Proteolysis of the collagen fibril in osteoarthritis

Poole, A. Robin; Nelson, Fred R.T.; Dahlberg, Leif; Tchetina, Elena V.; Kobayashi, Masahiko; Yasuda, Tadashi; Laverty, Sheila; Squires, Ginette R.; Kojima, Toshihisa; Wu, William; Billinghurst, R. Clark

doi:10.1042/bss0700115

Cited by 96 publications

(80 citation statements)

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“…Similar processes occur in cartilage explant cultures stimulated to undergo matrix degradation with cytokines such as IL-1, with the aggrecan degraded early (during the first week of culture), whereas the collagen is not rapidly degraded until later in the culture period when essentially all the aggrecan has been lost (Ellis et al, 1994;Kozaci et al, 1997). Metalloproteinases such as MMP-1 and MMP-13 have major roles in the degradation of collagen (Poole et al, 2003), whereas the aggrecanases ADAMTS-4 and ADAMTS-5 appear to mediate the aggrecan degradation (Arner, 2002). The transcription of MMP-1, MMP-3, and MMP-13 is known to be dependent on NF-B (Bondeson et al, 1999;Vincenti and Brinckerhoff, 2002;Andreakos et al, 2003), so it is not surprising that the IKK inhibitor BMS-345541 inhibited the transcription of these metalloproteinases in IL-1-stimulated SW-1353 chondrocytes in a concentration-dependent manner.…”

Section: Ikk Inhibition Blocks Collagen and Aggrecan Degradation 385mentioning

confidence: 96%

Collagen and Aggrecan Degradation Is Blocked in Interleukin-1-Treated Cartilage Explants by an Inhibitor of IκB Kinase through Suppression of Metalloproteinase Expression

Pattoli

MacMaster²,

Gregor³

et al. 2005

J Pharmacol Exp Ther

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It has previously been shown that BMS-345541 [4(2Ј-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline], a highly-selective inhibitor of IB kinase (IKK), blocks both inflammation and joint destruction in murine collagen-induced arthritis. Although this agent has been shown to inhibit nuclear factor-Bdependent cytokine expression in mice, we examined whether the inhibitor directly inhibits cytokine-driven metalloproteinase expression and cartilage degradation. In SW-1353 human chondrosarcoma cells, BMS-345541 inhibited interleukin-1 (IL-1)-dependent expression of matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 in a concentration-dependent manner. IL-1 treatment failed to induce and BMS-345541 did not inhibit the expression of aggrecanases ADAMTS-4 (a disintegrin and metalloproteinase domain with thrombospondin motif) and AD-AMTS-5, as well as the tissue inhibitor of metalloproteinase-3. In bovine cartilage explant cultures stimulated with IL-1 to induce aggrecan and collagen degradation over 3 weeks of culture, BMS-345541 was effective in inhibiting the degradation of both aggrecan and collagen. Secreted ADAMTS-4 was not inhibited by BMS-345541 in these explants, whereas ADAMTS-5 secretion was blocked in the same concentration range that inhibited aggrecan degradation. The ability of the IKK inhibitor to block aggrecan and collagen degradation through suppression of metalloproteinase expression, coupled with its ability to block inflammatory cytokine production, shows IKK to be a promising target for the development of novel agents to treat arthritic diseases.Degenerative joint disorders such as osteoarthritis (OA) and rheumatoid arthritis (RA) are characterized by the destruction and loss of articular cartilage and an imbalance of proinflammatory cytokines. In both disorders, the chondrocytes appear to play an important role in the pathogenesis of disease. Although chondrocytes are the primary source of type II collagen and aggrecan, two of the most important components of the cartilage matrix, these cells also produce proteolytic enzymes, which degrade collagen and aggrecan/ proteoglycan when stimulated with interleukin-1 (IL-1) or tumor necrosis factor-␣ (TNF-␣). Overproduction of these enzymes results in the erosion of articular cartilage, destruction of tissue and bone, and joint abnormalities. As evidenced by the efficacy of therapies targeting TNF-␣ (e.g., infliximab and etanercept) or IL-1 (e.g., anakinra), these cytokines play a critical role in both the inflammatory and destructive mechanisms of RA. In OA, IL-1 also appears to play a pivotal role in the degenerative process by driving collagen and aggrecan degradation (for a review, see Chevalier, 1997).The transcription factor nuclear factor-B (NF-B) mediates much of the downstream effects of both TNF-␣ and IL-1, including the transcription of matrix metalloproteinases (MMP) and other cytokines (Li and Verma, 2002). In unactivated cells, NF-B is inhibited by an interaction with an IB protein (e.g., IB␣, IB␤, and IB⑀). An essential step i...

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Section: Ikk Inhibition Blocks Collagen and Aggrecan Degradation 385mentioning

confidence: 96%

Collagen and Aggrecan Degradation Is Blocked in Interleukin-1-Treated Cartilage Explants by an Inhibitor of IκB Kinase through Suppression of Metalloproteinase Expression

Pattoli

MacMaster²,

Gregor³

et al. 2005

J Pharmacol Exp Ther

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“…Impaired or abnormal degradation and removal of ECM components contributes to the onset and progression of many diseases, including fibrosis, arthritis and cancer (Hotary et al, 2003;Kurban et al, 2006;Liotta and Kohn, 2001;Mutsaers et al, 1997;Poole et al, 2003). Two principal molecular mechanisms are believed to be involved in the turnover of ECM.…”

Section: Introductionmentioning

confidence: 99%

Caveolin-1-dependent β1 integrin endocytosis is a critical regulator of fibronectin turnover

Shi

Sottile

2008

Journal of Cell Science

215

193

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“…Different ECM proteins, and combinations of proteins, can have distinct effects on the phenotype of cells, affecting such important processes as cell survival, growth, differentiation, and migration (2,42,55,59,64). Additionally, ECM fragments produced by proteolysis can accumulate in vivo and contribute to changes in cell behavior (3,24,44,63). ECM fragments can have properties distinct from the intact parental proteins (8,14,41).…”

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confidence: 99%

Collagen I matrix turnover is regulated by fibronectin polymerization

Shi

Harman

Fujiwara

et al. 2010

American Journal of Physiology-Cell Physiology

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Extracellular matrix (ECM) remodeling occurs during normal homeostasis and also plays an important role during development, tissue repair, and in various disease processes. ECM remodeling involves changes in the synthesis, deposition, and degradation of ECM molecules. ECM molecules can be degraded extracellularly, as well as intracellularly following endocytosis. Our data show that the ECM protein fibronectin is an important regulator of ECM remodeling. We previously showed that agents that inhibit the polymerization of fibronectin into ECM fibrils promote the loss of preexisting fibronectin matrix and accelerate fibronectin endocytosis and degradation. In this paper we show that inhibition of fibronectin polymerization leads to the loss of collagen I matrix fibrils and a corresponding increase in the levels of endocytosed collagen I. In contrast, manipulations that stabilize fibronectin matrix fibrils, such as caveolin-1 depletion, stabilize collagen I matrix fibrils and cause a decrease in ECM collagen I endocytosis. Our data also show that endocytosis of ECM collagen I is regulated by both ␤1 integrins and Endo180/urokinase plasminogen activator associated protein (uPARAP). Unexpectedly, Endo180/uPARAP was also shown to promote the endocytosis of fibronectin from the ECM. These data demonstrate that fibronectin polymerization regulates the remodeling of ECM collagen I, in part, by regulating collagen I endocytosis. Furthermore, these data show that processes that regulate ECM deposition coordinately regulate the removal of proteins from the ECM. These data highlight the complexity of ECM remodeling. This multifaceted regulatory process may be important to ensure tight regulation of ECM fibronectin and collagen I levels. extracellular matrix; integrin; endocytosis; Endo180; urokinase plasminogen activator-associated protein EXTRACELLULAR MATRIX (ECM) remodeling is a critical process that occurs during development and tissue repair. ECM remodeling also occurs in a variety of pathological conditions, such as hypertension, restenosis following angioplasty, heart failure, fibrosis, and cancer (1,4,39,68). ECM synthesis, deposition, and degradation are all components of ECM remodeling. The balance between these processes determines whether net accumulation or loss of ECM occurs. Different ECM proteins, and combinations of proteins, can have distinct effects on the phenotype of cells, affecting such important processes as cell survival, growth, differentiation, and migration (2,42,55,59,64). Additionally, ECM fragments produced by proteolysis can accumulate in vivo and contribute to changes in cell behavior (3,24,44,63). ECM fragments can have properties distinct from the intact parental proteins (8,14,41). Hence, mechanisms that limit the accumulation of ECM fragments are likely to be important for regulating a variety of cell processes.A variety of extracellular proteases regulate ECM degradation. Prominent among these proteases are matrix metalloproteinases (MMPs). MMPs are important regulators of cell migration ...

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Proteolysis of the collagen fibril in osteoarthritis

Cited by 96 publications

References 0 publications

Collagen and Aggrecan Degradation Is Blocked in Interleukin-1-Treated Cartilage Explants by an Inhibitor of IκB Kinase through Suppression of Metalloproteinase Expression

Collagen and Aggrecan Degradation Is Blocked in Interleukin-1-Treated Cartilage Explants by an Inhibitor of IκB Kinase through Suppression of Metalloproteinase Expression

Caveolin-1-dependent β1 integrin endocytosis is a critical regulator of fibronectin turnover

Collagen I matrix turnover is regulated by fibronectin polymerization

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