Drug Res (Stuttg) 2017; 67(05): 258-265
DOI: 10.1055/s-0043-100633
Review
© Georg Thieme Verlag KG Stuttgart · New York

Role of Chemically Modified Tetracyclines in the Management of Periodontal Diseases: A Review

Archit A. Ghangurde
1   Department of Periodontics, Sharad Pawar Dental College, Sawangi Meghe, Wardha. Affiliated to Datta Meghe Institute of Medical Sciences, Nagpur, India
,
Kiran Kumar Ganji
2   Periodontics Section, Department of Preventive Dentistry, College of Dentistry, SAKAKA, Affiliated to Aljouf University, Aljouf, Kingdom of Saudi Arabia
,
Manohar L. Bhongade
3   Department of Periodontics, Sharad Pawar Dental College, Sawangi Meghe, Wardha. Affiliated to Datta Meghe Institute of Medical Sciences, Nagpur, India
,
Bhumika Sehdev
4   Department of Periodontics, Rajrajeshwari Dental College, Udaipur, India
› Author Affiliations
Further Information

Publication History

received 29 July 2016

accepted 04 December 2016

Publication Date:
07 March 2017 (online)

Abstract

Researchers have found that Chemically Modified Tetracyclines (CMTs) act through multiple mechanisms, affecting several parameters of osteoclast function and consequently inhibit bone resorption by altering intracellular calcium concentration and interacting with the putative calcium receptor; decreasing ruffled border area; diminishing acid production; diminishing the secretion of lysosomal cysteine proteinases (cathepsins); inducing cell retraction by affecting podosomes; inhibiting osteoclast gelatinase activity; selectively inhibiting osteoclast ontogeny or development; and inducing apoptosis or programmed cell death of osteoclasts. Thus TCs/CMTs, as anti-resorptive drugs, may act similarly to bisphosphonates and primarily affect osteoclast function. Researchers have evaluated the influence of various chemically modified tetracyclines from CMT-1 to CMT-10 on collagenases and gelatinases through in vitro or animal studies and concluded that all the CMTs except CMT-5 inhibited periodontal breakdown through MMP inhibition in the following order of efficacy: CMT-8>CMT-1>CMT-3>CMT-4>CMT-7. Thus the non-antimicrobial actions of the chemically modified analogues of tetracyclines have shown remarkably better mechanisms to those of agents with established anti-inflammatory/antioxidant potential. These findings clarify the multi-faceted actions of tetracyclines which are unique amongst antimicrobials, with therapeutic applications in periodontal and metabolic diseases. Hence, the present review describes the role of chemically modified tetracyclines in the management of periodontal diseases.

 
  • References

  • 1 Anwar H, Strap JL, Costerton JW. Establishment of aging biofilms:possible mechanism of bacterial resistance to antibiotic therapy. Antimicrob Agents Chemother 1992; 36: 1347-1351
  • 2 Bodinka A, Schmidt H, Henkel B. et al. Polymerase chain reaction for the identification of Porphyromonas gingivalis collagenase genes. Oral Microbiol Immunol 1994; 9: 161-165
  • 3 VanWinkelhoff AJ, Rams TE, Slots J. Systemic antibiotic therapy in periodontics. Periodontol 2000 1996; 10: 45-78
  • 4 Fiorellini JP, Paquette DW. The potential role of controlled-release delivery systems for chemotherapeutic agents in periodontics. Curr Opin Dent 1992; 2: 63-79
  • 5 Amin AR, Attur MG, Thakker GD. et al. A novel mechanism of action of tetracyclines: Effects on nitric oxide synthases. Proc. Natl. Acad. Sci 1996; 93: 14014-14019
  • 6 Amin AR, Patel RN, Thakker GD. et al. Post-transcriptional regulation of inducible nitric oxide synthase mRNA in murine macrophages by doxycycline and chemically modified tetracyclines. FEBS Lett 1997; 410: 259-264
  • 7 Anwar H, Strap JL, Costerton JW. Establishment of aging biofilms:possible mechanism of bacterial resistance to antibiotic therapy. Antimicrob Agents Chemother 1992; 36: 1347-1351
  • 8 Aoyagi M, Sasaki T, Ramamurthy N. et al. Tetracycline/Flurbiprofen combination therapy modulates bone remodeling in ovariectomized rats: preliminary observations. Bone 1996; 19: 629-635
  • 9 Armstrong DG, Jude EB. The role of matrix metalloproteinases in wound healing. J Am Pediatr Med Assoc 2002; 92: 12-18
  • 10 Baker P, Evans R, Coburn R. et al. Tetracycline and its derivatives strongly bind to and are released from the tooth surface in an active form. J Periodontol 1983; 54: 580-585
  • 11 Al-Ali W, Bissada NF, Greenwell H. The effect of local doxycycline with and without tricalcium phosphate on the regenerative healing potential of periodontal osseous defects in dogs. J Periodontol 1989; 60: 582-590
  • 12 Sorsa T, Uitto VJ, Suomalainen K. et al. Comparison of interstitial collagenases from human gingival, sulcular fluid and polymorphonuclear leukocytes. J Periodontal Res 1988; 23: 386-393
  • 13 Terranova VP, Franzetti LC, Hick S. et al. A biochemical approach to periodontal regeneration: tetracycline treatment of dentin promotes fibroblast adhesion and growth. J Periodontal Res 1986; 21: 330-337
  • 14 Lynch WS, Bergfeld WF. Pyodermagangrenosum responsive to minocycline hydrochloride. Cutis 1978; 21: 535-538
  • 15 Plewig G, Schopf E. Anti-inflammatory effects of antimicrobial agents: an in vivo study. J Invest Dermatol 1975; 65: 532-536
  • 16 Humbert P, Renaud A, Laurent L. et al. Tetracyclines for dystrophic epidermolysisbullosa. Lancet 1989; 2: 277
  • 17 White JE. Minocycline for dystrophic epidermolysisbullosa. Lancet 1989; 1: 966
  • 18 Golub LM, Lee HM, Lehrer G. et al. Minocycline reduces gingival collagenolytic activity during diabetes. J Periodontal Res 1983; 18: 516-526
  • 19 Mitscher LA. The chemistry of the tetracycline antibiotics. Crit. Rev Oral Biol Med 1991; 2: 297-322
  • 20 Golub LM, Ciancio S, Ramamurthy NS. et al. Low-dose doxycycline therapy: effect on gingival and crevicular fluid collagenase activity in humans. J Periodontal Res 1990; 25: 321-330
  • 21 McNamara TF, Golub LM, D’Angelo G. et al. The synthesis and characterization of a non-antibacterial chemically-modified tetracycline (CMT). J Dent Res 1987; 66: 1310-1314
  • 22 McNamara TF, Golub LM, Yu Z. et al. Reduced doxycycline blood levels in humans fail to promote resistant organisms. Crit Rev Oral Biol Med 1991; 2: 297-322
  • 23 Golub LM, McNamara TF, Ryan ME. et al. Adjunctive treatment with subantimicrobial doses of doxycycline: effects on gingival fluid collagenase activity and attachment loss in adult periodontitis. J Clin Periodontol 1987; 28: 146-156
  • 24 Greenwald RA, Golub LM, Lavietes B. et al. Tetracyclines inhibit human synovial collagenase in vivo and in vitro. J Rheumatol 1987; 14: 28-32
  • 25 Ramamurthy NS, Vernillo A, Lee HM. et al. The effect of tetracyclines on collagenase activity in UMR 106-01 rat osteoblastic osteosarcoma cells. Res Commun Chem Pathol Pharmacol 1990; 70: 323-335
  • 26 Rifkin B, Sanavi F, Gomes B. et al. The effects of minocycline and non-antibiotic tetracycline on parathyroid hormone stimulated bone resorption in vitro. Crit Rev Oral Biol Med 1991; 2: 297-322
  • 27 Zucker S, Lysik RM, Ramamurthy NS. et al. Diversity of plasma membrane proteinases in mouse melanoma cells: inhibition of collagenolytic and cytolytic activity by minocycline. J Natl Cancer Inst 1985; 75: 517-525
  • 28 Valcavi U, Companella G, Pacini N. Pirazol-derivatidellatetracyclina e clorotetraciclina. Gazz Chim Ital 1963; 93: 916-928
  • 29 Yu Z, Leung M, Ramamurthy N. et al. Serum levels of chemically-modified tetracycline: a comparison to tetracycline. Biochem Med Metab Biol 1992; 47: 10-20
  • 30 Skinner HCW, Nalbandian J. Tetracycline and mineralized tissue. Yale J Biol Med 1975; 48: 377-397
  • 31 Golub LM, Greenwald R, Ramamurthy N. et al. Tetracyclines inhibit metalloproteinases: in vivo effects in arthritic and diabetic rats and new in vitro Studies. Matrix Suppl 1992; 1: 315-316
  • 32 Greenwald RA. Tetracycline derivatives as potential inhibitors of connective tissue degradation. Drug News Perspect 1990; 3: 161
  • 33 Lee HM, Golub L, Suzuki K et al. Specificity of the anti-collagenase activity of tetracyclines. J Dent Res 1991; 70:
  • 34 Maehara R, Hinode D, Terai H. et al. Inhibition of bacterial and mammalian collagenolytic activities by tetracyclines. J Jpn Assoc Periodontol 1988; 30: 182
  • 35 Ramamurthy NS, Lee HM, Vidal AM et al. The substantivity of the anti-collagenase activity of minocycline in vivo. J Dent Res 1986; 65:
  • 36 Golub LM, Lee HM, Lehrer G. et al. Minocycline reduces gingival collagenolytic activity during diabetes: preliminary observations and a proposed new mechanism of action. J Periodont Res 1983; 18: 516-522
  • 37 Sorsa T. Personal communication; oral presentation at the 8th Int Conf on Periodontal Res San Antonio, Texas. 1990
  • 38 Sorsa T, Uitto VJ, Suomalainen K. et al. Comparison of interstitial collagenases from human gingival, sulcular fluid and polymorphonuclear leukocytes. J Periodontal Res 1988; 23: 386-393
  • 39 Golub LM, Wolff M, Lee HM. et al. Further evidence that tetracyclines inhibit collagenase activity in human crevicular fluid and from other mammalian sources. J Periodontal Res 1985; 20: 12-23
  • 40 Burns FR, Stack MS, Gray RD. et al. Inhibition of purified collagenase from alkali-burned rabbit corneas. Invest Ophthalmol Vis Sci 1989; 30: 1569-1575
  • 41 McCulloch CAG, Birek P, Overall C. et al. Randomized controlled trial of doxycycline in prevention of recurrent periodontitis in high risk patients: antimicrobial activity and collagenase inhibition. J Clin Periodontol 1990; 17: 616-622
  • 42 Robertson PB, Lanz M, Manidra PT. et al. Collagenolytic activity associated with bacteriodes species and actinobacillus actinomycetemcomitans. J Periodontal Res 1982; 17: 275-283
  • 43 Chang KM, Ramamurthy NS, Golub LM. Minocycline inhibits matrix-degrading enzymes in rat gingiva. Res Commun Mol Pathol Pharmacol 1996; 91: 303-318
  • 44 Tal H, Pitaru S, Moses O. et al. Collagen gel and membrane in guided tissue regeneration in periodontal fenestration defects in dogs. J Clin Periodontol 1996; 23: 1-6
  • 45 Lee HM, Golub LM, Gwinnett AJ. et al. Minocycline inhibits collagenase and elastase produced by rat macrophages in cell culture. J. Dent. Res 1985; 64: 1175-1180
  • 46 Arsenis C, Greenwald RA, Moak SA. et al. Inhibition of neutral metalloproteinase activities in epiphyseal and articular cartilages by tetracyclines both in vivo and in vitro. Trans Orthopaed Res Soc 1990; 15: 268-275
  • 47 Ito A, Nagase H. Evidence that human rheumatoid synovial matrix metalloproteinase 3 is an endogenous activator of procollagenase. Arch Biochem Biophys 1988; 267: 211-216
  • 48 Papapanou PN. Periodontal diseases: epidemiology. Ann Periodontol 1996; 1: 1-36
  • 49 Ding Y, Uitto VJ, Firth J. et al. Modulation of host matrix metalloproteinases by bacterial virulence factors relevant in human periodontal diseases. Oral Dis 1995; 1: 279-286
  • 50 Ebersole JL, Cappelli D, Steffen MJ. et al. Host response assessment in recurring periodontitis. J Clin Periodontol 1996; 23: 258-262
  • 51 Golub LM, Suomalainen K, Sorsa T. Host modulation with tetracyclines and their chemically modified analogues. Curr Opin Dent 1992; 2: 80-90
  • 52 Ingman T, Tervahartiala T, Ding Y. et al. Matrix metalloproteinases and their inhibitors in gingival crevicular fluid and saliva of periodontitis patients. J Clin Periodontol 1996; 23: 1127-1132
  • 53 Golub LM, Ramamurthy NS, McNamara TF. et al. Tetracyclines inhibit connective tissue breakdown: new therapeutic implications for an old family of drugs. Crit Rev Oral Biol Med 1991; 2: 297-322
  • 54 Rifkin BR, Vernillo AT, Golub LM. Blocking periodontal disease progression by inhibiting tissue-destructive enzymes: A potential therapeutic role for tetracyclines and their chemically modified analogs. Crit Rev Oral Biol Med 1991; 2: 297-321
  • 55 Yu Z, Ramamurthy NS, Leung M. et al. Chemically modified tetracycline normalizes collagen metabolism in diabetic rats: A dose response study. J Periodontal Res 1993; 28: 420-428
  • 56 Amin AR, Attur MG, Thakker GD. et al. A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc Natl Acad Sci 1996; 93: 14014-14019
  • 57 Stefanovic-Racic M, Meyers K, Meschter C. et al. Randomized controlled trial of doxycycline in prevention of recurrent periodontitis in high risk patients: antimicrobial activity and collagenase inhibition. J Proc Natl Acad Sci USA 1996; 93: 1124-1136
  • 58 Kaneko H, Sasaki T, Ramamurthy NS. et al. Tetracycline administration normalizes the structure and acid phosphatase activity of osteoclasts in streptozotocin-induced diabetic rats. Anat Rec 1990; 2: 227-237
  • 59 Sakurai H, Kohsaka H, Liu MF. et al. Monensin inhibits collagenase production in osteoblastic cell cultures and also inhibits both collagenase release and bone resorption in mouse calvaria cultures. Proc Natl Acad Sci USA 1997; 22: 1128-1132
  • 60 Ialenti A, Ianaro A, Moncada S. et al. Modulation of acute inflammation by endogenous nitric oxide. Eur J Pharmacol 1992; 211: 177-182
  • 61 Vane JR, Mitchell JA, Appleton I. et al. Inducible isoforms of cyclooxygenase and nitric oxide synthase in inflammation. Proc Natl Acad Sci USA 1994; 91: 2046-2050
  • 62 ElAttar TMA, Lin HS, Schultz RJ. Effect of minocycline on prostaglandin formation in gingival fibroblast. J Periodontal Res 1988; 23: 285-286
  • 63 Gabler WL, Creamer HR. Suppression of human neutrophil functions by tetracyclines. J Periodontal Res 1991; 26: 52-58
  • 64 Golub LM, Ramamurthy NS, McNamara TF. et al. Tetracyclines inhibit tissue collagenase activity: a new mechanism in the treatment of periodontal disease. J Periodontal Res 1984; 19: 651-655
  • 65 Vadas P, Greenwald RA, Street RT. Inhibition of synovial fluid phospholipase A2 activity by two tetracycline derivatives, minocycline and doxycycline. Arth Rheum 1991; 34: 160-164
  • 66 Bombardier S, Cattani P, Giabattoni G. et al. The synovial prostaglandin system in chronic inflammatory arthritis: differential effects of steroidal and non-steroidal anti-inflammatory drugs. Br J Pharmacol 1981; 73: 893-901
  • 67 Davies P, MacIntyre DE. Prostaglandins and inflammation. In Inflammation: basic principles and clinical correlates. Gallin JI, Goldstein IM, Snyderman R. eds. Raven Press; New York: 1992: 123
  • 68 Lindsey J, Kashiwagi D, Boyle D. et al. Prostaglandins increase proMMP-1 and proMMP-3 secretion by human ciliary smooth muscle cells. Curr Eye Res 1996; 15: 869-875
  • 69 Narko K, Ristimaki A, MacPhee M. et al. Tumorigenic transformation of immortalized ECV endothelial cells by cyclooxygenase-1 overexpression. J Biol Chem 1997; 272: 21455-21460
  • 70 Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin enoperoxide synthase 2. Cell 1995; 8: 493-501
  • 71 Boolbol SK, Dannenberg AJ, Chadburn A. et al. Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis. Cancer Res 1996; 56: 2556-2560
  • 72 Tsujii M, Kawano S, DuBois RN. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA 1997; 94: 3336-3340
  • 73 Burch RM, White MF. Connor JRI. Interleukin 1 stimulates prostaglandin synthesis and cyclic AMP accumulation in Swiss 3T3 fibroblasts: interactions between two second messenger systems. J Cell Physiol 1989; 29: 139-145
  • 74 Ohmori Y, Strassman G, Hamilton TA. cAMP differentially regulates expression of mRNA encoding IL-1a and IL-1b in murine peritoneal macrophages. J Immunol 1990; 145: 3333-3339
  • 75 Seftor EA, Seftor RA, Nieva DR. et al. Application of chemically modified tetracyclines (CMTs) in experimental models of cancer and arthritis. Adv Dent Res 1998; 12: 103-110
  • 76 Golub LM, Lee HM, Ryan ME. et al. Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv Dent Res 1998; 12: 12-26
  • 77 Seftor RE, Seftor EA, De LJ. et al. Chemically modified tetracyclines inhibit human melanoma cell invasion and metastasis. Clin Exp Metastasis 1998; 16: 217-225
  • 78 Rifkin B, Vernillo AT, Golub LM. et al. Modulation of bone resorption by tetracyclines. Ann N Y Acad Sci 1994; 732: 165-180
  • 79 Melcher AH. On the repair potential of periodontal tissues. J Periodontol 1976; 47: 2562-2560
  • 80 Nyman S, Gottlow J, Lindhe J. et al. New attachment formation by guided tissue regeneration. J Periodontal Res 1987; 22: 252-254
  • 81 Patino MG, Neiders ME, Andreana S. et al. Collagen as an implantable material in medicine and dentistry. J Oral Implantol 2002; 28: 220-225
  • 82 Ziccardi VB, Buchbinder D. Guided tissue regeneration in dentistry. N Y State Dent J 1996; 62: 48-51
  • 83 Pfeifer J, Van Swol RL, Ellinger R. Epithelial exclusion and tissue regeneration using a collagen membrane barrier in chronic periodontal defects: A histologic study. Int J Periodontics Restorative Dent 1989; 9: 262-273
  • 84 Gottlow J, Nyman S. Barrier membranes in the treatment of periodontal defects. Curr Opin Periodontol 1996; 3: 140-148
  • 85 Armstrong DG, Jude EB. The role of matrix metalloproteinases in wound healing. J Am Podiatr Med Assoc 2002; 92: 12-18
  • 86 Reynolds JJ, Hembry RM, Meikle MC. Connective tissue degradation in health and periodontal disease and the roles of matrix metalloproteinases and their natural inhibitors. Adv Dent Res 1994; 8: 312-319
  • 87 Korostoff JM, Wang JF, Sarment DL. Analysis of in situ protease activity in chronic adult periodontitis patients: Expression of activated MMP-2 and a 40 KD Serine protease. J Periodontol 2000; 71: 353-360
  • 88 Froum SJ, Gomez C, Breault MR. Current concepts of periodontal regeneration. A review of the literature. N Y State Dent J 2002; 68: 14-22
  • 89 Greenwald RA, Golub L, Ramamurthy N. et al. In vitro sensitivity of the three mammalian collagenases to tetracycline inhibition: Relationship to bone and cartilage degradation. Bone 1998; 22: 33-38
  • 90 Ramamurthy NS, McClain SA, Pirila E. et al. Wound healing in aged normal and ovariectomized rats: Effects of chemically modified doxycycline (CMT-8) on MMP expression and collagen synthesis. Ann N Y Acad Sci 1999; 30: 720-723
  • 91 Bettany JT, Peet NM, Wolowacz RG. et al. Tetracyclines induce apoptosis in osteoclasts. Bone 2000; 27: 75-80
  • 92 Kirkwood K, Martin T, Andreadis ST. et al. Chemically modified tetracyclines selectively inhibit IL-6 expression in osteoblasts by decreasing mRNA stability. Biochem pharmacol 2003; 66: 1809-1819
  • 93 Kirkwood KL, Golub LM, Bradford PG. Non-antimicrobial and antimicrobial tetracyclines inhibit IL-6 expression in murine osteoblasts. Ann N Y Acad Sci 1999; 878: 667-670
  • 94 Sindhura Reddy N, Sowmya S, Bumgardner JD. et al. Tetracycline nanoparticles loaded calcium sulfate composite beads for periodontal management. Biochim Biophys Acta. 2014; 1840: 2080-2090 doi:10.1016/j.bbagen.2014.02.007 Epub 2014 Feb 18. PubMed PMID: 24561265