IN-VITRO SENSITIVITY OF THE 3 MAMMALIAN COLLAGENASES TO TETRACYCLINE INHIBITION - RELATIONSHIP TO BONE AND CARTILAGE DEGRADATION

There are at least nine tetracycline (TC) analogs (both antimicrobial and nonantimicrobial) with documented capacity to inhibit, both in vit ro and in vivo, the connective tissue degrading activity of matrix met alloproteinases (MMPs). Of thee three MMPs that can degrade native hel ical collagens, MMP-13 (initially identified as rat osteoblast and hum an breast cancer collagenase, and now known to also be expressed by hu man cartilage and bone cells) is the most sensitive to TC inhibition ( IC50,, values in vitro generally less than 1 mu g/mL); the TCs inhibit both the collagenolytic as well as the gelatinolytic activity of this enzyme, The IC50,, for MMP-8 (neutrophil collagenase) in vitro ranges from 15 to 86 mu g/mL depending on assay conditions and choice of TC, whereas inhibition of the fibroblast enzyme (MMP-1) generally require s levels in excess of 200 mu g/mL (except for CMT-3), The TC compounds that are highly effective against MMP-13 in vitro are also highly inh ibitory of glycosaminoglycan release from interleukin-l-stimulated car tilage explants in culture, The current data correlate well with: (i) literature values for TC inhibition of bone resorption by isolated ost eoclasts; (ii) inhibition by TCs of avian tibial resorption in organ c ulture; and (iii) the dramatic ability of TCs to inhibit bone destruct ion in many rat models (rats have only MMP-8 and MMP-13, and no MMP-1) . By carefully selecting a TC-based MMP inhibitor and controlling dosa ges, it should he possible to inhibit pathologically excessive MMP-8 a nd/or MMP-13 activity, especially that causing bone erosion, without a ffecting the constitutive levels of MMP-1 needed for tissue remodeling and normal host function; in this regard, three newly developed CMTs (especially CMT-8 and, to a lesser extent, CMT-3 and -7) appear to be most effective. (C) 1998 by Elsevier Science Inc, All rights reserved.