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Gene Review

Adamts4  -  a disintegrin-like and metallopeptidase...

Mus musculus

Synonyms: 3830423K05, A disintegrin and metalloproteinase with thrombospondin motifs 4, ADAM-TS 4, ADAM-TS4, ADAMTS-2, ...
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Disease relevance of Adamts4

  • These results demonstrate that ADAMTS5 is the primary 'aggrecanase' responsible for aggrecan degradation in a murine model of osteoarthritis, and suggest rational strategies for therapeutic intervention in osteoarthritis [1].
  • The mice were challenged by surgical induction of joint instability leading to OA, to determine the importance of the enzymatic activity of ADAMTS-4 in the progression of the disease [2].
  • In mice with nutritionally induced obesity (high fat diet) as well as in lean controls, aggrecan mRNA expression was downregulated whereas ADAMTS-4 and ADAMTS-5 were upregulated with time [3].
  • Role of aggrecanase 1 in Lyme arthritis [4].
  • Eight weeks after surgical induction of joint instability, OA was significantly less severe in ADAMTS-4/5-double-knockout mice compared with WT mice [5].

High impact information on Adamts4

  • These results suggest that cleavage at preferred sites in the chondroitin sulfate-rich region is mediated by ADAMTS-4 or an aggrecanase other than ADAMTS-5 [6].
  • The active forms of ADAMTS-4 were increased in synovial fluid samples from patients with active Lyme arthritis and were elevated in the joints of mice infected with B burgdorferi [4].
  • RESULTS: ADAMTS-4, but not ADAMTS-5, was induced in human chondrocytes infected with B burgdorferi [4].
  • There was no difference in mRNA levels in the cartilage of WT compared with KO mice for the other potential aggrecanases ADAMTS-4, ADAMTS-5, or ADAMTS-9 [7].
  • There was no difference between WT and KO cartilage in either basal or stimulated aggrecan loss in vitro; however, subtle changes in the aggrecanase-generated aggrecan catabolites were observed in interleukin-1-treated cartilage [7].

Biological context of Adamts4

  • Following ovulation, ADAMTS1 and ADAMTS4 (but not ADAMTS5) were expressed in multiple cell types, including those within the highly vascular ovulation cone that marks the site of follicle rupture, endothelial cells of newly forming corpora lutea, and cumulus cells within the ovulated cumulus cell-oocyte complex (COC) [8].
  • OBJECTIVE: To determine the importance of the enzymatic activity of ADAMTS-4 in normal growth and development and to evaluate the role of ADAMTS-4 in the progression of osteoarthritis (OA) [2].
  • Our study provides evidence that ADAMTS-4 is the primary aggrecanase in murine growth plates; however, deletion of its enzymatic activity did not affect normal long bone remodeling [2].
  • Kinetics of aggrecanase- and metalloproteinase-induced neoepitopes in various stages of cartilage destruction in murine arthritis [9].

Anatomical context of Adamts4

  • In expanded COCs and differentiated granulosa cells, FSH induced expression of ADAMTS4 and versican message and protein, whereas increased levels of ADAMTS1 protein was observed in the media of granulosa cells where it was stabilized by heparin in this in vitro system [8].
  • Despite evidence of ADAMTS-4 expression and activity in growth plates of WT mice, catalytic silencing of this proteinase caused no abnormalities in skeletal development, growth, or remodeling [2].
  • Aggrecan, as well as the two aggrecanases ADAMTS-4 and ADAMTS-5 (A Disintegrin And Metalloproteinase with Thrombospondin motif) mRNAs, are expressed in subcutaneous (SC) and gonadal (GON) adipose tissues of mice [3].
  • Therefore the results indicated that ADAMTS-2 plays an essential role in the maturation of spermatogonia [10].
  • Aggrecanase and metalloproteinase-specific aggrecan neo-epitopes are induced in the articular cartilage of mice with collagen II-induced arthritis [11].

Associations of Adamts4 with chemical compounds

  • Hybridized and isosteric analogues of N1-acetyl-N4-dimethyl-piperazinium iodide (ADMP) and N1-phenyl-N4-dimethyl-piperazinium iodide (DMPP) with central nicotinic action [12].
  • Even though there was a 300% increase in aggrecan loss from ADAMTS-4/-5 Deltacat cartilage stimulated with retinoic acid, the loss was not associated with aggrecanase cleavage but with the release of predominantly intact aggrecan consistent with the phenotype of the ADAMTS-4/-5 Deltacat mouse [13].

Other interactions of Adamts4


Analytical, diagnostic and therapeutic context of Adamts4

  • To determine whether other family members might be expressed and regulated in the rodent ovary, those closely related to ADAMTS1 (ADAMTS4 and ADAMTS5) were analyzed in the mouse ovary by reverse transcription-polymerase chain reaction as well as by Western blot, immunohistochemical, and immunocytochemical analyses using highly specific antibodies [8].
  • Expression of messenger RNA for inducible nitric oxide synthase, matrix metalloproteinases (MMPs) 3, 9, and 13, and ADAMTS-4 was determined by quantitative polymerase chain reaction analysis [15].
  • METHODS: The distributions of neoepitopes of aggrecan generated by MMP (VDIPEN) and aggrecanase (NITEGE) cleavage were investigated by immunohistochemistry [16].
  • OBJECTIVE: To analyze the roles of two classes of proteinases, 'aggrecanase', and matrix metalloproteinases (MMPs), in chondrodestruction during murine collagen-induced arthritis (CIA) [11].


  1. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Glasson, S.S., Askew, R., Sheppard, B., Carito, B., Blanchet, T., Ma, H.L., Flannery, C.R., Peluso, D., Kanki, K., Yang, Z., Majumdar, M.K., Morris, E.A. Nature (2005) [Pubmed]
  2. Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice. Glasson, S.S., Askew, R., Sheppard, B., Carito, B.A., Blanchet, T., Ma, H.L., Flannery, C.R., Kanki, K., Wang, E., Peluso, D., Yang, Z., Majumdar, M.K., Morris, E.A. Arthritis Rheum. (2004) [Pubmed]
  3. Expression of aggrecan(ases) during murine preadipocyte differentiation and adipose tissue development. Voros, G., Sandy, J.D., Collen, D., Lijnen, H.R. Biochim. Biophys. Acta (2006) [Pubmed]
  4. Role of aggrecanase 1 in Lyme arthritis. Behera, A.K., Hildebrand, E., Szafranski, J., Hung, H.H., Grodzinsky, A.J., Lafyatis, R., Koch, A.E., Kalish, R., Perides, G., Steere, A.C., Hu, L.T. Arthritis Rheum. (2006) [Pubmed]
  5. Double-knockout of ADAMTS-4 and ADAMTS-5 in mice results in physiologically normal animals and prevents the progression of osteoarthritis. Majumdar, M.K., Askew, R., Schelling, S., Stedman, N., Blanchet, T., Hopkins, B., Morris, E.A., Glasson, S.S. Arthritis Rheum. (2007) [Pubmed]
  6. ADAMTS-5 Deficiency Does Not Block Aggrecanolysis at Preferred Cleavage Sites in the Chondroitin Sulfate-rich Region of Aggrecan. East, C.J., Stanton, H., Golub, S.B., Rogerson, F.M., Fosang, A.J. J. Biol. Chem. (2007) [Pubmed]
  7. ADAMTS-1-knockout mice do not exhibit abnormalities in aggrecan turnover in vitro or in vivo. Little, C.B., Mittaz, L., Belluoccio, D., Rogerson, F.M., Campbell, I.K., Meeker, C.T., Bateman, J.F., Pritchard, M.A., Fosang, A.J. Arthritis Rheum. (2005) [Pubmed]
  8. Regulated expression of ADAMTS family members in follicles and cumulus oocyte complexes: evidence for specific and redundant patterns during ovulation. Richards, J.S., Hernandez-Gonzalez, I., Gonzalez-Robayna, I., Teuling, E., Lo, Y., Boerboom, D., Falender, A.E., Doyle, K.H., LeBaron, R.G., Thompson, V., Sandy, J.D. Biol. Reprod. (2005) [Pubmed]
  9. Kinetics of aggrecanase- and metalloproteinase-induced neoepitopes in various stages of cartilage destruction in murine arthritis. van Meurs, J.B., van Lent, P.L., Holthuysen, A.E., Singer, I.I., Bayne, E.K., van den Berg, W.B. Arthritis Rheum. (1999) [Pubmed]
  10. Transgenic mice with inactive alleles for procollagen N-proteinase (ADAMTS-2) develop fragile skin and male sterility. Li, S.W., Arita, M., Fertala, A., Bao, Y., Kopen, G.C., Långsjö, T.K., Hyttinen, M.M., Helminen, H.J., Prockop, D.J. Biochem. J. (2001) [Pubmed]
  11. Aggrecanase and metalloproteinase-specific aggrecan neo-epitopes are induced in the articular cartilage of mice with collagen II-induced arthritis. Singer, I.I., Scott, S., Kawka, D.W., Bayne, E.K., Weidner, J.R., Williams, H.R., Mumford, R.A., Lark, M.W., McDonnell, J., Christen, A.J., Moore, V.L., Mudgett, J.S., Visco, D.M. Osteoarthr. Cartil. (1997) [Pubmed]
  12. Hybridized and isosteric analogues of N1-acetyl-N4-dimethyl-piperazinium iodide (ADMP) and N1-phenyl-N4-dimethyl-piperazinium iodide (DMPP) with central nicotinic action. Manetti, D., Bartolini, A., Borea, P.A., Bellucci, C., Dei, S., Ghelardini, C., Gualtieri, F., Romanelli, M.N., Scapecchi, S., Teodori, E., Varani, K. Bioorg. Med. Chem. (1999) [Pubmed]
  13. Distinguishing aggrecan loss from aggrecan proteolysis in ADAMTS-4 and ADAMTS-5 single and double deficient mice. Ilic, M.Z., East, C.J., Rogerson, F.M., Fosang, A.J., Handley, C.J. J. Biol. Chem. (2007) [Pubmed]
  14. 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. Clements, K.M., Price, J.S., Chambers, M.G., Visco, D.M., Poole, A.R., Mason, R.M. Arthritis Rheum. (2003) [Pubmed]
  15. Induction of cartilage damage by overexpression of T cell interleukin-17A in experimental arthritis in mice deficient in interleukin-1. Koenders, M.I., Lubberts, E., Oppers-Walgreen, B., van den Bersselaar, L., Helsen, M.M., Kolls, J.K., Joosten, L.A., van den Berg, W.B. Arthritis Rheum. (2005) [Pubmed]
  16. Matrix metalloproteinases and aggrecanases cleave aggrecan in different zones of normal cartilage but colocalize in the development of osteoarthritic lesions in STR/ort mice. Chambers, M.G., Cox, L., Chong, L., Suri, N., Cover, P., Bayliss, M.T., Mason, R.M. Arthritis Rheum. (2001) [Pubmed]
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