Inhibition of epiphyseal cartilage collagenase by tetracyclines in low phosphate rickets in rats

Abstract

Drugs in the tetracycline family can inhibit mammalian tissue collagenase both in vitro and in vivo by a mechanism that is independent of antibiotic action. The epiphyseal cartilages of rachitic rats contain extremely high levels of collagenase (CGase), and we have used this model to study further the phenomenon of tetracycline inhibition of tissue CGase. Rickets was induced in rats by phosphate/vitamin D deficiency and parameters of gross bone morphology, bone chemistry, and serum chemistry were evaluated in both rachitic and nonrachitic animals with and without treatment with oral tetracyclines (TETs). Minocycline (or doxycycline) partially suppressed the appearance of many of the expected changes in the rachitic animals, including gross bone hardness, growth plate widening, long bone length, suppression of weight gain, and decreased bone ash content. The effects were dose dependent and were associated with marked suppression of the enhanced CGase activity. Examination of collagen breakdown products by SDS-PAGE documented that the rachitic enzyme behaved like other mammalian collagenases including in vitro inhibition with minocycline 10-20 micrograms/ml and with a nonantibiotic tetracycline. No evidence of TET osseous toxicity was noted, and, in fact, administration of TET to nonrachitic animals had a mildly favorable effect on growth and development. TET suppression of CGase can be demonstrated in a well defined model system and this form of pharmacologic enzyme inhibition can be a useful probe for delineating the role of the enzyme in connective tissue pathology.

Doxycycline reduces airway inflammation and hyperresponsiveness in a murine model of toluene diisocyanate–induced asthma☆

“…[13][14][15][16][17][18] The mechanisms by which doxycycline inhibits the MMPs are not completely understood. Doxycycline binds directly to Zn 2+ or Ca 2+ associated with the enzyme, resulting in blocking the active site or inducing conformational changes that render the proenzyme susceptible to fragmentation during activation.…”

“…13 Doxycycline and other derivatives of tetracycline are potent MMP inhibitors. [14][15][16][17][18] Inhibition of MMPs by doxycycline occurs independently of antimicrobial activity. The beneficial effect of doxycycline on ECM degradation in animal models and human beings has been attributed to the inhibition of MMPs.…”

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

“…99 In vivo studies are also beginning to address the clinical potential in bone disorders of these tetracycline effects and to identify altemative mechanisms of tetracycline-reduced bone loss. Greenwald et al 39 reported that tetracyclines orally administered to rats with experimental rickets reduced the excessive collagenase activity in the epiphyseal growth plate, an effect that was associated with a partial normalization of the impaired growth and mineralization characteristic of this metabolic bone disease. The diabetic rat model continues to provide major new insights.…”

Reduction of the severity of canine osteoarthritis by prophylactic treatment with oral doxycycline

“…Tetracyclines inhibit the activity of neutral matrix metalloproteinases (MMPs) (1)(2)(3). This effect has been believed to be due, at least in part, to chelation of zinc and/or calcium (1,4), which maintain the normal structural conformation and hydrolytic activity of the MMPs (5).…”