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Inhibition of epiphyseal cartilage collagenase by tetracyclines in low phosphate rickets in rats
Author(s) -
Greenwald Robert A.,
Simonson Barry G.,
Moak Susan A.,
Rush Scott W.,
Ramamurthy N. S.,
Laskin Richard S.,
Golub Lorne M.
Publication year - 1988
Publication title -
journal of orthopaedic research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.041
H-Index - 155
eISSN - 1554-527X
pISSN - 0736-0266
DOI - 10.1002/jor.1100060512
Subject(s) - rickets , collagenase , connective tissue , endocrinology , minocycline , chemistry , medicine , in vivo , alkaline phosphatase , osteomalacia , tetracycline , cartilage , in vitro , enzyme , biochemistry , biology , vitamin d and neurology , antibiotics , pathology , anatomy , microbiology and biotechnology
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 μg/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.

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