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

Abstract

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.

Effects of doxycycline on progression of osteoarthritis: Results of a randomized, placebo‐controlled, double‐blind trial

“…Similar reductions in cartilage collagenase and gelatinase were obtained after administration of doxycycline to humans undergoing total joint arthroplasty (7). Furthermore, doxycycline administration markedly reduced the incidence and progression of joint pathology in the above-mentioned canine model of OA (6), which was consistent with evidence that it reduced the severity of spontaneous OA in the HartleyDunkin strain of guinea pig (8) and that treatment with a chemically modified tetracycline reduced the severity of joint pathology in a surgically induced model of OA in rabbits (9).…”

Effect of zoledronic acid on the doxycycline-induced decrease in tumour burden in a bone metastasis model of human breast cancer

“…Doxycycline has several properties relevant for treatment of bone metastasis, as doxycycline can inhibit tumour cell proliferation (Van den Bogert et al, 1983;Fife and Sledge, 1995;Duivenvoorden et al, 1997) and MMP activity, and accumulates at high concentrations in bone (Golub et al, 1991). We have also shown evidence to support the concept that the reduction in tumour burden by doxycycline is likely due to its properties as an inhibitor of tumour cell proliferation and that doxycycline significantly increases several parameters of bone formation (Duivenvoorden et al, 2002).…”

Doxycycline disrupts chondrocyte differentiation and inhibits cartilage matrix degradation

“…In addition to their antimicrobial properties, certain tetracyclines have been reported to inhibit two matrix metalloproteinases, collagenase and gelatinase (3,4), which are involved in degradation of cartilage components. Therefore, investigators have begun to test the potential of members of the tetracycline family, including doxycycline, minocycline, and other chemically modified tetracyclines, to decrease proteolytic degradation of cartilage associated with both osteoarthritis (OA) and rheumatoid arthritis (RA).…”