A14 Injected Timp-3 Protects Cartilage in a Rat Meniscal Tear Model

Black, Roy A.; Castner, B.; Slack, Jason V.; Tocker, Joel; Eisenman, Jack I.; Jacobson, Elliott R.; Delaney, John F.; Winters, D.; Hecht, Rudolph; Bendele, Alison M.

doi:10.1016/s1063-4584(07)60467-1

Cited by 13 publications

(14 citation statements)

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“…As TIMP-3 can inhibit both MMPs and ADAMTSs, it is a central inhibitor of cartilage degradation. Addition of exogenous TIMP-3, but not TIMP-1 or TIMP-2 blocks cartilage degradation in explant cultures [180], and injection of TIMP-3 blocks cartilage breakdown in a rat surgical model of OA [181]. The chondroprotective role of TIMP-3 is confirmed by the finding that Timp3 −/− mice develop increased cartilage degradation upon aging [182] and increased cartilage damage in an antigen-induced arthritis model [183].…”

Section: Inhibitors Of Mmps and Adamtssmentioning

confidence: 99%

Proteases involved in cartilage matrix degradation in osteoarthritis

Troeberg

Nagase

2012

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

471

435

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Osteoarthritis is a common joint disease for which there are currently no disease-modifying drugs available. Degradation of the cartilage extracellular matrix is a central feature of the disease and is widely though to be mediated by proteinases that degrade structural components of the matrix, primarily aggrecan and collagen. Studies on transgenic mice have confirmed the central role of Adamalysin with Thrombospondin Motifs 5 (ADAMTS-5) in aggrecan degradation, and the collagenolytic matrix metalloproteinase MMP-13 in collagen degradation. This review discusses recent advances in current understanding of the mechanisms regulating expression of these key enzymes, as well as reviewing the roles of other proteinases in cartilage destruction.

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Section: Inhibitors Of Mmps and Adamtssmentioning

confidence: 99%

Proteases involved in cartilage matrix degradation in osteoarthritis

Troeberg

Nagase

2012

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

471

435

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“…TIMP-3 levels are reduced in human osteoarthritic cartilage ( 5 ). Treatment with recombinant TIMP-3 has been shown to block cartilage degradation in vitro ( 6 ) and in in vivo models of osteoarthritis ( 7 ), further illustrating the chondroprotective activity of TIMP-3.…”

Section: Introductionmentioning

confidence: 98%

Engineered Tissue Inhibitor of Metalloproteinases-3 Variants Resistant to Endocytosis Have Prolonged Chondroprotective Activity

Doherty¹,

Visse²,

Dinakarpandian

et al. 2016

Journal of Biological Chemistry

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Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a central inhibitor of matrix-degrading and sheddase families of metalloproteinases. Extracellular levels of the inhibitor are regulated by the balance between its retention on the extracellular matrix and its endocytic clearance by the scavenger receptor low density lipoprotein receptor-related protein 1 (LRP1). Here, we used molecular modeling to predict TIMP-3 residues potentially involved in binding to LRP1 based on the proposed LRP1 binding motif of 2 lysine residues separated by about 21 Å and mutated the candidate lysine residues to alanine individually and in pairs. Of the 22 mutants generated, 13 displayed a reduced rate of uptake by HTB94 chondrosarcoma cells. The two mutants (TIMP-3 K26A/K45A and K42A/K110A) with lowest rates of uptake were further evaluated and found to display reduced binding to LRP1 and unaltered inhibitory activity against prototypic metalloproteinases. TIMP-3 K26A/K45A retained higher affinity for sulfated glycosaminoglycans than K42A/K110A and exhibited increased affinity for ADAMTS-5 in the presence of heparin. Both mutants inhibited metalloproteinase-mediated degradation of cartilage at lower concentrations and for longer than wild-type TIMP-3, indicating that their increased half-lives improved their ability to protect cartilage. These mutants may be useful in treating connective tissue diseases associated with increased metalloproteinase activity.

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“…We have adopted an alternative strategy of attempting to block cartilage degradation by increasing levels of the endogenous metalloproteinase inhibitor, tissue inhibitor of metalloproteinases (TIMP)-3, in the joint. The chondroprotective role of TIMP-3 is illustrated by studies showing that mice lacking the gene for Timp3 develop accelerated OA as they age ( Sahebjam et al, 2007 ) and, conversely, that recombinant TIMP-3 inhibits development of OA in a rat model of disease ( Black et al, 2006 ). TIMP-3 levels are reduced in OA cartilage, although the mRNA levels are not altered ( Morris et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

Suramin Inhibits Osteoarthritic Cartilage Degradation by Increasing Extracellular Levels of Chondroprotective Tissue Inhibitor of Metalloproteinases 3

et al. 2017

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Osteoarthritis is a common degenerative joint disease for which no disease-modifying drugs are currently available. Attempts to treat the disease with small molecule inhibitors of the metalloproteinases that degrade the cartilage matrix have been hampered by a lack of specificity. We aimed to inhibit cartilage degradation by augmenting levels of the endogenous metalloproteinase inhibitor, tissue inhibitor of metalloproteinases (TIMP)-3, through blocking its interaction with the endocytic scavenger receptor, low-density lipoprotein receptor–related protein 1 (LRP1). We discovered that suramin (C51H40N6O23S6) bound to TIMP-3 with a KD value of 1.9 ± 0.2 nM and inhibited its endocytosis via LRP1, thus increasing extracellular levels of TIMP-3 and inhibiting cartilage degradation by the TIMP-3 target enzyme, adamalysin-like metalloproteinase with thrombospondin motifs 5. NF279 (8,8′-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)]bis-1,3,5-naphthalenetrisulfonic acid hexasodium salt), a structural analog of suramin, has an increased affinity for TIMP-3 and increased ability to inhibit TIMP-3 endocytosis and protect cartilage. Suramin is thus a promising scaffold for the development of novel therapeutics to increase TIMP-3 levels and inhibit cartilage degradation in osteoarthritis.

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A14 Injected Timp-3 Protects Cartilage in a Rat Meniscal Tear Model

Cited by 13 publications

References 0 publications

Proteases involved in cartilage matrix degradation in osteoarthritis

Proteases involved in cartilage matrix degradation in osteoarthritis

Engineered Tissue Inhibitor of Metalloproteinases-3 Variants Resistant to Endocytosis Have Prolonged Chondroprotective Activity

Suramin Inhibits Osteoarthritic Cartilage Degradation by Increasing Extracellular Levels of Chondroprotective Tissue Inhibitor of Metalloproteinases 3

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