A seminal experiment involving a germ-free rat model of connective tissue breakdown (followed soon thereafter by a series of in vitro studies) identified an unexpected non-antimicrobial property of tetracyclines (TCs). This ability of TCs to inhibit matrix metalloproteinases (MMPs) such as collagenase was found to reflect multiple direct and indirect mechanisms of action, and to be therapeutically useful in a variety of dental (e.g., adult periodontitis) and medical (e.g., arthritis, osteoporosis, cancer) diseases. The site on the TC molecule responsible for its MMP-inhibitory activity was identified which led to the development of a series of chemically modified non-antimicrobial analogs, called CMTs, which also have therapeutic potential but do not appear to induce antibiotic side-effects. Longitudinal double-blind studies on humans with adult periodontitis have demonstrated that a sub-antimicrobial dose of doxycycline (previously reported to suppress collagenase activity in the periodontal pocket) is safe and effective and has recently been approved by the FDA as an adjunct to scaling and root planing.
Aimes R., Quigley J. (1995). Matrix metalloproteinase-2 is an interstitial collagenase. J Biol Chem270:5872-5876.
2.
Amin AR, Attur MG, Thakker GD, Patel PD, Vyas PR, Patel RN, et al. (1996). A novel mechanism of action of tetracyclines: effects on nitric oxide syntheses. Proc Natl Acad Sci USA93:14014-14019.
3.
Amin AR, Patel RN, Thakker GD, Lowenstein CJ, Attur MG, Abramson SB (1997). Post-transcriptional regulation of inducible nitric oxide synthase mRNA in murine macrophages by doxycycline and chemically modified tetracyclines. FEBS Lett410:259-264.
4.
Bain S., Ramamurthy NS, Impeduglia T., Scolman S., Golub LM, Rubin C. (1997). Tetracycline prevents cancellous bone loss and maintains near-normal rates of bone formation in diabetic rats. Bone21:147-153.
5.
Bouwsma 0, Payonk G., Baron H., Sipos T. (1992a). Low-dose doxycycline: effects on clinical parameters on adult periodontitis (abstract). J Dent Res71(Spec Iss):245.
Brandt KD (1995a). Modification by oral doxycycline administration of articular cartilage breakdown in osteoarthritis. J Rheumatol22 (Suppl 43):149-151.
8.
Brandt KD (1995b). Toward pharmacologic modification of joint damage in osteoarthritis. Ann Intern Med122:874-875.
9.
Burns FR, Stack MS, Gray RD, Paterson CA (1989). Inhibition of purified collagenase from alkaline-burned rabbit corneas. Invest Ophthalmol Vis Sci30:1569-1574.
10.
Carp H., Janoff A. (1979). In vitro suppression of serum-elastase inhibitory capacity by reactive oxygen species generated by phagocytosing polymorphonuclear leukocytes. J Clin Invest63:793-797.
11.
Caton J., Blieden T., Adams D., Crout R., Hefti A., Killoy W., et al. (1997). Subantimicrobial doxycycline therapy for periodontitis (abstract). J Dent Res76(Spec Iss): 153.
12.
Cechowska-Pasko M., Palka J., Bankowski E. (1996). Decrease in the glycosaminoglycan content in the skin of diabetic rats. The role of IGF-1, IGF-binding proteins and proteolytic activity. Mol Cell Biochem154:1-8.
13.
Chang KM, Ramamurthy NS, McNamara TF, Evans RT, Klausen B., Murray PA, et al. (1994). Tetracyclines inhibit Porphyromonas gingivalis-induced alveolar bone loss in rats by a non-antimicrobial mechanism. J Periodont Res29:242-249.
14.
Ciancio S.Ashley R. (1998). Safety and efficacy of subantimicrobial-dose doxycycline therapy in patients with adult periodontitis. Adv Dent Res12:27-31.
15.
Cole A., Chubinskaya S., Luchene L., Chlebek K., Orth MW, Greenwald RA, et al. (1994). Doxycycline disrupts chondrocyte differentiation and inhibits cartilage matrix degradation. Arthrit Rheum37:1727-1734.
16.
Craig RA, Yu Z., Xu L., Baria R., Ramamurthy N., Bland J., et al. (1998). A chemically-modified tetracycline inhibits streptozotocin-induced diabetic depression of skin collagen synthesis and steady-state type I procollagen mRNA. Biochim Biophys Acta1402:250-260.
17.
Crout RJ, Lee HM, Schroeder K., Crout H., Ramamurthy NS, Wiener M., et al. (1996). The "cyclic" regimen of low-dose doxycycline for adult periodontitis: a preliminary study. J Periodontol67:506-514.
18.
Desrochers PE, Mookhtiar K., Van-Wart HE, Hasty K.a, Weiss SJ (1992). Proteolytic inactivation of α1-proteinase inhibitor and α1-antichymotrypsin by oxidatively activated human neutrophil metalloproteinases. J Biol Chem267:5005-5012.
19.
Eady EA, Cove JH, Holland KT, Cunliffe WJ (1990). Superior antibacterial action and reduced incidence of bacterial resistance in minocycline compared to tetracycline-treated acne patients. Br J Dermatol122:233-244.
20.
ElAttar Tma, Lin HS, Schultz R. (1988). Effect of minocycline on prostaglandin formation in gingival fibroblasts. J Periodont Res23:285-289,
21.
Fiehn NE, Westergaard J. (1990). Doxycycline-resistant bacteria in periodontally-diseased individuals after systemic doxycycline therapy and in healthy individuals . Oral Microbiol Immunol5:219-222.
22.
Gangbar S., Overall CM, McCulloch Cag, Sodek J. (1990). Identification of polymorphonuclear leukocyte collagenase and gelatinase activities in mouthrinse samples: correlation with periodontal disease activity in adult and juvenile periodontitis. J Periodont Res25:257-267.
23.
Giannobile WV (1997). Crevicular fluid biomarkers of oral bone loss . Curr Opin Periodoutol4:11-20.
24.
Giannobile WV, Lynch SE, Denmark RG, Paquette DW, Fiorellini JP, Williams RC (1995). Crevicular fluid osteocalcin and pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP) as markers of rapid bone turnover in periodontitis. J Clin Periodontol22:903-910.
25.
Golub LM, Greenwald RA, Zebrowski EJ, Ramamurthy NS (1978a). The effect of experimental diabetes on the molecular characteristics of rat tail tendon collagen. Biochim Biophys Acta534:73-81.
26.
Golub LM, Schneir M., Ramamurthy NS (1978b). Enhanced collagenase activity in diabetic rat gingiva: in vitro and in vivo evidence. J Dent Res57:520-525.
27.
Golub LM, Lee HM, Lehrer G., Nemiroff A., McNamara TF, Kaplan R., et al. (1983). Minocycline reduces gingival collagenolytic activity during diabetes: preliminary observations and a proposed new mechanism of action. J Periodont Res18:516-526.
28.
Golub LM, Ramamurthy NS, McNamara TF, Gomes BC, Wolff MS, Casino A., et al. (1984). Tetracyclines inhibit tissue collagenase activity: a new mechanism in the treatment of periodontal disease. J Periodont Res19:651-655.
Golub LM, Ciancio S., Ramamurthy NS, Leung M., McNamara TF (1990a). Low-dose doxycycline therapy: effect on gingival and crevicular fluid collagenase activity in humans. J Periodont Res25:321-330.
31.
Golub LM, Ramamurthy NS, Lee HMRifkin B. (1990b). Tetracycline administration prevents diabetes-induced osteopenia in the rat. Res Commun Chem Path Pharmacol68:27-40.
32.
Golub LM, Greenwald RA, Ramamurthy NS, McNamara TF, Rifkin BR (1991). Tetracyclines inhibit connective tissue breakdown: new therapeutic implications for an old family of drugs. Crit Rev Oral Biol Med2:297-322.
33.
Golub L., Suomalainen K., Sorsa T. (1992). Host modulation with tetracyclines and their chemically-modified analogues. Curr Opin Dent2:80-90.
34.
Golub LM, Evans RT, McNamara TF, Lee HM, Ramamurthy NS (1994a). Non-antimicrobial tetracycline inhibits gingival matrix metalloproteinases in Porphyromonas gingivalis-induced periodontitis in rats. Ann NY Acad Sci732:96-111.
35.
Golub LM, Wolff M., Roberts S., Lee HM, Leung M., Payonk GS (1994b). Treating periodontal diseases by blocking tissue-destructive enzymes. J Am Dent Assoc125:163-169.
36.
Golub LM, Sorsa T., Lee HM (1995). Doxycycline inhibits neutrophil (PMN)-type matrix metalloproteinases in human adult periodontitis gingiva. J Clin Periodontol22:100-109.
37.
Golub LM, Schuler EK, Gallagher BM (1996). New therapeutic uses for an old family of drugs: travels of a dental researcher from the lab to the University's Office of Technology Transfer and beyond. Tech Health Care4:311-316.
38.
Golub LM, Lee HM, Greenwald RA, Ryan ME, Sorsa T., Salo T., et al. (1997). A matrix metalloproteinase inhibitor reduces bone-type collagen degradation fragments and specific collagenases in gingival crevicular fluid during adult periodontitis. Inflamm Res46:310-319.
39.
Gomes BC, Golub LM, Ramamurthy NS (1984). Tetracyclines inhibit parathyroid hormone-induced bone resorption in organ culture. Experientia40:1273-1275.
40.
Greenwald RA (1996). Monitoring collagen degradation in patients with arthritis: the search for suitable surrogates. Arthrit Rheum39:1455-1465.
41.
Greenwald R., Golub L., Lavaites B., Ramamurthy N., Gruber B., Laskin RS, et al. (1987). Minocycline inhibits rheumatoid synovial collagenase in vivo and in vitro. J Rheumatol14:23-28.
42.
Greenwald RA, Simonson B., Moak S., Ramamurthy N., Laskin R., Golub L. (1988). Inhibition of epiphyseal cartilage collagenase by tetracyclines in low phosphate rickets in rats. Orthop Res6:695-703.
43.
Greenwald RA, Golub LM, Ramamurthy NS, Chowdhury M., Moak SA, Sorsa T. (1998). In vitro sensitivity of the three mammalian collagenases to tetracycline inhibition: relationship to bone and cartilage degradation . Bone22:33-38.
44.
Grodstein F., Colditz GA, Stampfer MJ (1996). Postmenopausal hormone use and tooth loss: a prospective study. J Am Dent Assoc127:370-377.
45.
Gross J., Lapiere CM (1962). Collagenolytic activity in amphibian tissues: a tissue culture assay. Proc Natl Acad Sci (USA)48:1014-1021.
46.
Jonat C., Chung RZ, Baragi VM (1996). Transcriptional downregulation of stromelysin by tetracycline. J Cell Biochem60:341-347.
47.
Karimbux NY, Ramamurthy NS, Golub LM, Nishimura I. (1998). The expression of collagen I and XII in RNAs in Porphyromonas gingivalis-induced periodontitis in rats: the effect of doxycycline and chemically-modified tetracycline (CMT-1). J Periodontol69:34-40.
48.
Katayama Y., Akatsu T., Yamamoto M., Kugai N., Nagata N. (1996). Role of nonenzymatic glycosylation of type I collagen in diabetic osteopenia. J Bone Min Res11 :931-937.
49.
Konttinen YT, Ceponis A., Takagi M., Jumppanen M., Sorsa T., Sutinen M., et al. (1998). Components of the collagenolytic MT,2-MMP/TIMP-2/MMP-2 system are found at the pannus-cartilage junction in rheumatoid arthritis . Arthrit Rheum (in press).
50.
Kornman KS, Karl EH ( 1982). The effect of long-term low-dose tetracycline therapy on the subgingival microflora in refractory adult periodontitis. J Periodontol53:604-610.
51.
Landino LM, Crews BC, Timmons MD, Morrow JD, Mainett LJ (1996). Peroxynitrite, the coupling product of nitric oxide and superoxide, activates prostaglandin biosynthesis. Proc Natl Acad Sci USA93:15069-15074.
52.
Lauhio A., Salo T., Tjaderhane L., Lahdewirta J., Golub LM, Sorsa T. (1995). Tetracyclines in treatment of rheumatoid arthritis . The Lancet346:645-646.
53.
Lee HM, Hall JE, Sorsa T., Simon S., Golub LM (1992). Doxycycline inhibits PMN-mediated tissue breakdown in culture (abstract). J Dent Res71 (Spec Iss):245 .
54.
Lee HM, Golub LM, Chan D., Leung M., Schroeder K., Wolff M., et al. (1997). α1-proteinase inhibitor in gingival crevicular fluid of humans with adult periodontitis: serpinolytic inhibition by doxycycline. J Periodont Res32:9-19.
55.
Leung MK, Folkes GA, Ramamurthy NS, Schneir M., Golub LM (1986). Diabetes stimulates procollagen degradation in rat tendon in vitro. Biochim Biophys Acta880:147-152.
56.
Lindy 0, Konttinen YT, Sorsa T., Ding Y., Santavirta S., Ceponis A., et al. (1997). Matrix metalloproteinase 13 (collagenase 3) in human rheumatoid synovium. Arthrit Rheum40:1391-1399.
Maehara R., Hinode D., Terai H., Sat M., Nakamura R., Matsuda M., et al. (1988). Inhibition of bacterial and mammalian collagenolytic activities by tetracyclines. J Jpn Assoc Periodontol30:182-188.
59.
Masumori N., Tsukamoto T., Miyao N., et al. (1994). Inhibitory effect of minocycline on in vitro invasion and experimental metastasis of mouse renal adenocarcinoma. J Urol151:1400-1404.
60.
McCulloch Cag, Birek P., Overall C., Aitken S., Lee W., Kulkarni G. (1990). Randomized control trial of doxycycline in prevention of recurrent periodontitis in high risk patients: antimicrobial activity and collagenase inhibition. J Clin Periodontol17:616-624.
61.
McNamara TF, Ramamurthy NS, Mulvihill JE, Golub LM (1982). Altered crevicular microflora in the alloxan diabetic rat. Arch Oral Biol27:217-224.
62.
McNamara TF, Golub LM, Yu Z., Ramamurthy NS (1990). Reduced doxycycline blood levels in humans fail to promote resistant organisms (abstract). In: Proceedings, International Conference on Periodontal Disease: Pathogens and Host Immune Responses, Osaka, Japan, p. 100.
63.
Michaelis J., Vissers Mcm, Winterbourn CC (1990). Human neutrophil collagenase cleaves α1-antitrypsin . Biochem270:809-814.
64.
Milano S., Arcoleo F., D'Agostino P., Cillari E. (1997). Intraperitoneal injection of tetracyclines protects mice from lethal endotoxemia downregulating inducible nitric oxide synthase in various organs and cytokine and nitrate secretion in blood. Antimicrob Agents Chemother41:117-121.
65.
Mitscher LA (1978). The chemistry of the tetracycline antibiotics . New York: Marcel Dekker, pp. 172-180.
66.
Mohler KM, Sleath PR, Fitzner JN, Ceretti DP, Alderson M., Kerwar SS, et al. (1994). Protection against a lethal dose of endotoxin by an inhibitor of tumor necrosis factor processing. Nature370:218-223.
Ohyori N., Sasaki T., Debari K., Ramamurthy NS, Golub LM (1998). Long-term therapy with a new chemically-modified tetracycline (CMT-8) inhibits bone loss in femurs of ovariectomized rats. Bone (submitted for publication).
69.
Paemen L., Martens E., Norga K., Masure S., Roets E., Hoogmartens J., et al. (1996). The gelatinase inhibitory activity of tetracyclines and chemically modified tetracycline analogs as measured by a novel microliter assay for inhibitors. Biochem Pharmacol52:105-111.
70.
Payne JB, Zachs NR, Reinhardt RA, Nummikoski PV, Patil K. (1997). The association between estrogen status and alveolar bone density changes in postmenopausal women with a history of periodontitis . J Periodontol68:24-31.
71.
Poison AM, Bouwsma OJ, McNamara TF, Golub LM (1986). Enhancement of normal bone density after tetracycline administration (abstract). J Dent Res65(Spec Iss): .
72.
Pruzanski W., Greenwald RA, Street IP, Laliberte P., Stefanski E., Vadas P. (1992). Inhibition of enzymatic activity of phospholipases A2 by minocycline and doxycycline. Biochem Pharmacol44:1165-1170.
73.
Ralston SHGrabowski PS (1996). Mechanisms of cytokine induced bone resorption: role of nitric oxide, cyclic guanosine monophosphate and prostaglandins. Bone19:29-33.
74.
Ramamurthy NS, Zebrowski EJ, Golub LM (1972). The effect of alloxan diabetes on gingival collagen metabolism in the rat. Arch Oral Biol17:1551-1560.
75.
Ramamurthy NS, Zebrowski EJ, Baker C., Golub LM (1973a). Alloxan diabetes and reduced bone density in rat mandible. Res Commun Chem Pathol Pharmacol5:614-620.
76.
Ramamurthy NS, Zebrowski EJ, Golub LM (1973b). Collagenolytic activity of alloxan diabetic rat gingivae. Diabetes22:272-274.
77.
Ramamurthy NS, Golub LM, Leung M. (1983). The effect of diabetes on lysyl oxidase activity and extractability of newly synthesized collagen in rat gingiva and skin. Gerodontology2:15-19.
78.
Ramamurthy NS, Vernillo A., Lee HM, Golub LM, Rifkin BR (1990). The effect of tetracyclines on collagenase activity in UMR 106-01 rat osteoblastic osteosarcoma cells. Res Commun Chem Pathol Pharmacol70:323-328.
79.
Ramamurthy NS, Vernillo AT, Greenwald RA, Lee HM, Sorsa T.Golub LM, et al. (1993). Reactive oxygen species activate and tetracyclines inhibit rat osteoblast collagenase. J Bone Min Res8:1247-1253.
80.
Ramamurthy NS, Golub LM, Sorsa T., Salo T., Ding Y. ( 1997). In vivo and in vitro inhibition of matrix metalloproteinases including MMP-13 by several CMTs (abstract). In: 2nd International Conference on the Biological Mechanics of Tooth Eruption, Resorption & Replacement by Implants, Toledo, Spain, October.
81.
Richard M., Broquet P., Vignon E., Peschard MJ, Carret JP, Louisot P. (1991). Calmodulin-dependent collagenase and proteoglycanase activities in chondrocytes from human osteoarthritic cartilage. Biochem Biophys Res Commun174:1204-1207.
82.
Rifkin BR, Vernillo A., Golub L., Ramamurthy N. (1994). Modulation of bone resorption by tetracyclines . Ann NY Acad Sci732:165-180.
83.
Risteli J., Elomaa I., Niemi S., Novamo A., Risteli I. (1993). Radioimmunoassay for the pyridinoline cross-linked carboxyterminal telopeptide of type I collagen: a new serum marker of bone collagen degradation. Clin Chem39:635-640.
84.
Ryan ME, Ramamurthy N., Golub L. (1995). Six CMTs modulate MMPs and non-enzymatic glycosylation in diabetic rats (abstract). J Dent Res74(Spec Iss):138.
85.
Ryan ME, Ramamurthy NS, Golub LM (1996a). Matrix metalloproteinases and their inhibition in periodontal treatment. Curr Opin Periodontol3:85-96.
86.
Ryan ME, Greenwald RA, Golub LM (1996b). Potential of tetracyclines to modify cartilage breakdown in osteoarthritis. Curr Opin Rheumatol8:238-247.
87.
Ryan ME, Ramamurthy NS, Gottesman E., Evans RT, Sorsa T., Golub LM (1997). P. gingival is-induced rat model of periodontitis:active/inactive phases (abstract). J Dent Res76(Spec Iss):290.
88.
Sasaki T., Ramamurthy NS, Golub LM (1992). Tetracycline administration increases collagen synthesis in osteoblasts of diabetic rats: a quantitative autoradiograph study . Calcif Tissue Int50:411-419.
89.
Schlondorff D., Satriano J. (1985). Interactions with calmodulin: potential mechanism for some inhibitory actions of tetracyclines and calcium channel blockers . Biochem Pharmacol34:3391-3393.
90.
Schneir M., Ramamurthy NS, Golub LM (1982). Skin collagen metabolism in the streptozotocin-induced diabetic rat: evidence for enhanced intracellular and extracellular catabolism . Diabetes31:426-431.
91.
Schneir M., Ramamurthy NS, Golub LM (1990). Minocycline treatment of diabetic rats increases skin collagen production and mass. Matrix10: 112-123.
92.
Schroeder K., Lee H., Wolff M., Ramamurthy N., Golub LM (1990). Low-dose tetracyclines (TCs) decrease elastase and β-glucuronidase activities in gingival crevicular fluid (GCF) (abstract) . J Dent Res69(Spec Iss):245 .
93.
Schroeder K., Ramamurthy NS, Tofil P., Smith R., Lee HM, Golub LM (1992). Low-dose doxycycline prevents attachment loss in adult periodontitis (abstract). J Dent Res71(Spec Iss):758.
94.
Seedor JA, Perry HD, McNamara TF, Golub LM, Buxton DF, Guthrie DS (1987). Tetracycline treatment of alkaliinduced corneal ulceration in the rabbit. Arch Ophthalmol105:268-271.
95.
Seftor Reb, Seftor EA, DeLarco JE, Kleiner DE, Leferson J., Stetler-Stevenson WG, et al. (1998). Chemically-modified tetracyclines inhibit human melanoma cell invasion and metastasis. Clin Exp Metastasis16:217-225.
96.
Shapira L., Soskolne WA, Houri Y., Barak V., Halabi A., Stabholz A. (1996). Protection against endotoxic shock and lipopolysaccharide-induced local inflammation by tetracycline: correlation with inhibition of cytokine secretion. Infect Immun64:825-828.
97.
Smith GN, Mickler EA, Hasty KA, Brandt KD (1996). Inhibition by doxycycline of a truncated form of recombinant human MMP-13. Arthrit Rheum39(Suppl 9):S226.
98.
Sorsa T., Ingman T., Suomalainen K., Haapasalo M., Konttinen YT, Lindy O., et al. (1992). Identification of proteases from periodontopathogenic bacteria as activators of latent human neutrophil and fibroblast-type interstitial collagenases. Infect Inunun60:4491-4495.
99.
Sorsa T., Lindy 0, Konttinen YT, Suomalainen K., et al. (1993). Doxycycline in the protection of serum alpha-1-antitrypsin from human neutrophil collagenase and gelatinase. Antimicrob Agents Chemother37:592-594.
100.
Sorsa T., Ding Y., Salo T., Lauhio A., Teronen 0, Ingman T., et al. (1994). Effects of tetracyclines on neutrophil, gingival and salivary collagenases: a functional and Western blot assessment with special references to their cellular sources in periodontal diseases . Ann NY Acad Sci732:112-131.
101.
Sorsa T., Salo T., Koivunen E., Tyynel J., Konttinen YT, Bergmann U., et al. (1997). Activation of type IV procollagenases by human tumor-associated trypsin-2. J Biol Chem272:21067-21074.
102.
Sorsa T., Ramamurthy NS, Vernillo AT, Zhang X., Konttinen YT, Rifkin BR, et al. (1998). Functional sites of chemically-modified tetracyclines: inhibition of the oxidative activation of human neutrophil and chicken osteoclast pro-matrix metalloproteinases. J Rheumatol25:975-982.
103.
Sotomayor EA, Teicher BA, Schwartz GN, Holden SA, Menon K., Herman TS, et al. (1992). Minocycline in combination with chemotherapy or radiation therapy in vitro and in vivo. Cancer Chemother Pharmacol30:377-384.
104.
Tamargo RJ, Bok RA, Brein H. (1991). Angiogenesis inhibition by minocycline. Cancer Res51:672-676.
105.
Taskiran D., Stefanovic-Racic M., Georgescu H., Evans CE (1994). Nitric oxide mediates suppression of cartilage proteoglycan synthesis by interleukin-1. Biochem Biophys Res Commun200:142-148.
106.
Tatakis DN, Schneeberger G., Dziak R. (1991). Recombinant interleukin-1 stimulates prostaglandin E2 production by osteoblastic cells: role of calcium, calmodulin and cAMP . Lymphokine Cytokine Res10:95-99.
107.
Thomas J., Crout RJ, Crout RM, Cook D., Keating J., Casto G., et al. (1995). Antibiotic resistance evaluation with low-dose doxycycline (LDD) in adult periodontitis (abstract). J Dent Res74(Spec Iss): 575.
108.
Trachtman H., Futtenweit S., Greenwald R., Moak S., Singhal P., Frank N., et al. (1996). Chemically modified tetracyclines inhibit inducible nitric oxide synthase expression and nitric oxide production in cultured rat mesangial cells. Biochem Biophys Res Commun229:243-248.
109.
Uematsu S., Mogi M., Degachi T. (1996). Interleukin (IL)-l, IL-6, tumor necrosis factor-a epidermal growth factor, and a2-macroglobulin levels are elevated in gingival crevicular fluid during human orthodontic tooth movement. J Dent Res75:562-567.
110.
Usman A., Moak SA, Golub LM, Greenwald RA (1996). The anti-collagenase properties of tetracycline analogs are correlated with their affinity for zinc (abstract). Arthrit Rheum39(Suppl. 9):S132.
111.
Valcavi U., Companella G., Pacini N. (1963). Pirazol-derivati della tetracyclina e chlorotetracyclina . Gazz Chem Ital93:916-921 [in Italian].
112.
Vlassara H., Brownlee M., Manoque K., Dinarello C., Pasagian A. (1988). Cachectin/TNF and IL-1 induced by glucose modified proteins: role in normal tissue remodeling. Science240:1546-1548.
113.
Webster GF, Tosso SM, Hegemann L. (1994). Inhibition of a model of in vitro granuloma formation by tetracyclines and ciprofloxacin: involvement of protein kinase C. Arch Dermatol130:748-752.
114.
Whiteman M., Halliwell B. (1997). Prevention of peroxynitrite-dependent tyrosine nitration and inactivation of α1-antiproteinase by antibiotics. Free Rad Res26:49-56.
115.
Williams S., Wakisaka A., Zeng QQ, Baines J., Martin G., Wechter WJ, et al. (1996). Minocycline prevents the decrease in bone mineral density and trabecular bone in ovariectomized aged rats. Bone19:637-644.
116.
Yu L., Smith G., Hasty K., Brandt K. (1991). Doxycycline inhibits type XI collagenolytic activity of extracts from human osteoarthritic cartilage and of gelatinase. J Rheumatol18:1450-1452.
117.
Yu Z., Leung MK, Ramamurthy NS, McNamara TF, Golub LM (1991). HPLC determination of a chemically-modified non-antimicrobial tetracycline: biologic implications. Biochem Med Metabol Biol47:10-20.
118.
Zemicke RF, Wohl GR, Greenwald RA, Moak SA, Leng W., Golub LM (1997). Administration of systemic matrix metalloproteinase inhibitors maintains bone mechanical integrity in adjuvant arthritis. J Rheumatol24:1324-1331.
119.
Zhang Y., DeWitt DC, McNeely TB, Wahl SM, Wahl LM ( 1997). Secretory leukocyte protease inhibitor suppresses the production of monocyte prostaglandin H synthase-2, prostaglandin E2, and matrix metalloproteinases. J Clin Invest99:894-900.
120.
Zucker S., Lysik RM, Ramamurthy NS, Golub LM, Wieman JM, Wilkie DP (1985). Diversity of plasma membrane proteinases in mouse melanoma cells: inhibition of collagenolytic and cytolytic activity by minocycline . J Natl Cancer Inst75:517-525.
121.
Zucker S., Wieman J., Lipik RM, Imhof B., Nagase H., Ramamurthy NS, et al. (1989). Gelatin degrades type IV collagenase isolated from human small cell lung cancer. Invas Metast9:167-181.
