected using biotinylated goat anti-rabbit IgG and avidin-streptavidinperoxidase (Elite kit; Vector, Burlingame, CA).…”

Section: Methodsmentioning

confidence: 99%

Joint inflammation and chondrocyte death become independent of Fcγ receptor type III by local overexpression of interferon‐γ during immune complex–mediated arthritis

Nabbe¹,

Boross²,

Holthuysen³

et al. 2005

Arthritis & Rheumatism

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Objective. It has previously been shown that the onset and the degree of joint inflammation during immune complex (IC)-mediated arthritis depend on Fc␥ receptor type III (Fc␥RIII). Local adenoviral overexpression of interferon-␥ (IFN␥) in the knee joint prior to onset of IC-mediated arthritis aggravated severe cartilage destruction. In Fc␥RI Ϫ/Ϫ mice, however, chondrocyte death was not enhanced by IFN␥, whereas matrix metalloproteinase (MMP)-mediated aggrecan breakdown was markedly elevated, suggesting a role for the activating Fc␥RIII in the latter process. We undertook this study to determine the role of Fc␥RIII in joint inflammation and severe cartilage destruction in IFN␥-stimulated IC-mediated arthritis, using Fc␥RIII ؊/؊ mice.Methods. Fc␥RIII ؊/؊ and wild-type (WT) mice were injected in the knee joint with recombinant adenovirus encoding murine IFN␥ (AdIFN␥) or with adenovirus encoding enhanced green fluorescent protein 1 day prior to induction of IC-mediated arthritis. Histologic sections were obtained 3 days after arthritis onset to study inflammation and cartilage damage. MMPmediated expression of the VDIPEN neoepitope was detected by immunolocalization. Chemokine and Fc␥R expression levels were determined in synovial washouts and synovium, respectively.Results. Injection of AdIFN␥ in naive knee joints markedly increased levels of messenger RNA for Fc␥RI, Fc␥RII, and Fc␥RIII. Upon IFN␥ overexpression prior to induction of IC-mediated arthritis, joint inflammation was similar in Fc␥RIII ؊/؊ and WT mice. The percentage of macrophages in the knee joint was increased, which correlated with high concentrations of the macrophage attractant macrophage inflammatory protein 1␣. Furthermore, IFN␥ induced 2-fold and 3-fold increases in chondrocyte death in WT controls and Fc␥RIII ؊/؊ mice, respectively. Notably, VDIPEN expression also remained high in Fc␥RIII ؊/؊ mice.Conclusion. IFN␥ bypasses the dependence on Fc␥RIII in the development of IC-mediated arthritis. Furthermore, both Fc␥RI and Fc␥RIII can mediate MMP-dependent cartilage matrix destruction.

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

Abstract: IntroductionThe destruction of articular cartilage in immune inflammatory arthritic disease involves the proteolytic degradation of its extracellular matrix. (21,(26)(27)(28), and induction of the cytokines IFNy, TNFa, and IL-1IB (20, 29-1. Abbreviations used in this paper:

Cited by 116 publications

References 52 publications

Structure and function of aggrecan

Structure and function of aggrecan

T Lymphocytes Activated by Persistent Viral Infection Differentially Modify the Expression of Metalloproteinases and Their Endogenous Inhibitors, TIMPs, in Human Astrocytes: Relevance to HTLV-I-Induced Neurological Disease

Joint inflammation and chondrocyte death become independent of Fcγ receptor type III by local overexpression of interferon‐γ during immune complex–mediated arthritis

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