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Expression of MT1-MMP during deciduous tooth resorption in odontoclasts

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Abstract

Membrane type 1-matrix metalloproteinase (MT1-MMP) is a membrane-bound matrix metalloproteinase capable of mediating pericellular proteolysis of extracellular matrix components. In osteoclasts, the localization of MT1-MMP has been reported at the tips of specialized membrane protrusions (podosomes and lamellipodia) so that osteoclasts might use MT1-MMP to perform focal proteolysis and move through the extracellular matrix to the bone surface. The objectives of this study were to investigate an association of MT1-MMP in physiological root resorption of the deciduous tooth by reverse transcriptase-polymerase chain reaction (RT-PCR) and Northern blot analysis, and to identify MT1-MMP-producing cell during deciduous tooth resorption by in situ hybridization and immunohistochemistry. RT-PCR and Northern blot analysis revealed the exclusively high expression of MT1-MMP mRNA in bovine root-resorbing tissue, which lies between the root of the deciduous tooth and its permanent successor. Expression of MT1-MMP mRNA was seen in odontoclasts aligning in the surface layer of the root-resorbing tissue at sites of root resorption. Furthermore, immmunohistochemistry also confirmed the localization of MT1-MMP protein to the odontoclasts. The present identification of MT1-MMP in odontoclasts during deciduous tooth resorption might be relevant to the migration activity that these cells have to gain access to the root surface.

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References

  1. R Furseth (1968) ArticleTitleThe resorption processes of human deciduous teeth studied by light microscopy, microradiography and electron microscopy Arch Oral Biol 13 417–431 Occurrence Handle4869382 Occurrence Handle1:STN:280:CCeB3c3ltVA%3D Occurrence Handle10.1016/0003-9969(68)90168-4

    Article  PubMed  CAS  Google Scholar 

  2. N Sahara N Okafuji A Toyoki I Suzuki T Deguchi K Suzuki (1992) ArticleTitleOdontoclastic resorption at the pulpal surface of coronal dentin prior to the shedding of human deciduous teeth Arch Histol Cytol 55 273–285 Occurrence Handle1419277 Occurrence Handle1:STN:280:ByyD2c%2FlvVM%3D

    PubMed  CAS  Google Scholar 

  3. N Sahara N Okafuji A Toyoki Y Ashizawa T Deguchi K Suzuki (1994) ArticleTitleOdontoclastic resorption of the superficial nonmineralized layer of predentine in the shedding of human deciduous teeth Cell Tissue Res 277 19–26 Occurrence Handle8055536 Occurrence Handle1:STN:280:ByuA3s3oslA%3D

    PubMed  CAS  Google Scholar 

  4. N Sahara A Toyoki Y Ashizawa T Deguchi K Suzuki (1996) ArticleTitleCytodifferentiation of the odontoclast prior to the shedding of human deciduous teeth: an ultrastructural and cytochemical study Anat Rec 244 33–49 Occurrence Handle8838422 Occurrence Handle1:STN:280:BymH3srltlI%3D Occurrence Handle10.1002/(SICI)1097-0185(199601)244:1<33::AID-AR4>3.0.CO;2-G

    Article  PubMed  CAS  Google Scholar 

  5. AR Ten Cate RD Anderson (1986) ArticleTitleAn ultrastructural study of tooth resorption in the kitten J Dent Res 65 1087–1093 Occurrence Handle3461025 Occurrence Handle1:STN:280:BimB2sbhs1c%3D

    PubMed  CAS  Google Scholar 

  6. JM delaisse MT Engsig V Everts M del Carmen Ovejero M Ferreras L Lund TH Vu Z Werb B Winding A Lochter MA Karsdal T Troen T Kirkegaard T Lenhard AM Heegaard L Neff R Baron NT Foged (2000) ArticleTitleProteinases in bone resorption: obvious and less obvious roles Clin Chim Acta 291 223–234 Occurrence Handle10675725 Occurrence Handle1:CAS:528:DC%2BD3cXhtFagurg%3D Occurrence Handle10.1016/S0009-8981(99)00230-2

    Article  PubMed  CAS  Google Scholar 

  7. V Everts JM Delaisse W Korper W Beertsen (1998) ArticleTitleCysteine proteinases and matrix metalloproteinases play distinct roles in the subosteoclastic resorption zone J Bone Miner Res 13 1420–1430 Occurrence Handle9738514 Occurrence Handle1:CAS:528:DyaK1cXmtVequrg%3D Occurrence Handle10.1359/jbmr.1998.13.9.1420

    Article  PubMed  CAS  Google Scholar 

  8. V Everts JM Delaisse W Korper A Niehof G Vaes W Beertsen (1992) ArticleTitleDegradation of collagen in the bone-resorbing compartment underlying the osteoclast involves both cysteine-proteinases and matrix metalloproteinases J Cell Physiol 150 221–231 Occurrence Handle1734028 Occurrence Handle1:CAS:528:DyaK38XhtVegu7w%3D Occurrence Handle10.1002/jcp.1041500202

    Article  PubMed  CAS  Google Scholar 

  9. K Kusano C Miyaura M Inada T Tamura A Ito H Nagase K Kamoi T Suda (1998) ArticleTitleRegulation of matrix metalloproteinases (MMP-2, -3, -9, and -13) by interleukin-1 and interleukin-6 in mouse calvaria: association of MMP induction with bone resorption Endocrinology 139 1338–1345 Occurrence Handle9492070 Occurrence Handle1:CAS:528:DyaK1cXhtlejurY%3D Occurrence Handle10.1210/en.139.3.1338

    Article  PubMed  CAS  Google Scholar 

  10. K Tezuka K Nemoto Y Tezuka T Sato Y Ikeda M Kobori H Kawashima H Eguchi Y Hakeda M Kumegawa (1994) ArticleTitleIdentification of matrix metalloproteinase 9 in rabbit osteoclasts J Biol Chem 269 15006–15009 Occurrence Handle8195136 Occurrence Handle1:CAS:528:DyaK2cXkslCqtLs%3D

    PubMed  CAS  Google Scholar 

  11. K Tezuka Y Tezuka A Maejima T Sato K Nemoto H Kamioka Y Hakeda M Kumegawa (1994) ArticleTitleMolecular cloning of a possible cysteine proteinase predominantly expressed in osteoclasts J Biol Chem 269 1106–1109 Occurrence Handle8288568 Occurrence Handle1:CAS:528:DyaK2cXis1Cntrc%3D

    PubMed  CAS  Google Scholar 

  12. MJ Bossard TA Tomaszek SK Thompson BY Amegadzie CR Hanning C Jones JT Kurdyla DE McNulty FH Drake M Gowen MA Levy (1996) ArticleTitleProteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification J Biol Chem 271 12517–12524 Occurrence Handle8647860 Occurrence Handle1:CAS:528:DyaK28XjtFantrc%3D Occurrence Handle10.1074/jbc.271.21.12517

    Article  PubMed  CAS  Google Scholar 

  13. S Saneshige H Mano K Tezuka S Kakudo Y Mori et al. (1995) ArticleTitleRetinoic acid directly stimulates osteoclastic bone resorption and gene expression of cathepsin K/OC-2 Biochem J 309 721–724 Occurrence Handle7639684 Occurrence Handle1:CAS:528:DyaK2MXnt1yjtb0%3D

    PubMed  CAS  Google Scholar 

  14. B Linsuwanont Y Takagi K Ohya H Shimokawa (2002) ArticleTitleLocalization of cathepsin K in bovine odontoclasts during deciduous tooth resorption Calcif Tissue Int 70 127–133 Occurrence Handle11870419 Occurrence Handle1:CAS:528:DC%2BD38XjvV2gu7s%3D Occurrence Handle10.1007/s002230010018

    Article  PubMed  CAS  Google Scholar 

  15. S Domon H Shimokawa Y Matsumoto S Yamaguchi K Soma (1999) ArticleTitleIn situ hybridization for matrix metalloproteinase-1 and cathepsin K in rat root-resorbing tissue induced by tooth movement Arch Oral Biol 44 907–915 Occurrence Handle10580538 Occurrence Handle1:CAS:528:DyaK1MXmsVWisLY%3D Occurrence Handle10.1016/S0003-9969(99)00091-6

    Article  PubMed  CAS  Google Scholar 

  16. Y Okada K Naka K Kawamura T Matsumoto I Nakanishi N Fujimoto H Sato M Seiki (1995) ArticleTitleLocalization of matrix metalloproteinase 9 (92-kilodalton gelatinase/type IV collagenase = gelatinase B) in osteoclasts: implications for bone resorption Lab Invest 72 311–322 Occurrence Handle7898050 Occurrence Handle1:CAS:528:DyaK2MXls1Clurw%3D

    PubMed  CAS  Google Scholar 

  17. P Reponen C Sahlberg C Munaut I Thesleff K Tryggvason (1994) ArticleTitleHigh expression of 92-kD type IV collagenase (gelatinase B) in the osteoclast lineage during mouse development J Cell Biol 124 1091–1102 Occurrence Handle8132709 Occurrence Handle1:CAS:528:DyaK2cXhtlSmsLc%3D Occurrence Handle10.1083/jcb.124.6.1091

    Article  PubMed  CAS  Google Scholar 

  18. DP Rice HJ Kim I Thesleff (1997) ArticleTitleDetection of gelatinase B expression reveals osteoclastic bone resorption as a feature of early calvarial bone development Bone 21 479–486 Occurrence Handle9430236 Occurrence Handle1:CAS:528:DyaK1cXjvF2ktg%3D%3D Occurrence Handle10.1016/S8756-3282(97)00182-8

    Article  PubMed  CAS  Google Scholar 

  19. B Linsuwanont Y Takagi K Ohya H Shimokawa (2002) ArticleTitleExpression of matrix metalloproteinase-9 mRNA and protein during deciduous tooth resorption in bovine odontoclasts Bone (NY) 31 472–478 Occurrence Handle1:CAS:528:DC%2BD38XotVequ7w%3D

    CAS  Google Scholar 

  20. H Will B Hinzmann (1995) ArticleTitlecDNA sequence and mRNA tissue distribution of a novel human matrix metalloproteinase with a potential transmembrane segment Eur J Biochem 231 602–608 Occurrence Handle7649159 Occurrence Handle1:CAS:528:DyaK2MXns1OisLk%3D Occurrence Handle10.1111/j.1432-1033.1995.tb20738.x

    Article  PubMed  CAS  Google Scholar 

  21. T Takino H Sato A Shinagawa M Seiki (1995) ArticleTitleIdentification of the second membrane-type matrix metalloproteinase (MT-MMP-2) gene from a human placenta cDNA library. MT-MMPs form a unique membrane-type subclass in the MMP family J Biol Chem 270 23013–23020 Occurrence Handle7559440 Occurrence Handle1:CAS:528:DyaK2MXosFyjsL8%3D Occurrence Handle10.1074/jbc.270.39.23013

    Article  PubMed  CAS  Google Scholar 

  22. H Sato T Takino Y Okada J Cao A Shinagawa E Yamamoto M Seiki (1994) ArticleTitleA matrix metalloproteinase expressed on the surface of invasive tumour cells Nature 370 61–65 Occurrence Handle8015608 Occurrence Handle1:CAS:528:DyaK2cXlvFOhtrs%3D Occurrence Handle10.1038/370061a0

    Article  PubMed  CAS  Google Scholar 

  23. XS Puente AM Pendas E Llano G Velasco C Lopez-Otin (1996) ArticleTitleMolecular cloning of a novel membrane-type matrix metalloproteinase from a human breast carcinoma Cancer Res 56 944–949 Occurrence Handle8640782 Occurrence Handle1:CAS:528:DyaK28XhtlKks7c%3D

    PubMed  CAS  Google Scholar 

  24. D Pei (1999) ArticleTitleIdentification and characterization of the fifth membrane-type matrix metalloproteinase MT5-MMP J Biol Chem 274 8925–8932 Occurrence Handle10085137 Occurrence Handle1:CAS:528:DyaK1MXitFyrtbo%3D Occurrence Handle10.1074/jbc.274.13.8925

    Article  PubMed  CAS  Google Scholar 

  25. C Gilles M Polette J Piette C Munaut EW Thompson P Birembaut JM Foidart (1996) ArticleTitleHigh level of MT-MMP expression is associated with invasiveness of cervical cancer cells Int J Cancer 65 209–213 Occurrence Handle8567119 Occurrence Handle1:STN:280:BymC2M3nslY%3D Occurrence Handle10.1002/(SICI)1097-0215(19960117)65:2<209::AID-IJC14>3.0.CO;2-8

    Article  PubMed  CAS  Google Scholar 

  26. H Ueno H Nakamura M Inoue K Imai M Noguchi H Sato M Seiki Y Okada (1997) ArticleTitleExpression and tissue localization of membrane-types 1, 2, and 3 matrix metalloproteinases in human invasive breast carcinomas Cancer Res 57 2055–2060 Occurrence Handle9158005 Occurrence Handle1:CAS:528:DyaK2sXjtlKnsr0%3D

    PubMed  CAS  Google Scholar 

  27. T Sato M del Carmen Ovejero P Hou AM Heegaard M Kumegawa NT Foged JM Delaisse (1997) ArticleTitleIdentification of the membrane-type matrix metalloproteinase MT1-MMP in osteoclasts J Cell Sci 110 589–596 Occurrence Handle9092941 Occurrence Handle1:CAS:528:DyaK2sXitlamsr8%3D

    PubMed  CAS  Google Scholar 

  28. N Hiraoka E Allen IJ Apel MR Gyetko SJ Weiss (1998) ArticleTitleMatrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins Cell 95 365–377 Occurrence Handle9814707 Occurrence Handle1:CAS:528:DyaK1cXntlCqtrY%3D Occurrence Handle10.1016/S0092-8674(00)81768-7

    Article  PubMed  CAS  Google Scholar 

  29. H Nakahara L Howard EW Thompson H Sato M Seiki Y Yeh WT Chen (1997) ArticleTitleTransmembrane/cytoplasmic domain-mediated membrane type 1-matrix metalloprotease docking to invadopodia is required for cell invasion Proc Natl Acad Sci U S A 94 7959–7964 Occurrence Handle9223295 Occurrence Handle1:CAS:528:DyaK2sXksl2nurs%3D Occurrence Handle10.1073/pnas.94.15.7959

    Article  PubMed  CAS  Google Scholar 

  30. H Nakamura H Ueno K Yamashita T Shimada E Yamamoto M Noguchi N Fujimoto H Sato M Seiki Y Okada (1999) ArticleTitleEnhanced production and activation of progelatinase A mediated by membrane-type 1 matrix metalloproteinase in human papillary thyroid carcinomas Cancer Res 59 467–473 Occurrence Handle9927064 Occurrence Handle1:CAS:528:DyaK1MXntFOisQ%3D%3D

    PubMed  CAS  Google Scholar 

  31. A Okada JP Bellocq N Rouyer MP Chenard MC Rio P Chambon P Basset (1995) ArticleTitleMembrane-type matrix metalloproteinase (MT-MMP) gene is expressed in stromal cells of human colon, breast, and head and neck carcinomas Proc Natl Acad Sci USA 92 2730–2734 Occurrence Handle7708715 Occurrence Handle1:CAS:528:DyaK2MXksl2rsb8%3D Occurrence Handle10.1073/pnas.92.7.2730

    Article  PubMed  CAS  Google Scholar 

  32. A Sakamoto Y Oda Y Iwamoto M Tsuneyoshi (1999) ArticleTitleExpres-sion of membrane type 1 matrix metalloproteinase, matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2 in human cartilaginous tumors with special emphasis on mesenchymal and dedifferentiated chondrosarcoma J Cancer Res Clin Oncol 125 541–548 Occurrence Handle10473866 Occurrence Handle1:CAS:528:DyaK1MXmt1ersbw%3D Occurrence Handle10.1007/s004320050314

    Article  PubMed  CAS  Google Scholar 

  33. MP d'Ortho H Will S Atkinson G Butler A Messent J Gavrilovic B Smith R Timpl L Zardi G Murphy (1997) ArticleTitleMembrane-type matrix metalloproteinases 1 and 2 exhibit broad-spectrum proteolytic capacities comparable to many matrix metalloproteinases Eur J Biochem 250 751–757 Occurrence Handle9461298 Occurrence Handle10.1111/j.1432-1033.1997.00751.x

    Article  PubMed  Google Scholar 

  34. N Koshikawa G Giannelli V Cirulli K Miyazaki V Quaranta (2000) ArticleTitleRole of cell surface metalloprotease MT1-MMP in epithelial cell migration over laminin-5 J Cell Biol 148 615–624 Occurrence Handle10662785 Occurrence Handle1:CAS:528:DC%2BD3cXhtFSqt7c%3D Occurrence Handle10.1083/jcb.148.3.615

    Article  PubMed  CAS  Google Scholar 

  35. E Ohuchi K Imai Y Fujii H Sato M Seiki Y Okada (1997) ArticleTitleMembrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules J Biol Chem 272 2446–2451 Occurrence Handle8999957 Occurrence Handle1:CAS:528:DyaK2sXotFeguw%3D%3D Occurrence Handle10.1074/jbc.272.4.2446

    Article  PubMed  CAS  Google Scholar 

  36. MP d'Ortho H Stanton M Butler SJ Atkinson G Murphy RM Hembry (1998) ArticleTitleMT1-MMP on the cell surface causes focal degradation of gelatin films FEBS Lett 421 159–164 Occurrence Handle9468298 Occurrence Handle10.1016/S0014-5793(97)01555-X

    Article  PubMed  Google Scholar 

  37. S Cowell V Knauper ML Stewart MP D'Ortho H Stanton RM Hembry C Lopez-Otin JJ Reynolds G Murphy (1998) ArticleTitleInduction of matrix metalloproteinase activation cascades based on membrane-type 1 matrix metalloproteinase: associated activation of gelatinase A, gelatinase B and collagenase 3 Biochem J 331 453–458 Occurrence Handle9531484 Occurrence Handle1:CAS:528:DyaK1cXivV2isLg%3D

    PubMed  CAS  Google Scholar 

  38. AY Strongin I Collier G Bannikov BL Marmer GA Grant GI Goldberg (1995) ArticleTitleMechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease J Biol Chem 270 5331–5338 Occurrence Handle7890645 Occurrence Handle1:CAS:528:DyaK2MXksVSlur4%3D Occurrence Handle10.1074/jbc.270.10.5331

    Article  PubMed  CAS  Google Scholar 

  39. Z Zhou SS Apte R Soininen R Cao GY Baaklini RW Rauser J Wang Y Cao K Tryggvason (2000) ArticleTitleImpaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I Proc Natl Acad Sci USA 97 4052–4057 Occurrence Handle10737763 Occurrence Handle1:CAS:528:DC%2BD3cXislSgtLo%3D Occurrence Handle10.1073/pnas.060037197

    Article  PubMed  CAS  Google Scholar 

  40. V Knauper H Will C Lopez-Otin B Smith SJ Atkinson H Stanton RM Hembry G Murphy (1996) ArticleTitleCellular mechanisms for human procollagenase-3 (MMP-13) activation. Evidence that MT1-MMP (MMP-14) and gelatinase a (MMP-2) are able to generate active enzyme J Biol Chem 271 17124–17131 Occurrence Handle8663255 Occurrence Handle1:STN:280:BymB1M7osFI%3D Occurrence Handle10.1074/jbc.271.29.17124

    Article  PubMed  CAS  Google Scholar 

  41. H Morita H Yamashiya M Shimizu S Sasaki (1970) ArticleTitleThe collagenolytic activity during root resorption of bovine deciduous tooth Arch Oral Biol 15 503–508 Occurrence Handle5270180 Occurrence Handle1:STN:280:CS%2BB3sjgsVU%3D Occurrence Handle10.1016/0003-9969(70)90102-0

    Article  PubMed  CAS  Google Scholar 

  42. H Oguchi (1975) ArticleTitleIn vitro studies of bone resorption by the root-resorbing tissue from the bovine deciduous tooth Bull Tokyo Med Dent Univ 22 175–183 Occurrence Handle1064488 Occurrence Handle1:CAS:528:DyaE2sXlsV2msrs%3D

    PubMed  CAS  Google Scholar 

  43. T Okamura H Shimokawa Y Takagi H Ono S Sasaki (1993) ArticleTitleDetection of collagenase mRNA in odontoclasts of bovine root-resorbing tissue by in situ hybridization Calcif Tissue Int 52 325–330 Occurrence Handle8467413 Occurrence Handle1:CAS:528:DyaK3sXktVGntbY%3D Occurrence Handle10.1007/BF00296659

    Article  PubMed  CAS  Google Scholar 

  44. O Braissant W Wahli (1998) ArticleTitleA simplified in situ hybridization protocol using non-radioactively labeled probes to detect abundant and rare mRNAs on tissue sections Biochemica 1 10–16

    Google Scholar 

  45. MS Burstone (1958) ArticleTitleHistochemical demonstration of acid phosphatases with naphthol AS-phosphates J Natl Cancer Inst 21 523–539 Occurrence Handle13576105 Occurrence Handle1:CAS:528:DyaG1MXht1ahtg%3D%3D

    PubMed  CAS  Google Scholar 

  46. T Pap G Pap KM Hummel JK Franz E Jeisy I Sainsbury RE Gay M Billingham W Neumann S Gay (1999) ArticleTitleMembrane-type-1 matrix metalloproteinase is abundantly expressed in fibroblasts and osteoclasts at the bone-implant interface of aseptically loosened joint arthroplasties in situ J Rheumatol 26 166–169 Occurrence Handle9918259 Occurrence Handle1:STN:280:DyaK1M7hsVOqsw%3D%3D

    PubMed  CAS  Google Scholar 

  47. T Pap Y Shigeyama S Kuchen JK Fernihough B Simmen RE Gay M Billingham S Gay (2000) ArticleTitleDifferential expression pattern of membrane-type matrix metalloproteinases in rheumatoid arthritis Arthritis Rheum 43 1226–1232 Occurrence Handle10857781 Occurrence Handle1:CAS:528:DC%2BD3cXkvFWnur0%3D Occurrence Handle10.1002/1529-0131(200006)43:6<1226::AID-ANR5>3.0.CO;2-4

    Article  PubMed  CAS  Google Scholar 

  48. XH Luo EY Liao X Su XP Wu (2004) ArticleTitleParathyroid hormone inhibits the expression of membrane-type matrix metalloproteinase-1 (MT1-MMP) in osteoblast-like MG-63 cells J Bone Miner Metab 22 19–25 Occurrence Handle14691682 Occurrence Handle1:CAS:528:DC%2BD3sXhtVSjsbzF Occurrence Handle10.1007/s00774-003-0442-6

    Article  PubMed  CAS  Google Scholar 

  49. K Irie E Tsuruga Y Sakakura T Muto T Yajima (2001) ArticleTitleImmunohistochemical localization of membrane type 1-matrix metalloproteinase (MT1-MMP) in osteoclasts in vivo Tissue Cell 33 478–482 Occurrence Handle11949783 Occurrence Handle1:CAS:528:DC%2BD3MXovVKitbc%3D Occurrence Handle10.1054/tice.2001.0201

    Article  PubMed  CAS  Google Scholar 

  50. L Blavier JM Delaisse (1995) ArticleTitleMatrix metalloproteinases are obligatory for the migration of preosteoclasts to the developing marrow cavity of primitive long bones J Cell Sci 108 3649–3659 Occurrence Handle8719871 Occurrence Handle1:CAS:528:DyaK2MXpvV2rtL4%3D

    PubMed  CAS  Google Scholar 

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Correspondence to Hitoyata Shimokawa.

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Linsuwanont-Santiwong, B., Takagi, Y., Ohya, K. et al. Expression of MT1-MMP during deciduous tooth resorption in odontoclasts. J Bone Miner Metab 24, 447–453 (2006). https://doi.org/10.1007/s00774-006-0714-z

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