Kinetics of aggrecanase- and metalloproteinase-induced neoepitopes in various stages of cartilage destruction in murine arthritis

Meurs, Joyce B. J. van; Lent, P.L.E.M. van; Holthuysen, A.E.M.; Singer, Irwin; Bayne, Ellen K.; Berg, Wim B. van den

doi:10.1002/1529-0131(199906)42:6<1128::aid-anr9>3.0.co;2-2

Cited by 129 publications

(133 citation statements)

References 37 publications

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“…Similar results have recently been reported using immunohistological analysis following MMP-3 digestion of murine articular cartilage [34]. Taken together, these results raise the possibility that detection of the … DIPEN neoepitope in articular cartilage may not be solely due to primary MMP-generated aggrecan release from articular cartilage, but could also result from secondary cleavage of aggrecanase-generated metabolites.…”

Section: Figure 4 Western Blot Analysis Of Aggrecan Fragments Generatsupporting

confidence: 87%

Aggrecanase versus matrix metalloproteinases in the catabolism of the interglobular domain of aggrecan in vitro

Little

Flannery

Hughes

et al. 1999

Biochemical Journal

113

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The importance of aggrecanase versus matrix metalloproteinase (MMP) enzymic activities in the degradation of aggrecan in normal and osteoarthritic (OA) articular cartilage in vitro was studied in order to further our understanding of the potential role of these two enzyme activities in aggrecan catabolism during the pathogenesis of cartilage degeneration. Porcine and bovine articular cartilage was maintained in explant culture for up to 20 days in the presence or absence of the catabolic stimuli retinoic acid, interleukin-1 or tumour necrosis factor-α. Release of proteoglycan from cartilage was measured as glycosaminoglycan (GAG) release using a colorimetric assay. Analysis of proteoglycan degradation products, both released into culture media and retained within the cartilage matrix, was performed by Western blotting using antibodies specific for the N- and C-terminal neoepitopes generated by aggrecanase- and MMP-related catabolism of the interglobular domain of the aggrecan core protein (IGD). In addition, studies determining the mRNA expression for MMP-3 and MMP-13 in these same cultures were undertaken. These analyses indicated that all three catabolic agents stimulated the release of > 80% of the GAG from the articular cartilage over 4 days. The degree of GAG release corresponded to an increase in aggrecanase-generated aggrecan catabolites released into the media and retained within the cartilage. Importantly, there was no evidence for the release of MMP-generated aggrecan metabolites into the medium, nor the accumulation of MMP-generated catabolites within the tissue in these same cultures. Expression of the mRNAs for two MMPs known to be capable of degrading the aggrecan IGD, MMP-3 and MMP-13, was detected. However, increased expression of these MMPs was not correlated with aggrecan degradation. Analyses using porcine cartilage, cultured with or without catabolic stimulation for 12 h to 20 days, indicated that primary cleavage of the IGD by aggrecanase was responsible for release of aggrecan metabolites at both the early and late time points of culture. Cultures of late-stage OA human articular cartilage samples indicated that aggrecanase activity was upregulated in the absence of catabolic stimulation when compared with normal porcine or bovine cartilage. In addition, even in this late-stage degenerate cartilage, aggrecanase and not MMP activity was responsible for the release of the majority of aggrecan from the cartilage. This study demonstrates that the release of aggrecan from both normal and OA cartilage in response to catabolic stimulation in vitro involves a primary cleavage by aggrecanase and not MMPs.

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Section: Figure 4 Western Blot Analysis Of Aggrecan Fragments Generatsupporting

confidence: 87%

Aggrecanase versus matrix metalloproteinases in the catabolism of the interglobular domain of aggrecan in vitro

Little

Flannery

Hughes

et al. 1999

Biochemical Journal

113

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“…As proteoglycan depletion was not significantly suppressed by inhibition of both enzymes, these two enzymes were not essential for the degradation of proteoglycan. Because proteoglycan degradation is mediated by many MMPs and aggrecanase (23,24), the compensatory or redundant activities of the other MMPs or aggrecanase probably have a greater influence on proteoglycan depletion in the double KO mice.…”

Section: Discussionmentioning

confidence: 99%

The Role of Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 in Antibody-Induced Arthritis

Itoh

Matsuda

Tanioka

et al. 2002

The Journal of Immunology

278

201

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Matrix metalloproteinases (MMPs) are a large group of enzymes responsible for matrix degradation. Among them, the family of gelatinases (MMP-2/gelatinase A and MMP-9/gelatinase B) is overproduced in the joints of patients with rheumatoid arthritis. Because of their degradative effects on the extracellular matrix, gelatinases have been believed to play an important role in progression and cartilage degradation in this disease, although their precise roles are yet to be defined. To clarify these roles, we investigated the development of Ab-induced arthritis, one of the murine models of rheumatoid arthritis, in MMP-2 or MMP-9 knockout (KO) mice. Surprisingly, the MMP-2 KO mice exhibited severe clinical and histologic arthritis than wild-type mice. The MMP-9 KO mice displayed milder arthritis. Recovery from exacerbated arthritis in the MMP-2 KO mice was possible by injection of wild-type fibroblasts. These results indicated a suppressive role of MMP-2 and a pivotal role of MMP-9 in the development of inflammatory joint disease.

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“…Moreover, synovial macrophages and fibroblasts are also involved in the production of latent MMPs (34). Activation of proMMPs leads to destruction of proteoglycans and type II collagen fibers that form the cartilage matrix (13)(14)(15). The factors involved in activation of proMMPs are still not identified.…”

Section: Discussionmentioning

confidence: 99%

“…If cartilage destruction continues, irreversible collagen fiber degradation occurs. Stromelysin and collagenase are the main MMPs involved in this process (13)(14)(15). MMPs are secreted in an inactive form by chondrocytes, stored in the cartilage matrix, and activated after further cleavage (16).…”

mentioning

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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Kinetics of aggrecanase- and metalloproteinase-induced neoepitopes in various stages of cartilage destruction in murine arthritis

Cited by 129 publications

References 37 publications

Aggrecanase versus matrix metalloproteinases in the catabolism of the interglobular domain of aggrecan in vitro

Aggrecanase versus matrix metalloproteinases in the catabolism of the interglobular domain of aggrecan in vitro

The Role of Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 in Antibody-Induced Arthritis

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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