Tetracyclines inhibit parathyroid hormone-induced bone resorption in organ culture

Gomes, B.C.; Golub, Lorne M.; Ramamurthy, N. S.

doi:10.1007/bf01946671

Cited by 85 publications

(55 citation statements)

References 14 publications

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“…Numerous clinical studies (see "Introduction") as well as case reports (Fasciano and Fazio, 1981;Moskow, 1986) support the usefulness of tetracyclines as adjuncts in the treatment of periodontal diseases. A recent series of studies addressed the additional ability of these drugs to inhibit the activity of mammalian collagenases and the likelihood that this newly discovered property contributes significantly to their clinical efficacy in the management of periodontal and perhaps other diseases as well (Golub et al, , 1985aGomes et al, 1984;Zucker et al, 1985;Perry and Golub, 1985;Seedor et al, 1985;Greenwald et al, 1986Greenwald et al, , 1987.…”

Section: Discussionmentioning

confidence: 97%

“…The evidence includes the following facts: (i) These drugs inhibit collagenase activity and collagen breakdown in germ-free as well as conventional rats Golub et al, 1985b); (ii) their administration in vivo inhibits collagenase activity and/or collagen destruction in non-infected tissues of humans (Perry and Golub, 1985;Greenwald et al, 1986), as well as in experimental animals Golub et al, 1985b;Seedor et al, 1985); (iii) these drugs directly inhibit mammalian collagenolytic activity in vitro Golub et al, 1984;Gomes et al, 1984;Golub et al, 1985a,b;Zucker et al, 1985); and (iv) their administration to humans in low doses substantially reduces the collagenase activity in the fluid of the periodontal pocket without producing a detectable effect on the subgingival microflora (Golub et al, 1985a;Golub et al, 1987). The present study provides direct evidence that the antibiotic and anti-collagenase properties of tetracycline reside in different parts of the molecule, since chemically modifying the drug to eliminate its anti-bacterial efficacy (Mitscher, 1978; did not reduce its anti-collagenase activity.…”

Section: Discussionmentioning

confidence: 98%

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A Non-antibacterial Chemically-modified Tetracycline Inhibits Mammalian Collagenase Activity

et al. 1987

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Tetracyclines (including the semi-synthetic analogues, minocycline and doxycycline) are considered useful adjuncts in periodontal therapy because they suppress Gram-negative periodontopathogens. Recently, these antibiotics were found to inhibit mammalian collagenase activity, a property which may also be of therapeutic value. It has been suggested that the anti-collagenase properties of the tetracyclines are independent of their antibiotic efficacy. To advance this hypothesis further, we chemically converted tetracycline hydrochloride to its non-antimicrobial analogue, de-dimethylaminotetracycline. This chemically-modified tetracycline (CMT), although no longer an effective antibiotic, was found to inhibit the in vitro activity of collagenase from partially purified extracts of human rheumatoid synovial tissue and rachitic rat epiphysis. In a preliminary in vivo study, pathologically-excessive collagenase in skin and gingiva was induced by rendering adult male rats diabetic, and the oral administration of CMT to these rats significantly reduced the excessive collagenase activity in both tissues. Moreover, CMT administration did not affect the severe hyperglycemia in these rats but did prevent, at least in part, the diabetes-induced loss of body weight, skin weight, and skin collagen mass; these effects suggest a lack of toxicity in this animal model. A proposed clinical advantage of CMT over conventional tetracyclines, in the treatment of diseases characterized by excessive collagenolytic activity, is the lack of development of antibiotic-resistant micro-organisms during prolonged use. However, the consideration of clinical trials to support this hypothesis must await further laboratory and extensive toxicity tests.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 98%

A Non-antibacterial Chemically-modified Tetracycline Inhibits Mammalian Collagenase Activity

et al. 1987

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“…One of the earliest demonstrations of this unexpected enzymatic inhibitory property involved PTH-induced bone resorption in organ culture. Gomes et al [17] showed that minocycline and doxycycline inhibited both 4SCa++ release and collagen breakdown in rat long bones cultured under the influence of parathyroid hormone (PTH). Rifkin et al [6] extended this observation using a panel of CMTs.…”

Section: Discussionmentioning

confidence: 99%

Effect of tetracyclines which have metalloproteinase inhibitory capacity on basal and heparin-stimulated bone resorption by chick osteoclasts

et al. 1993

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Several tetracyclines (TETs) are potent inhibitors of collagenase (CGase) and can inhibit connective tissue degradation in a variety of inflammatory and degenerative disorders. The role of CGase in bone resorption by osteoclasts (OC) remains unclear. Disaggregated OCs from chick embryos were cultured for 24 h on devitalized bovine cortical bone +/- heparin in the presence of various TETs. Doxycycline (Dox) inhibited pit formation in a dose-dependent manner. CMT, a TET derivative which inhibits matrix metalloproteinases (MMPs) but is not antimicrobial, also inhibited chick OC bone resorption. Heparin markedly stimulated bone resorption at 5 micrograms/ml, which was reversed by Dox, 5 micrograms/ml. TETs can reversibly inhibit both basal and heparin-stimulated bone resorption by chick OCs. These findings suggest that MMPs may play a role in osteoclastic bone resorption, and that safe and effective inhibitors of MMPs, including certain TETs, might have a potential therapeutic role.

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“…Using standard organ culture systems, both antimicrobial (minocycline, doxycycline, tetracycline) and nonantimicrobial (see below) tetracyclines were found to inhibit bone resorption induced by parathyroid hormone (PTH), prostaglandin (PGE2), and bacterial endotoxin. 16,17 60 The tetracycline inhibition of bone resorption occurred without a reduction of osteoclast recruitment to bone surfaces by PTH and in the absence of ultrastructural evidence of bone cell toxicity. Nontetracycline antibiotics (penicillin, ampicillin, streptomycin, cefazolin) were ineffective in these systems.…”

Section: Proanabolic As Well As Anticatabolic Activity Of Tetracymentioning

confidence: 96%

Tetracyclines Inhibit Connective Tissue Breakdown: New Therapeutic Implications for an Old Family of Drugs

Golub

Ramamurthy

McNamara

et al. 1991

Critical Reviews in Oral Biology & Medicine

484

367

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Tetracyclines have long been considered useful adjuncts in peridontal therapy based on their antimicrobial efficacy against putative periodontopathogens. However, recently these drugs were found to inhibit mammalian collagenases and several other matrix metalloproteinases (MMPs) by a mechanism independent of their antimicrobial activity. Evidence is presented that this property may be therapeutically useful in retarding pathologic connective tissue breakdown, including bone resorption. The experiments leading to this discovery are described and possible mechanisms are addressed, including the specificity of tetracyclines' anti-collagenase activity, the role of the drugs' metal ion (Zn2+, Ca2+)-binding capacity, and the site on the tetracycline molecule responsible for this nonantimicrobial property. Of extreme interest, the tetracycline molecule has been chemically modified in multiple ways, generating a new family of compounds called CMTs (chemically modified tetracyclines) that lack antimicrobial but still retain anti-collagenase activity. The first of these CMTs, 4-de-di-methylaminotetracycline, was found not to produce a major side-effect of antimicrobial tetracycline therapy--its administration to experimental animals did not result in the emergence of tetracycline-resistant microorganisms in the oral flora and gut. Numerous examples of the clinical potential of this non-antimicrobial property of tetracyclines in the treatment of periodontal and several medical diseases (e.g., sterile corneal ulcers, rheumatoid arthritis, skin bullous lesions, tumor-induced angiogenesis and metastasis) are discussed.

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Tetracyclines inhibit parathyroid hormone-induced bone resorption in organ culture

Cited by 85 publications

References 14 publications

A Non-antibacterial Chemically-modified Tetracycline Inhibits Mammalian Collagenase Activity

A Non-antibacterial Chemically-modified Tetracycline Inhibits Mammalian Collagenase Activity

Effect of tetracyclines which have metalloproteinase inhibitory capacity on basal and heparin-stimulated bone resorption by chick osteoclasts

Tetracyclines Inhibit Connective Tissue Breakdown: New Therapeutic Implications for an Old Family of Drugs

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