메뉴 건너뛰기




Volumn 13, Issue 1, 1998, Pages 59-66

The migration of purified osteoclasts through collagen is inhibited by matrix metalloproteinase inhibitors

Author keywords

[No Author keywords available]

Indexed keywords

APROTININ; BATIMASTAT; CARBONATE DEHYDRATASE; COLLAGEN; CYSTEINE PROTEINASE; ETHOXZOLAMIDE; MATRIX METALLOPROTEINASE; MATRIX METALLOPROTEINASE INHIBITOR; N [N (3 CARBOXYOXIRANE 2 CARBONYL)LEUCYL]AGMATINE; RP 59794; SERINE PROTEINASE; UNCLASSIFIED DRUG;

EID: 0031930170     PISSN: 08840431     EISSN: None     Source Type: Journal    
DOI: 10.1359/jbmr.1998.13.1.59     Document Type: Article
Times cited : (95)

References (64)
  • 2
    • 2642683256 scopus 로고
    • An ultrastructural study of the components which make up the resting surface of bone
    • Vanderwiel CJ 1980 An ultrastructural study of the components which make up the resting surface of bone. Metab Bone Dis Rel Res 2S:109-116.
    • (1980) Metab Bone Dis Rel Res , vol.2 S , pp. 109-116
    • Vanderwiel, C.J.1
  • 3
    • 0026553029 scopus 로고
    • An assessment of the prevalence of organic material on bone surfaces
    • Chow J, Chambers TJ 1992 An assessment of the prevalence of organic material on bone surfaces. Calcif Tissue Int 50:118-122.
    • (1992) Calcif Tissue Int , vol.50 , pp. 118-122
    • Chow, J.1    Chambers, T.J.2
  • 6
    • 0028901949 scopus 로고
    • Localization of CD44, the hyaluronate receptor, on the plasma membrane of osteocytes and osteoclasts in rat tibiae
    • Nakamura H, Kenmotsu SI, Sakai H, Ozawa H 1995 Localization of CD44, the hyaluronate receptor, on the plasma membrane of osteocytes and osteoclasts in rat tibiae. Cell Tissue Res 280:225-233.
    • (1995) Cell Tissue Res , vol.280 , pp. 225-233
    • Nakamura, H.1    Kenmotsu, S.I.2    Sakai, H.3    Ozawa, H.4
  • 7
    • 0029091220 scopus 로고
    • Detection of transcripts and binding sites for colony-stimulating factor-1 during bone development
    • Hofstetter W, Wetterwald A, Cecchini MG, Mueller Ch Felix R 1995 Detection of transcripts and binding sites for colony-stimulating factor-1 during bone development. Bone 17:145-151.
    • (1995) Bone , vol.17 , pp. 145-151
    • Hofstetter, W.1    Wetterwald, A.2    Cecchini, M.G.3    Mueller, Ch.4    Felix, R.5
  • 8
    • 0027296497 scopus 로고
    • Complement and the recruitment of mononuclear osteoclasts
    • Mangham DC, Scoones DJ, Drayson MT 1993 Complement and the recruitment of mononuclear osteoclasts. J Clin Pathol 46:517-521.
    • (1993) J Clin Pathol , vol.46 , pp. 517-521
    • Mangham, D.C.1    Scoones, D.J.2    Drayson, M.T.3
  • 9
    • 0029616246 scopus 로고
    • Matrix metalloproteinases are obligatory for the migration of preosteoclasts to the developing marrow cavity of primitive long bones
    • Blavier L, Delaissé JM 1995 Matrix metalloproteinases are obligatory for the migration of preosteoclasts to the developing marrow cavity of primitive long bones. J Cell Sci 108:3649-3659.
    • (1995) J Cell Sci , vol.108 , pp. 3649-3659
    • Blavier, L.1    Delaissé, J.M.2
  • 11
    • 0021646608 scopus 로고
    • Effect of substrate composition on bone resorption by rabbit osteoclasts
    • Chambers TJ, Thomson BM, Fuller K 1984 Effect of substrate composition on bone resorption by rabbit osteoclasts. J Cell Sci 70:61-71.
    • (1984) J Cell Sci , vol.70 , pp. 61-71
    • Chambers, T.J.1    Thomson, B.M.2    Fuller, K.3
  • 12
    • 0022273629 scopus 로고
    • Bone cells predispose bone surfaces to resorption by exposure of mineral to osteoclastic contact
    • Chambers TJ, Fuller K 1985 Bone cells predispose bone surfaces to resorption by exposure of mineral to osteoclastic contact. J Cell Sci 76:155-165.
    • (1985) J Cell Sci , vol.76 , pp. 155-165
    • Chambers, T.J.1    Fuller, K.2
  • 13
    • 0021718670 scopus 로고
    • Mouse osteoblasts synthesize collagenase in response to bone resorbing agents
    • Heath JK, Atkinson SJ, Meikle MC, Reynolds JJ 1984 Mouse osteoblasts synthesize collagenase in response to bone resorbing agents. Biochim Biophys Acta 802:151-154.
    • (1984) Biochim Biophys Acta , vol.802 , pp. 151-154
    • Heath, J.K.1    Atkinson, S.J.2    Meikle, M.C.3    Reynolds, J.J.4
  • 14
    • 0023269833 scopus 로고
    • Hormonal regulation of the production of collagenase and a collagenase inhibitor activity by rat osteogenic sarcoma cells
    • Partridge NC, Jeffrey JJ, Ehlich LS, Teitelbaum Sl Fliszar C, Welgus HG, Kahn AJ 1987 Hormonal regulation of the production of collagenase and a collagenase inhibitor activity by rat osteogenic sarcoma cells. Endocrinology 120:1956-1962.
    • (1987) Endocrinology , vol.120 , pp. 1956-1962
    • Partridge, N.C.1    Jeffrey, J.J.2    Ehlich, L.S.3    Teitelbaum, Sl.4    Fliszar, C.5    Welgus, H.G.6    Kahn, A.J.7
  • 15
    • 0029866199 scopus 로고    scopus 로고
    • Minocycline impairment of both osteoid tissue removal and osteoclastic resorption in a synchronized model of remodelling in the rat
    • Klapisz-Wolikow M, Saffar JL 1996 Minocycline impairment of both osteoid tissue removal and osteoclastic resorption in a synchronized model of remodelling in the rat. J Cell Physiol 167:359-368.
    • (1996) J Cell Physiol , vol.167 , pp. 359-368
    • Klapisz-Wolikow, M.1    Saffar, J.L.2
  • 17
    • 0028262145 scopus 로고
    • Expression of matrix metalloproteinase-2 and 9 during early human wound healing
    • Salo T, Makela M, Kylmaniemi M, Autio-Harmainen H, Larjava H 1994 Expression of matrix metalloproteinase-2 and 9 during early human wound healing. Lab Invest 70:176-182.
    • (1994) Lab Invest , vol.70 , pp. 176-182
    • Salo, T.1    Makela, M.2    Kylmaniemi, M.3    Autio-Harmainen, H.4    Larjava, H.5
  • 18
    • 0029041446 scopus 로고
    • T cell gelatinases mediate basement membrane transmigration in vitro
    • Leppert D, Waubant E, Galardy R, Bunett NW, Hauser SL 1995 T cell gelatinases mediate basement membrane transmigration in vitro. J Immunol 154:4379-4389.
    • (1995) J Immunol , vol.154 , pp. 4379-4389
    • Leppert, D.1    Waubant, E.2    Galardy, R.3    Bunett, N.W.4    Hauser, S.L.5
  • 19
    • 0027210581 scopus 로고
    • Matrix metalloproteinase-9 (92 kDa gelatinase/type IV collagenase) from U937 monoblastoid cells: Correlation with cellular invasion
    • Watanabe H, Nakanishi I, Yamashita K, Hayakawa T, Okada Y 1993 Matrix metalloproteinase-9 (92 kDa gelatinase/type IV collagenase) from U937 monoblastoid cells: Correlation with cellular invasion. J Cell Sci 104:991-999.
    • (1993) J Cell Sci , vol.104 , pp. 991-999
    • Watanabe, H.1    Nakanishi, I.2    Yamashita, K.3    Hayakawa, T.4    Okada, Y.5
  • 20
    • 0027731213 scopus 로고
    • (Pro) collagenase (matrix metalloproteinase-1) is present in rodent osteoclasts and in the underlying bone-resorbing compartment
    • Delaissé JM, Eeckhout Y, Neff L, Francois-Gillet C, Henriet P, Su Y, Vaes G, Baron R 1993 (Pro) collagenase (matrix metalloproteinase-1) is present in rodent osteoclasts and in the underlying bone-resorbing compartment. J Cell Sci 106:1071-1082.
    • (1993) J Cell Sci , vol.106 , pp. 1071-1082
    • Delaissé, J.M.1    Eeckhout, Y.2    Neff, L.3    Francois-Gillet, C.4    Henriet, P.5    Su, Y.6    Vaes, G.7    Baron, R.8
  • 22
    • 0028223234 scopus 로고
    • Expression of 92-kD type IV collagenase (gelatinase B) in the osteoclast lineage during mouse development
    • Reponen P, Sahlberg C, Munaut C, Theslef I, Tryggvason K 1994 Expression of 92-kD type IV collagenase (gelatinase B) in the osteoclast lineage during mouse development. J Cell Biol 124:1091-1102.
    • (1994) J Cell Biol , vol.124 , pp. 1091-1102
    • Reponen, P.1    Sahlberg, C.2    Munaut, C.3    Theslef, I.4    Tryggvason, K.5
  • 23
    • 0027960243 scopus 로고
    • The effects of selective inhibitors of matrix metalloproteinases (MMPs) on bone resorption and the identification of MMPs and TIMP-1 in isolated osteoclasts
    • Hill PA, Murphy G, Docherty AJP, Hembry RM, Millican TA, Reynolds JJ, Meikle MC 1994 The effects of selective inhibitors of matrix metalloproteinases (MMPs) on bone resorption and the identification of MMPs and TIMP-1 in isolated osteoclasts. J Cell Sci 107:3055-3064.
    • (1994) J Cell Sci , vol.107 , pp. 3055-3064
    • Hill, P.A.1    Murphy, G.2    Docherty, A.J.P.3    Hembry, R.M.4    Millican, T.A.5    Reynolds, J.J.6    Meikle, M.C.7
  • 24
    • 0028957812 scopus 로고
    • Localization of matrix-metalloproteinase, 9 (92-kilodalton gelatinase/type IV collagenase = gelatinase B) in osteoclasts: Implications for bone resorption
    • Okada Y, Naka K, Kawamura K, Matsumoto T, Nakanishi I, Fujimoto N, Sato H, Seiki M 1995 Localization of matrix-metalloproteinase, 9 (92-kilodalton gelatinase/type IV collagenase = gelatinase B) in osteoclasts: Implications for bone resorption. Lab Invest 72:311-322.
    • (1995) Lab Invest , vol.72 , pp. 311-322
    • Okada, Y.1    Naka, K.2    Kawamura, K.3    Matsumoto, T.4    Nakanishi, I.5    Fujimoto, N.6    Sato, H.7    Seiki, M.8
  • 25
    • 0030024108 scopus 로고    scopus 로고
    • Parathyroid hormone- induced resorption in fetal rat limb bones is associated with production of the metalloproteinases collagenase and gelatinase B
    • Witty JP, Foster SA, Stricklin GP, Matrisian LM, Stern PH 1996 Parathyroid hormone- induced resorption in fetal rat limb bones is associated with production of the metalloproteinases collagenase and gelatinase B. J Bone Miner Res 11:72-78.
    • (1996) J Bone Miner Res , vol.11 , pp. 72-78
    • Witty, J.P.1    Foster, S.A.2    Stricklin, G.P.3    Matrisian, L.M.4    Stern, P.H.5
  • 27
    • 0030026637 scopus 로고    scopus 로고
    • Human cathepsin 02, a matrix protein-degrading cysteine protease expressed in osteoclasts
    • Brömme D, Okamoto K, Wang BB, Biroc S 1996 Human cathepsin 02, a matrix protein-degrading cysteine protease expressed in osteoclasts. J Biol Chem 271:2126-2132.
    • (1996) J Biol Chem , vol.271 , pp. 2126-2132
    • Brömme, D.1    Okamoto, K.2    Wang, B.B.3    Biroc, S.4
  • 29
    • 0029809357 scopus 로고    scopus 로고
    • Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency
    • Gelb BD, Shi GP, Chapman HA, Desnick RJ 1996 Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 273:1236-1238.
    • (1996) Science , vol.273 , pp. 1236-1238
    • Gelb, B.D.1    Shi, G.P.2    Chapman, H.A.3    Desnick, R.J.4
  • 30
    • 0002801861 scopus 로고
    • Mechanism of mineral solubilization and matrix degradation in osteoclastic bone resorption
    • BR Rifkin, CV Gay (eds.). CRC Press, Boca Raton, FL, U.S.A.
    • Delaissé JM, Vaes G 1992 Mechanism of mineral solubilization and matrix degradation in osteoclastic bone resorption. In: BR Rifkin, CV Gay (eds.) Biology and Physiology of the Osteoclast. CRC Press, Boca Raton, FL, U.S.A., pp. 289-314.
    • (1992) Biology and Physiology of the Osteoclast , pp. 289-314
    • Delaissé, J.M.1    Vaes, G.2
  • 31
    • 0026544215 scopus 로고
    • Degradation of collagen in the bone-resorbing compartment underlying the osteoclast involves both cysteine-proteinases and matrix metalloproteinases
    • Everts V, Delaissé JM, Korper W, Niehof A, Vaes G, Beertsen W 1992 Degradation of collagen in the bone-resorbing compartment underlying the osteoclast involves both cysteine-proteinases and matrix metalloproteinases. J Cell Physiol 150:221-231.
    • (1992) J Cell Physiol , vol.150 , pp. 221-231
    • Everts, V.1    Delaissé, J.M.2    Korper, W.3    Niehof, A.4    Vaes, G.5    Beertsen, W.6
  • 32
    • 0023607260 scopus 로고
    • The effects of inhibitors of cysteine-proteinases and collagenase on the resorptive activity of isolated osteoclasts
    • Delaissé JM, Boyde A, Maconnachie E, Ali NN, Sear CHJ, Eeckhout Y, Vaes G, Jones SJ 1987 The effects of inhibitors of cysteine-proteinases and collagenase on the resorptive activity of isolated osteoclasts. Bone 8:305-313.
    • (1987) Bone , vol.8 , pp. 305-313
    • Delaissé, J.M.1    Boyde, A.2    Maconnachie, E.3    Ali, N.N.4    Sear, C.H.J.5    Eeckhout, Y.6    Vaes, G.7    Jones, S.J.8
  • 33
    • 0029010425 scopus 로고
    • Localisation of mRNA for collagenase in osteocytic, bone surface and chondrocytic cells but not osteoclasts
    • Fuller K, Chambers TJ 1995 Localisation of mRNA for collagenase in osteocytic, bone surface and chondrocytic cells but not osteoclasts. J Cell Sci 108:2221-2230.
    • (1995) J Cell Sci , vol.108 , pp. 2221-2230
    • Fuller, K.1    Chambers, T.J.2
  • 34
    • 0025088810 scopus 로고
    • Low molecular weight, sequence based, collagenase inhibitors selectively block the interaction between collagenase and TIMP (tissue inhibitor of metalloproteinases)
    • Lelievre Y, Bouboutou R, Boiziau J, Faucher D, Achard D, Cartwright T 1990 Low molecular weight, sequence based, collagenase inhibitors selectively block the interaction between collagenase and TIMP (tissue inhibitor of metalloproteinases). Matrix 10:292-299.
    • (1990) Matrix , vol.10 , pp. 292-299
    • Lelievre, Y.1    Bouboutou, R.2    Boiziau, J.3    Faucher, D.4    Achard, D.5    Cartwright, T.6
  • 35
    • 0029586589 scopus 로고
    • Matrix metalloproteinase inhibition: A review of anti- tumour activity
    • Brown PD, Giavazzi R 1995 Matrix metalloproteinase inhibition: A review of anti- tumour activity. Ann Oncol 6:967-974.
    • (1995) Ann Oncol , vol.6 , pp. 967-974
    • Brown, P.D.1    Giavazzi, R.2
  • 38
    • 0031040331 scopus 로고    scopus 로고
    • Misregulation of stromelysin-1 expression in mouse mammary tumor cells accompanies acquisition of stromelysin-1-dependent invasive properties
    • Lochter A, Screbow A, Sympson CJ, Terracio N, Werb Z, Bissell M 1997 Misregulation of stromelysin-1 expression in mouse mammary tumor cells accompanies acquisition of stromelysin-1-dependent invasive properties. J Biol Chem 272: 5007-5015.
    • (1997) J Biol Chem , vol.272 , pp. 5007-5015
    • Lochter, A.1    Screbow, A.2    Sympson, C.J.3    Terracio, N.4    Werb, Z.5    Bissell, M.6
  • 42
    • 24544442025 scopus 로고    scopus 로고
    • Stimulators of osteoclast motility upregulate urokinase plasminogen activator activity in osteoclasts
    • abstract
    • Yu X, Foged NT, Delaissé JM 1997 Stimulators of osteoclast motility upregulate urokinase plasminogen activator activity in osteoclasts. J Bone Miner Res 12 (Suppl 1):S418 (abstract).
    • (1997) J Bone Miner Res , vol.12 , Issue.1 SUPPL.
    • Yu, X.1    Foged, N.T.2    Delaissé, J.M.3
  • 43
    • 0027550662 scopus 로고
    • Urokinase and urokinase receptor: A paracrine/ autocrine system regulating cell migration and invasiveness
    • Blasi F 1993 Urokinase and urokinase receptor: a paracrine/ autocrine system regulating cell migration and invasiveness. BioEssays 15:273-328.
    • (1993) BioEssays , vol.15 , pp. 273-328
    • Blasi, F.1
  • 44
    • 0026742378 scopus 로고
    • Inhibition of cysteine proteinases in lysosomes and whole cells
    • Wilcox D, Mason RW 1992 Inhibition of cysteine proteinases in lysosomes and whole cells. Biochem J 285:495-502.
    • (1992) Biochem J , vol.285 , pp. 495-502
    • Wilcox, D.1    Mason, R.W.2
  • 47
    • 0029089986 scopus 로고
    • Osteoclast molecular phenotyping by random cDNA sequencing
    • Sakai D, Tong HS, Minkin C 1995 Osteoclast molecular phenotyping by random cDNA sequencing. Bone 17:111-119.
    • (1995) Bone , vol.17 , pp. 111-119
    • Sakai, D.1    Tong, H.S.2    Minkin, C.3
  • 48
    • 0009058757 scopus 로고    scopus 로고
    • MMP-12, a proteinase that is indispensable for macrophage invasion is highly expressed in osteoclasts
    • abstract
    • Hou P, Ovejero MC, Sato T, Kumegawa M, Foged NT, Delaissé JM 1997 MMP-12, a proteinase that is indispensable for macrophage invasion is highly expressed in osteoclasts. J Bone Miner Res 12 (Suppl 1):S417 (abstract).
    • (1997) J Bone Miner Res , vol.12 , Issue.1 SUPPL.
    • Hou, P.1    Ovejero, M.C.2    Sato, T.3    Kumegawa, M.4    Foged, N.T.5    Delaissé, J.M.6
  • 49
    • 0029845733 scopus 로고    scopus 로고
    • Production of collagenase by human osteoblasts and osteoclasts in vivo
    • Bord S, Horner A, Hembry RM, Reynolds JJ, Compston JE 1996 Production of collagenase by human osteoblasts and osteoclasts in vivo. Bone 19:35-40.
    • (1996) Bone , vol.19 , pp. 35-40
    • Bord, S.1    Horner, A.2    Hembry, R.M.3    Reynolds, J.J.4    Compston, J.E.5
  • 50
    • 0029063214 scopus 로고
    • Expression of interstitial collagenase during skeletal development of the mouse is restricted to osteoblast-like cells and hypertrophic chondrocytes
    • Gack S, Vallon R, Schmidt J, Grigoriadis A, Tuckerman J, Schenkel J, Weiher H, Wagner EF, Angel P 1995 Expression of interstitial collagenase during skeletal development of the mouse is restricted to osteoblast-like cells and hypertrophic chondrocytes. Cell Growth Differ 6:759-767.
    • (1995) Cell Growth Differ , vol.6 , pp. 759-767
    • Gack, S.1    Vallon, R.2    Schmidt, J.3    Grigoriadis, A.4    Tuckerman, J.5    Schenkel, J.6    Weiher, H.7    Wagner, E.F.8    Angel, P.9
  • 51
    • 0028006234 scopus 로고
    • Expression of metalloproteinases and tissue inhibitors of metalloproteinases in human osteoblast-like cells: Differentiation is associated with repression of metalloproteinase biosynthesis
    • Rifas L, Fausto A, Scott MJ, Avioli LV, Welgus HG 1994 Expression of metalloproteinases and tissue inhibitors of metalloproteinases in human osteoblast-like cells: Differentiation is associated with repression of metalloproteinase biosynthesis. Endocrinology 134:213-221.
    • (1994) Endocrinology , vol.134 , pp. 213-221
    • Rifas, L.1    Fausto, A.2    Scott, M.J.3    Avioli, L.V.4    Welgus, H.G.5
  • 57
    • 0029999333 scopus 로고    scopus 로고
    • Proteases associated with invadopodia, and their role in degradation of extracellular matrix
    • Chen WT 1996 Proteases associated with invadopodia, and their role in degradation of extracellular matrix. Enzyme Protein 49:59-71.
    • (1996) Enzyme Protein , vol.49 , pp. 59-71
    • Chen, W.T.1
  • 60
    • 0030061583 scopus 로고    scopus 로고
    • Quantification of the collagenolytic activity of isolated osteoclasts by enzyme-linked immunosorbent assay
    • Foged NT, Delaissé JM, Hou P, Lou H, Sato T, Winding B, Bonde M 1996 Quantification of the collagenolytic activity of isolated osteoclasts by enzyme-linked immunosorbent assay. J Bone Miner Res 11:226-237.
    • (1996) J Bone Miner Res , vol.11 , pp. 226-237
    • Foged, N.T.1    Delaissé, J.M.2    Hou, P.3    Lou, H.4    Sato, T.5    Winding, B.6    Bonde, M.7
  • 61
    • 0025744525 scopus 로고
    • Clear zone in osteoclast function: Role of podosomes in regulation of bone-resorbing activity
    • Teti A, Marchisio PC, Zambonin Zallone A 1991 Clear zone in osteoclast function: Role of podosomes in regulation of bone-resorbing activity. Am J Physiol 261:C1-C7.
    • (1991) Am J Physiol , vol.261
    • Teti, A.1    Marchisio, P.C.2    Zambonin Zallone, A.3
  • 62
    • 0028334194 scopus 로고
    • Carbonic anhydrase II mRNA expression in individual osteoclasts under 'resorbing' and 'nonresorbing' conditions
    • Asotra S, Gupta AK, Sodek JE, Aubin JE, Heersche JNM 1994 Carbonic anhydrase II mRNA expression in individual osteoclasts under 'resorbing' and 'nonresorbing' conditions. J Bone Miner Res 9:1115-1122.
    • (1994) J Bone Miner Res , vol.9 , pp. 1115-1122
    • Asotra, S.1    Gupta, A.K.2    Sodek, J.E.3    Aubin, J.E.4    Heersche, J.N.M.5
  • 63
    • 0030451828 scopus 로고    scopus 로고
    • Chemical and physical properties of the extracellular matrix are required for the actin ring formation in osteoclasts
    • Nakamura I, Takahashi N, Sasaki T, Jimi E, Kurokawa T, Suda T 1996 Chemical and physical properties of the extracellular matrix are required for the actin ring formation in osteoclasts. J Bone Miner Res 11:1873-1879.
    • (1996) J Bone Miner Res , vol.11 , pp. 1873-1879
    • Nakamura, I.1    Takahashi, N.2    Sasaki, T.3    Jimi, E.4    Kurokawa, T.5    Suda, T.6
  • 64
    • 0028339901 scopus 로고
    • Odontoclastic resorption of the superficial non-mineralized layer of predentine in the shedding of human deciduous teeth
    • Sahara N, Okafuji N, Toyoki A, Ashizawa Y, Deguchi T, Suzuki K 1994 Odontoclastic resorption of the superficial non-mineralized layer of predentine in the shedding of human deciduous teeth. Cell Tissue Res 277:19-26.
    • (1994) Cell Tissue Res , vol.277 , pp. 19-26
    • Sahara, N.1    Okafuji, N.2    Toyoki, A.3    Ashizawa, Y.4    Deguchi, T.5    Suzuki, K.6


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.