Mechanisms involved in cartilage proteoglycan catabolism

Caterson, Bruce; Flannery, Carl R.; Hughes, Claire E.; Little, Christopher B.

doi:10.1016/s0945-053x(00)00078-0

Cited by 268 publications

(226 citation statements)

References 58 publications

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“…Although it has been widely accepted (22,23,30,(37)(38)(39)(40)(41)(42) that ADAMTS4 (aggrecanase-1) cleaves only at the Glu 373 -Ala 374 bond within the IGD, the results described here suggest that both of the major cleavages that are known to occur in vivo, at Glu 373 -Ala 374 and Asn 341 -Phe 342 , can be catalyzed by ADAMTS4. Previously, cleavage at the Asn 341 -Phe 342 site in the aggrecan IGD was considered a specific property of the MMP family, with the exception of a snake venom enzyme (30,34) 341 -Phe 342 bond in the experiments described here was due to contamination of the ADAMTS4 preparation with an MMP-like activity was eliminated by the observation that although 10 mM EDTA and TIMP-3 totally blocked the cleavage, neither TIMP-1 nor TIMP-2 was inhibitory, even at 750 nM.…”

Section: Discussionmentioning

confidence: 53%

ADAMTS4 Cleaves at the Aggrecanase Site (Glu373-Ala374) and Secondarily at the Matrix Metalloproteinase Site (Asn341-Phe342) in the Aggrecan Interglobular Domain

Westling

Fosang

Thompson

et al. 2002

Journal of Biological Chemistry

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Aggrecan is the major cartilage hyalectan (1), which, together with the collagen network, provides this tissue with its unique mechanical properties of compressibility and stiffness (2-4). Extraction of aggrecan in its native form (5) and subsequent structural analysis (6) have revealed that the molecular organization of aggrecan is perfectly suited to its central functional role in articular cartilage. The N-terminal region of aggrecan is composed of two globular domains (G1 1 and G2) separated by the interglobular domain (IGD). G1 interacts with hyaluronan and link protein, thereby keeping the aggrecan molecule anchored within the cartilage tissue. Further interactions with other matrix components such as tenascin-R and fibulin-1 and fibulin-2 (7, 8) may occur through a third globular domain (G3) at the extreme C terminus of the core protein. The extended core protein between G2 and G3 is composed of a short keratan sulfate-rich region followed by a longer chondroitin sulfate-substituted domain. The charge repulsion and hydration of the long negatively charged glycosaminoglycan (GAG) chains are thought to maintain the C-terminal portions of aggrecan in an extended conformation (9). The swelling pressure of the aggrecan-link protein complex with hyaluronan is restrained by the tension in the collagen network; and together, these components form a fiber-reinforced concentrated gel within the cartilage, which transmits forces across the articular joint.In diseases characterized by cartilage degradation such as rheumatoid arthritis and osteoarthritis, increased aggrecan release from the cartilage occurs early (10, 11) and before the bulk of the collagen network is degraded (12). Proteolytic cleavage of aggrecan within the IGD separates the GAG-rich region from the hyaluronan-anchored G1 domain, resulting in GAG release from the cartilage matrix to the synovial fluid. Biomechanical tests on cartilage discs have shown that proteolysis within the IGD of aggrecan, and not cleavages near the C terminus, is primarily responsible for the loss of compressive resistance that accompanies interleukin-1-mediated degradation of the tissue (13). Identification of the proteinases responsible for this "destructive" cleavage of aggrecan has therefore been a major focus of experimentation in arthritis-related research.In this regard, two major cleavage sites that occur in vivo have been identified in the IGD of human aggrecan. One is a matrix metalloproteinase (MMP)-sensitive site at VDIPEN 341 2F 342 FGVGG, which can be cleaved at neutral pH by any one of a range of MMPs, including MMP-1-3, -7-9, -13,

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Section: Discussionmentioning

confidence: 53%

ADAMTS4 Cleaves at the Aggrecanase Site (Glu373-Ala374) and Secondarily at the Matrix Metalloproteinase Site (Asn341-Phe342) in the Aggrecan Interglobular Domain

Westling

Fosang

Thompson

et al. 2002

Journal of Biological Chemistry

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“…BC4 is a monoclonal antibody recognizing the neo-epitope generated by MMPs on the core protein of aggrecan (Caterson et al, 2000). The expression of these epitopes was determined by the fluorescent immunostaining.…”

Section: Histochemistry and Immunohistochemistrymentioning

confidence: 99%

Effects of moniliformin and selenium on human articular cartilage metabolism and their potential relationships to the pathogenesis of Kashin-Beck disease

Zhang

Cao

Yang

et al. 2010

J. Zhejiang Univ. Sci. B

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Abstract:Objective: To investigate the effects of mycotoxin moniliformin (MON) on the metabolism of aggrecan and type II collagen in human chondrocytes in vitro and the relationship between MON and Kashin-Beck disease (KBD). Methods: Human chondrocytes were isolated and cultured on bone matrix gelatin to form an artificial cartilage model in vitro with or without MON toxin. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The expression of aggrecan and type II collagen in the cartilage was determined using immunocytochemical staining. Results: MON toxin inhibited chondrocyte viability in dose-dependent and time-dependent manners. MON reduced aggrecan and type II collagen syntheses in the tissue-engineered cartilage. MON also increased the expression of matrix metalloproteinase-1 (MMP-1), MMP-13, BC4 epitopes, and CD44 in cartilages. However, the expression of 3B3(−) epitopes in cartilages was inhibited by MON. Selenium partially alleviated the damage of aggrecan induced by MON toxin. Conclusion: MON toxin promoted the catabolism of aggrecan and type II collagen in human chondrocytes.

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“…The number of cells in the whole depth of the AC (from the surface to the osteochondral junction) was counted in at least four optical sections, and cellularity was expressed as a mean number of chondrocytes/0.01 mm 2 . Total articular cartilage thickness and thicknesses of uncalcified and calcified cartilages were measured on three representative SO-stained sections at three different regions (lateral, middle, and medial) in at least five animals of each genotype at each age.…”

Section: Histology Histopathological Grading and X-gal Stainingcontmentioning

confidence: 99%

β1 Integrin Deficiency Results in Multiple Abnormalities of the Knee Joint

Raducanu

Hunziker

Drosse³

et al. 2009

Journal of Biological Chemistry

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The lack of ␤1 integrins on chondrocytes leads to severe chondrodysplasia associated with high mortality rate around birth. To assess the impact of ␤1 integrin-mediated cell-matrix interactions on the function of adult knee joints, we conditionally deleted the ␤1 integrin gene in early limb mesenchyme using the Prx1-cre transgene. Mutant mice developed short limbed dwarfism and had joint defects due to ␤1 integrin deficiency in articular regions. The articular cartilage (AC) was structurally disorganized, accompanied by accelerated terminal differentiation, altered shape, and disrupted actin cytoskeleton of the chondrocytes. Defects in chondrocyte proliferation, cytokinesis, and survival resulted in hypocellularity. However, no significant differences in cartilage erosion, in the expression of matrix-degrading proteases, or in the exposure of aggrecan and collagen II cleavage neoepitopes were observed between control and mutant AC. We found no evidence for disturbed activation of MAPKs (ERK1/2, p38, and JNK) in vivo. Furthermore, fibronectin fragment-stimulated ERK activation and MMP-13 expression were indistinguishable in control and mutant femoral head explants. The mutant synovium was hyperplastic and frequently underwent chondrogenic differentiation. ␤1-null synoviocytes showed increased proliferation and phospho-focal adhesion kinase expression. Taken together, deletion of ␤1 integrins in the limb bud results in multiple abnormalities of the knee joints; however, it does not accelerate AC destruction, perturb cartilage metabolism, or influence intracellular MAPK signaling pathways. Chondrocytes of the articular cartilage (AC)2 secrete a unique set of extracellular matrix (ECM) molecules that assemble into interactive associates composed of collagens, proteoglycans (PGs), and non-collagenous glycoproteins (1). The fibrillar collagen meshwork supplies cartilage with its tensile strength, whereas the hydrated glycosaminoglycan (GAG) chains of PGs (mainly aggrecan) generate an osmotic swelling pressure that resists compressive forces. In diarthrodial joints, the molecular composition and the physical properties of the cartilage are principal determinants for the shock-absorbing function of articular surfaces upon mechanical loading. During the development of osteoarthritis (OA), an imbalance between anabolic and catabolic processes increases the proteolysis of PGs and collagens (2, 3), which eventually leads to the mechanical weakening of the AC and culminates in its progressive destruction. Physiological and pathological remodeling of the AC ECM is primarily attributed to the activities of matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin-like repeat (ADAMTS) proteases (4, 5) and is controlled by the communication between the cells and their environment.An increasing amount of evidence suggests that interactions between chondrocytes and the ECM through the integrin family of heterodimeric (␣␤) transmembrane receptors play a central role in cartilage function (6). Int...

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Mechanisms involved in cartilage proteoglycan catabolism

Cited by 268 publications

References 58 publications

ADAMTS4 Cleaves at the Aggrecanase Site (Glu373-Ala374) and Secondarily at the Matrix Metalloproteinase Site (Asn341-Phe342) in the Aggrecan Interglobular Domain

ADAMTS4 Cleaves at the Aggrecanase Site (Glu373-Ala374) and Secondarily at the Matrix Metalloproteinase Site (Asn341-Phe342) in the Aggrecan Interglobular Domain

Effects of moniliformin and selenium on human articular cartilage metabolism and their potential relationships to the pathogenesis of Kashin-Beck disease

β1 Integrin Deficiency Results in Multiple Abnormalities of the Knee Joint

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