Metalloproteases as potential therapeutic targets in arthritis treatment

Dysregulated proteolysis of the extracellular matrix of articular cartilage represents a unifying hallmark of the arthritides, and has been a target for therapeutic intervention for some time, although clinical efficacy has been elusive. Members of the ‘A disintegrin and metalloprotease with thrombospondin motifs’ and matrix metalloprotease families are considered to be collectively responsible for cartilage catabolism, such that inhibition of these activities is theoretically a highly attractive strategy for preventing further proteolytic damage. This review outlines the biology of these metalloproteases and what we have learnt from inhibition studies and transgenics, and highlights the important questions that this information raises for the future development of therapeutics directed towards metalloproteases for arthritis treatment.

[1]  M. Neuenhahn,et al.  NF-κB Is a Negative Regulator of IL-1β Secretion as Revealed by Genetic and Pharmacological Inhibition of IKKβ , 2007, Cell.

[2]  Yiling Lu,et al.  Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery , 2005, Nature Reviews Drug Discovery.

[3]  R. Flavell,et al.  Mitogen-activated protein kinase kinase 3 is a pivotal pathway regulating p38 activation in inflammatory arthritis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[4]  M. Karin,et al.  c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. , 2001, The Journal of clinical investigation.

[5]  C. López-Otín,et al.  Biochemical Characterization of Human Collagenase-3 (*) , 1996, The Journal of Biological Chemistry.

[6]  A. Poole,et al.  Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. , 2001, The Journal of clinical investigation.

[7]  R. Mason,et al.  Gene deletion of either interleukin-1beta, interleukin-1beta-converting enzyme, inducible nitric oxide synthase, or stromelysin 1 accelerates the development of knee osteoarthritis in mice after surgical transection of the medial collateral ligament and partial medial meniscectomy. , 2003, Arthritis and rheumatism.

[8]  D. Edwards,et al.  The ADAMTS metalloproteinases. , 2005, The Biochemical journal.

[9]  S. Kumar,et al.  Intracellular signaling pathways as a target for the treatment of rheumatoid arthritis. , 2001, Current opinion in pharmacology.

[10]  Mahboob Rahman,et al.  Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Y. Okada,et al.  ADAMs in cancer cell proliferation and progression , 2007, Cancer science.

[12]  W. Li,et al.  Oncostatin M-Induced Matrix Metalloproteinase and Tissue Inhibitor of Metalloproteinase-3 Genes Expression in Chondrocytes Requires Janus Kinase/STAT Signaling Pathway1 , 2001, The Journal of Immunology.

[13]  L. Sharma,et al.  Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo-controlled, double-blind trial. , 2005, Arthritis and rheumatism.

[14]  J. Peterson.  The importance of estimating the therapeutic index in the development of matrix metalloproteinase inhibitors. , 2006, Cardiovascular research.

[15]  A. Sands,et al.  Knockouts model the 100 best-selling drugs—will they model the next 100? , 2003, Nature Reviews Drug Discovery.

[16]  Li Zhang,et al.  Design, synthesis and preliminary evaluation of new cinnamoyl pyrrolidine derivatives as potent gelatinase inhibitors. , 2006, Bioorganic & medicinal chemistry.

[17]  P. Tak,et al.  Inhibitor of nuclear factor κB kinase β is a key regulator of synovial inflammation , 2001 .

[18]  A. Samarel,et al.  Fibronectin Fragment Activation of Proline-rich Tyrosine Kinase PYK2 Mediates Integrin Signals Regulating Collagenase-3 Expression by Human Chondrocytes through a Protein Kinase C-dependent Pathway* , 2003, Journal of Biological Chemistry.

[19]  R. Gay,et al.  Antisense strategies in degenerative joint diseases: sense or nonsense? , 2006, Advanced Drug Delivery Reviews.

[20]  T. Cawston,et al.  Understanding the role of tissue degrading enzymes and their inhibitors in development and disease. , 2006, Best practice & research. Clinical rheumatology.

[21]  Gavin C. Jones,et al.  ADAMTS proteinases: a multi-domain, multi-functional family with roles in extracellular matrix turnover and arthritis , 2005, Arthritis research & therapy.

[22]  L. Ivashkiv,et al.  The JAK/STAT pathway in rheumatoid arthritis: pathogenic or protective? , 2003, Arthritis and rheumatism.

[23]  S. Chu,et al.  Regulation of Gelatinases Expression by Cytokines, Endotoxin, and Pharmacological Agents in the Human Osteoarthritic Knee , 2004, Connective tissue research.

[24]  C. Flannery.  MMPs and ADAMTSs: functional studies. , 2006, Frontiers in bioscience : a journal and virtual library.

[25]  X. Puente,et al.  Human and mouse proteases: a comparative genomic approach , 2003, Nature Reviews Genetics.

[26]  D. Edwards,et al.  Histone deacetylase inhibitors modulate metalloproteinase gene expression in chondrocytes and block cartilage resorption , 2005, Arthritis research & therapy.

[27]  C. López-Otín,et al.  Loss of collagenase-2 confers increased skin tumor susceptibility to male mice , 2003, Nature Genetics.

[28]  C. Brinckerhoff,et al.  Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors , 2001, Arthritis Research & Therapy.

[29]  S. Shapiro,et al.  Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. , 1997, Science.

[30]  B. Ray,et al.  Transcriptional Induction of Matrix Metalloproteinase-9 in the Chondrocyte and Synoviocyte Cells Is Regulated via a Novel Mechanism: Evidence for Functional Cooperation between Serum Amyloid A-Activating Factor-1 and AP-11 , 2005, The Journal of Immunology.

[31]  R. Wynn,et al.  Purification and cloning of aggrecanase-1: a member of the ADAMTS family of proteins. , 1999, Science.

[32]  A. J. Day,et al.  Selective inhibition of ADAMTS-1, -4 and -5 by catechin gallate esters. , 2003, European journal of biochemistry.

[33]  A. Rowan,et al.  Collagenase gene regulation by pro-inflammatory cytokines in cartilage. , 2007, Frontiers in bioscience : a journal and virtual library.

[34]  J. Block,et al.  Basic Fibroblast Growth Factor Stimulates Matrix Metalloproteinase-13 via the Molecular Cross-talk between the Mitogen-activated Protein Kinases and Protein Kinase Cδ Pathways in Human Adult Articular Chondrocytes* , 2007, Journal of Biological Chemistry.

[35]  D. Sliva,et al.  Signaling pathways responsible for cancer cell invasion as targets for cancer therapy. , 2004, Current cancer drug targets.

[36]  M. El Mabrouk,et al.  Signaling pathways implicated in oncostatin M-induced aggrecanase-1 and matrix metalloproteinase-13 expression in human articular chondrocytes. , 2007, Biochimica et biophysica acta.

[37]  A. Fourie,et al.  ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro , 2005, Nature.

[38]  G. Firestein,et al.  Mitogen activated protein kinase inhibitors: where are we now and where are we going? , 2006, Annals of the rheumatic diseases.

[39]  R. Schneiderman,et al.  Aggrecan turnover in human articular cartilage: use of aspartic acid racemization as a marker of molecular age. , 1998, Archives of biochemistry and biophysics.

[40]  I. Clark,et al.  Acetylation in the regulation of metalloproteinase and tissue inhibitor of metalloproteinases gene expression. , 2007, Frontiers in bioscience : a journal and virtual library.

[41]  F. Breedveld,et al.  Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of TIMP-1 and TIMP-3 , 2003, Gene Therapy.

[42]  S. Chu,et al.  Upregulation of urokinase-type plasminogen activator and inhibitor and gelatinase expression via 3 mitogen-activated protein kinases and PI3K pathways during the early development of osteoarthritis. , 2007, The Journal of rheumatology.

[43]  Gavin C. Jones.  ADAMTS proteinases: potential therapeutic targets? , 2006, Current pharmaceutical biotechnology.

[44]  R. Black,et al.  Identification and Characterization of 4-[[4-(2-Butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-(3S)thiomorpholinecarboxamide (TMI-1), a Novel Dual Tumor Necrosis Factor-α-Converting Enzyme/Matrix Metalloprotease Inhibitor for the Treatment of Rheumatoid Arthritis , 2004, Journal of Pharmacology and Experimental Therapeutics.

[45]  P. Ghosh.  Seminars in Arthritis and Rheumatism , 1999 .

[46]  D. Felson,et al.  The futility of current approaches to chondroprotection. , 2007, Arthritis and rheumatism.

[47]  K. Struhl.  Histone acetylation and transcriptional regulatory mechanisms. , 1998, Genes & development.

[48]  S. Jimenez,et al.  NF-κB as a potential therapeutic target in osteoarthritis and rheumatoid arthritis , 2006 .

[49]  C. Little,et al.  ADAMTS-1-knockout mice do not exhibit abnormalities in aggrecan turnover in vitro or in vivo. , 2005, Arthritis and rheumatism.

[50]  M. Karin,et al.  Joint damage and inflammation in c-Jun N-terminal kinase 2 knockout mice with passive murine collagen-induced arthritis. , 2002, Arthritis and rheumatism.

[51]  F. Legendre,et al.  Role of interleukin 6 (IL-6)/IL-6R-induced signal tranducers and activators of transcription and mitogen-activated protein kinase/extracellular. , 2005, The Journal of rheumatology.

[52]  J. Rutter,et al.  Synergistic induction of matrix metalloproteinase 1 by interleukin-1alpha and oncostatin M in human chondrocytes involves signal transducer and activator of transcription and activator protein 1 transcription factors via a novel mechanism. , 2001, Arthritis and rheumatism.

[53]  R. D. Dyer,et al.  Discovery and Characterization of a Novel Inhibitor of Matrix Metalloprotease-13 That Reduces Cartilage Damage in Vivo without Joint Fibroplasia Side Effects* , 2007, Journal of Biological Chemistry.

[54]  J. V. van Meurs,et al.  Cleavage of aggrecan at the Asn341-Phe342 site coincides with the initiation of collagen damage in murine antigen-induced arthritis: a pivotal role for stromelysin 1 in matrix metalloproteinase activity. , 1999, Arthritis and rheumatism.

[55]  J. Heath,et al.  Synergistic effects of glycoprotein 130 binding cytokines in combination with interleukin-1 on cartilage collagen breakdown. , 2001, Arthritis and rheumatism.

[56]  Michael H. Rabinowitz,et al.  Inhibition of tumor necrosis factor-alpha (TNF-alpha) production and arthritis in the rat by GW3333, a dual inhibitor of TNF-alpha-converting enzyme and matrix metalloproteinases. , 2001, The Journal of pharmacology and experimental therapeutics.

[57]  C. Sardet,et al.  Post-activation Turn-off of NF-κB-dependent Transcription Is Regulated by Acetylation of p65* , 2003, The Journal of Biological Chemistry.

[58]  D. Alexander,et al.  Retroviral gene transfer of an antisense construct against membrane type 1 matrix metalloproteinase reduces the invasiveness of rheumatoid arthritis synovial fibroblasts. , 2005, Arthritis and rheumatism.

[59]  Shigeyoshi Itohara,et al.  The Role of Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 in Antibody-Induced Arthritis , 2002, The Journal of Immunology.

[60]  Z. Werb,et al.  Altered endochondral bone development in matrix metalloproteinase 13-deficient mice , 2004, Development.

[61]  P. Robbins,et al.  Gene therapy for arthritis: what next? , 2006, Arthritis and rheumatism.

[62]  B. Fingleton.  Matrix metalloproteinase inhibitors for cancer therapy: the current situation and future prospects , 2003, Expert opinion on therapeutic targets.

[63]  Constance E. Brinckerhoff,et al.  Matrix metalloproteinases: a tail of a frog that became a prince , 2002, Nature Reviews Molecular Cell Biology.

[64]  Pascal Richette,et al.  Peroxisome Proliferator-activated Receptor-γ Down-regulates Chondrocyte Matrix Metalloproteinase-1 via a Novel Composite Element* , 2004, Journal of Biological Chemistry.

[65]  A. Zelenetz,et al.  Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[66]  T. Benedek.  A history of the understanding of cartilage. , 2006, Osteoarthritis and cartilage.

[67]  Bo Peng,et al.  Comparison of the pharmacology of hydroxamate- and carboxylate-based matrix metalloproteinase inhibitors (MMPIs) for the treatment of osteoarthritis , 2006, Inflammation Research.

[68]  R. W. Rauser,et al.  Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[69]  A. Noël,et al.  Diet-Induced Obesity and Reduced Skin Cancer Susceptibility in Matrix Metalloproteinase 19-Deficient Mice , 2004, Molecular and Cellular Biology.

[70]  S. Itohara,et al.  Unaltered Secretion of β-Amyloid Precursor Protein in Gelatinase A (Matrix Metalloproteinase 2)-deficient Mice* , 1997, The Journal of Biological Chemistry.

[71]  R. Gay,et al.  Effects of a novel tyrosine kinase inhibitor in rheumatoid arthritis synovial fibroblasts , 2007, Annals of the rheumatic diseases.

[72]  R. Copeland,et al.  Aggrecan Protects Cartilage Collagen from Proteolytic Cleavage* , 2003, Journal of Biological Chemistry.

[73]  B. Fingleton,et al.  Matrix metalloproteinases as valid clinical targets. , 2007, Current pharmaceutical design.

[74]  L. Lohmander,et al.  The structure of aggrecan fragments in human synovial fluid. Evidence for the involvement in osteoarthritis of a novel proteinase which cleaves the Glu 373-Ala 374 bond of the interglobular domain. , 1992, The Journal of clinical investigation.

[75]  Xu-wen Liu,et al.  Novel functions of TIMPs in cell signaling , 2006, Cancer and Metastasis Reviews.

[76]  J. Pelletier,et al.  In vivo selective inhibition of mitogen-activated protein kinase kinase 1/2 in rabbit experimental osteoarthritis is associated with a reduction in the development of structural changes. , 2003, Arthritis and rheumatism.

[77]  J. Foidart,et al.  In Vivo Evidence That the Stromelysin-3 Metalloproteinase Contributes in a Paracrine Manner to Epithelial Cell Malignancy , 1998, The Journal of cell biology.

[78]  Bernard Pirard,et al.  Insight into the structural determinants for selective inhibition of matrix metalloproteinases. , 2007, Drug discovery today.

[79]  Neil D. Rawlings,et al.  MEROPS: the peptidase database , 2009, Nucleic Acids Res..

[80]  A. Fosang,et al.  ADAMTS-5 Deficiency Does Not Block Aggrecanolysis at Preferred Cleavage Sites in the Chondroitin Sulfate-rich Region of Aggrecan* , 2007, Journal of Biological Chemistry.

[81]  H. Yoshikawa,et al.  Expression of extracellular matrix metalloproteinase inducer and enhancement of the production of matrix metalloproteinases in rheumatoid arthritis. , 2002, Arthritis and rheumatism.

[82]  D. Eyre,et al.  Articular cartilage collagen: an irreplaceable framework? , 2006, European cells & materials.

[83]  A. Parker,et al.  Expression profiling of metalloproteinases and their inhibitors in cartilage. , 2004, Arthritis and rheumatism.

[84]  I. Boutron,et al.  Reporting of radiographic methods in randomised controlled trials assessing structural outcomes in rheumatoid arthritis , 2006, Annals of the Rheumatic Diseases.

[85]  E. Lavallie,et al.  Glycosaminoglycan-binding properties and aggrecanase activities of truncated ADAMTSs: comparative analyses with ADAMTS-5, -9, -16 and -18. , 2006, Biochimica et biophysica acta.

[86]  Andrew J. Ewald,et al.  Matrix metalloproteinases and the regulation of tissue remodelling , 2007, Nature Reviews Molecular Cell Biology.

[87]  H. Ma,et al.  Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice. , 2004, Arthritis and rheumatism.

[88]  T. Rush,et al.  Synthesis and biological evaluation of biphenylsulfonamide carboxylate aggrecanase-1 inhibitors. , 2006, Bioorganic & medicinal chemistry letters.

[89]  Gabriele Bergers,et al.  MMP-9/Gelatinase B Is a Key Regulator of Growth Plate Angiogenesis and Apoptosis of Hypertrophic Chondrocytes , 1998, Cell.

[90]  F. Berenbaum.  Signaling transduction: target in osteoarthritis , 2004, Current opinion in rheumatology.

[91]  D. A. Brandt,et al.  Reduction of the severity of canine osteoarthritis by prophylactic treatment with oral doxycycline. , 1992, Arthritis and rheumatism.

[92]  C. Brinckerhoff,et al.  Signal transduction and cell‐type specific regulation of matrix metalloproteinase gene expression: Can MMPs be good for you? , 2007, Journal of cellular physiology.

[93]  R. Wynn,et al.  Cloning and Characterization of ADAMTS11, an Aggrecanase from the ADAMTS Family* , 1999, The Journal of Biological Chemistry.

[94]  Jianglin Fan,et al.  Overexpression of human matrix metalloproteinase-12 enhances the development of inflammatory arthritis in transgenic rabbits. , 2004, The American journal of pathology.

[95]  Wenfang Xu,et al.  Design, synthesis, and evaluation of novel galloyl pyrrolidine derivatives as potential anti-tumor agents. , 2006, Bioorganic & medicinal chemistry.

[96]  Gillian Murphy,et al.  Structure and function of matrix metalloproteinases and TIMPs. , 2006, Cardiovascular research.

[97]  C. Rommel,et al.  PI3Kδ and PI3Kγ: partners in crime in inflammation in rheumatoid arthritis and beyond? , 2007, Nature Reviews Immunology.

[98]  L. Banken,et al.  Tolerability and pharmacokinetics of the collagenase-selective inhibitor Trocade in patients with rheumatoid arthritis. , 2001, Rheumatology.

[99]  M. Vieth,et al.  Kinomics: characterizing the therapeutically validated kinase space. , 2005, Drug discovery today.

[100]  N. Yoshida,et al.  Absence of mechanical allodynia and Aβ‐fiber sprouting after sciatic nerve injury in mice lacking membrane‐type 5 matrix metalloproteinase , 2004, FEBS letters.

[101]  A. Rowan,et al.  Adenoviral gene transfer of interleukin-1 in combination with oncostatin M induces significant joint damage in a murine model. , 2003, The American journal of pathology.

[102]  O. Vasiljeva,et al.  Emerging roles of cysteine cathepsins in disease and their potential as drug targets. , 2007, Current pharmaceutical design.

[103]  H. Genant,et al.  The evidence for magnetic resonance imaging as an outcome measure in proof-of-concept rheumatoid arthritis studies. , 2005, The Journal of rheumatology.

[104]  A. Rowan,et al.  A model of inflammatory arthritis highlights a role for oncostatin M in pro-inflammatory cytokine-induced bone destruction via RANK/RANKL , 2004, Arthritis research & therapy.

[105]  B. Cauwe,et al.  The Biochemical, Biological, and Pathological Kaleidoscope of Cell Surface Substrates Processed by Matrix Metalloproteinases , 2007, Critical reviews in biochemistry and molecular biology.

[106]  R. Khokha,et al.  Increased collagen and aggrecan degradation with age in the joints of Timp3(-/-) mice. , 2007, Arthritis and rheumatism.

[107]  A. Mai.  The therapeutic uses of chromatin-modifying agents , 2007, Expert opinion on therapeutic targets.

[108]  H. Ma,et al.  Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis , 2005, Nature.

[109]  S. Bates,et al.  A review of depsipeptide and other histone deacetylase inhibitors in clinical trials. , 2004, Current pharmaceutical design.

[110]  P. Tak,et al.  Signal transduction pathways and transcription factors as therapeutic targets in inflammatory disease: towards innovative antirheumatic therapy. , 2005, Current pharmaceutical design.

[111]  Qingbo Xu,et al.  Activation, differential localization, and regulation of the stress-activated protein kinases, extracellular signal-regulated kinase, c-JUN N-terminal kinase, and p38 mitogen-activated protein kinase, in synovial tissue and cells in rheumatoid arthritis. , 2000, Arthritis and rheumatism.

[112]  A. Rowan,et al.  Oncostatin M in combination with tumor necrosis factor alpha induces cartilage damage and matrix metalloproteinase expression in vitro and in vivo. , 2003, Arthritis and rheumatism.

[113]  Alessio Amadasi,et al.  Molecular modeling of binding between amidinobenzisothiazoles, with antidegenerative activity on cartilage, and matrix metalloproteinase-3. , 2007, Bioorganic & medicinal chemistry.

[114]  P. Roughley,et al.  The structure and function of cartilage proteoglycans. , 2006, European cells & materials.

[115]  A. Mobasheri,et al.  Suppression of NF-kappaB activation by curcumin leads to inhibition of expression of cyclo-oxygenase-2 and matrix metalloproteinase-9 in human articular chondrocytes: Implications for the treatment of osteoarthritis. , 2007, Biochemical pharmacology.

[116]  M. Neya,et al.  Prevention of progressive joint destruction in adjuvant induced arthritis in rats by a novel matrix metalloproteinase inhibitor, FR217840. , 2005, European journal of pharmacology.

[117]  M. Goldring,et al.  The role of oncostatin M in animal and human connective tissue collagen turnover and its localization within the rheumatoid joint. , 1998, Arthritis and rheumatism.

[118]  S. Chakrabarti,et al.  Regulation of matrix metalloproteinase‐9 release from IL‐8‐stimulated human neutrophils , 2005, Journal of leukocyte biology.

[119]  J. Ward,et al.  MT1-MMP-Deficient Mice Develop Dwarfism, Osteopenia, Arthritis, and Connective Tissue Disease due to Inadequate Collagen Turnover , 1999, Cell.

[120]  J. Hamilton,et al.  Extravascular coagulation and the plasminogen activator/plasmin system in rheumatoid arthritis. , 2002, Arthritis and rheumatism.

[121]  Anne-Marie Malfait,et al.  Substrate-dependent inhibition kinetics of an active site-directed inhibitor of ADAMTS-4 (Aggrecanase 1). , 2007, Biochemistry.

[122]  Ae-June Wang,et al.  A therapeutic strategy uses histone deacetylase inhibitors to modulate the expression of genes involved in the pathogenesis of rheumatoid arthritis. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[123]  M. Rots,et al.  Step into the groove: engineered transcription factors as modulators of gene expression. , 2006, Advances in genetics.

[124]  W. Parks,et al.  Activation and silencing of matrix metalloproteinases. , 2008, Seminars in cell & developmental biology.

[125]  C. Brinckerhoff,et al.  Molecular targets in osteoarthritis: metalloproteinases and their inhibitors. , 2007, Current drug targets.

[126]  J. Saklatvala.  Inflammatory signaling in cartilage: MAPK and NF-kappaB pathways in chondrocytes and the use of inhibitors for research into pathogenesis and therapy of osteoarthritis. , 2007, Current drug targets.

[127]  A. Rowan,et al.  Activity of matrix metalloproteinase‐9 against native collagen types I and III , 2007, The FEBS journal.

[128]  M. Hyttinen,et al.  Transgenic mice with inactive alleles for procollagen N-proteinase (ADAMTS-2) develop fragile skin and male sterility. , 2001, The Biochemical journal.

[129]  A. Gilbert,et al.  5-((1H-pyrazol-4-yl)methylene)-2-thioxothiazolidin-4-one inhibitors of ADAMTS-5. , 2007, Bioorganic & medicinal chemistry letters.

[130]  D. Griggs,et al.  Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5. , 2007, Arthritis and rheumatism.

[131]  R. Kinne,et al.  Predominant activation of MAP kinases and pro-destructive/pro-inflammatory features by TNF α in early-passage synovial fibroblasts via TNF receptor-1: failure of p38 inhibition to suppress matrix metalloproteinase-1 in rheumatoid arthritis , 2007, Annals of the rheumatic diseases.

[132]  Georg Schett,et al.  Activation of p38 MAPK is a key step in tumor necrosis factor-mediated inflammatory bone destruction. , 2006, Arthritis and rheumatism.

[133]  T. Huizinga,et al.  Drug evaluation: apratastat, a novel TACE/MMP inhibitor for rheumatoid arthritis. , 2006, Current opinion in investigational drugs.

[134]  E. Olson,et al.  Histone Deacetylase 7 Maintains Vascular Integrity by Repressing Matrix Metalloproteinase 10 , 2006, Cell.

[135]  S. Libregts,et al.  Crucial role of macrophages in matrix metalloproteinase-mediated cartilage destruction during experimental osteoarthritis: involvement of matrix metalloproteinase 3. , 2007, Arthritis and rheumatism.

[136]  S. Krane,et al.  Synovial collagenase: its presence in culture from joint disease of diverse etiology. , 1969, Arthritis and rheumatism.

[137]  D. Dinakarpandian,et al.  Collagenase unwinds triple‐helical collagen prior to peptide bond hydrolysis , 2004, The EMBO journal.

[138]  J. Roh,et al.  Valproic acid-mediated neuroprotection in intracerebral hemorrhage via histone deacetylase inhibition and transcriptional activation , 2007, Neurobiology of Disease.

[139]  F. De Ceuninck,et al.  High binding capacity of cyclophilin B to chondrocyte heparan sulfate proteoglycans and its release from the cell surface by matrix metalloproteinases: possible role as a proinflammatory mediator in arthritis. , 2003, Arthritis and rheumatism.

[140]  B. Hogan,et al.  Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[141]  A. Gilbert,et al.  Synthesis and evaluation of aryl thioxothiazolidinone inhibitors of ADAMTS-5 (Aggrecanase-2). , 2007, Bioorganic & medicinal chemistry letters.

[142]  R W Jubb,et al.  The breakdown of collagen by chondrocytes , 1980, The Journal of pathology.

[143]  J. Enghild,et al.  Altered Proteolytic Activities of ADAMTS-4 Expressed by C-terminal Processing* , 2004, Journal of Biological Chemistry.

[144]  G. Ramakrishnan,et al.  Depsipeptide a histone deacetlyase inhibitor down regulates levels of matrix metalloproteinases 2 and 9 mRNA and protein expressions in lung cancer cells (A549). , 2007, Chemico-biological interactions.

[145]  J. Mudgett,et al.  Susceptibility of stromelysin 1-deficient mice to collagen-induced arthritis and cartilage destruction. , 1998, Arthritis and rheumatism.

[146]  W. English,et al.  Matrix metalloproteinases in arthritic disease , 2002, Arthritis research.

[147]  H. Birkedal‐Hansen,et al.  Enamelysin (Matrix Metalloproteinase 20)-deficient Mice Display an Amelogenesis Imperfecta Phenotype* , 2002, The Journal of Biological Chemistry.

[148]  C. Brinckerhoff,et al.  Matrix metalloproteinases: role in arthritis. , 2006, Frontiers in bioscience : a journal and virtual library.

[149]  C. Brinckerhoff,et al.  The AP-1 site and MMP gene regulation: what is all the fuss about? , 1997, Matrix biology : journal of the International Society for Matrix Biology.

[150]  C. Rommel,et al.  PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond? , 2007, Nature reviews. Immunology.

[151]  Z. Werb,et al.  How matrix metalloproteinases regulate cell behavior. , 2001, Annual review of cell and developmental biology.

[152]  K. Maskos,et al.  Mapping and characterization of the functional epitopes of tissue inhibitor of metalloproteinases (TIMP)‐3 using TIMP‐1 as the scaffold: A new frontier in TIMP engineering , 2002, Protein science : a publication of the Protein Society.

[153]  A. Rowan,et al.  Inhibition of furin-like enzymes blocks interleukin-1alpha/oncostatin M-stimulated cartilage degradation. , 2003, Arthritis and rheumatism.

[154]  M. Neya,et al.  Prevention of progressive joint destruction in collagen‐induced arthritis in rats by a novel matrix metalloproteinase inhibitor, FR255031 , 2005, British journal of pharmacology.

[155]  D. Boyd,et al.  Regulation of matrix metalloproteinase gene expression , 2007, Journal of cellular physiology.

[156]  K Ulrich Wendt,et al.  Structural basis for the highly selective inhibition of MMP-13. , 2005, Chemistry and Biology.