Abstract
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 μg/ml, which was reversed by Dox, 5 μg/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.
Similar content being viewed by others
References
L. M. Golub, H. M. Lee, G. Lehrer, N. S. Ramamurthy and T. F. McNamara,Minocycline reduces gingival collagenolytic activity during diabetes: Preliminary observations and a proposed new mechanism of action. J. Periodont. Res.18, 516–526 (1983).
R. A. Greenwald,Tetracycline derivatives as potential inhibitors of connective tissue degradation. Drug News Perspectives3, 161–166 (1990).
L. M. Golub, R. A. Greenwald, N. S. Ramamurthy, T. F. McNamara and B. Rifkin,Tetracyclines inhibit connective tissue breakdown: New therapeutic implications for an old family of drugs. Crit. Rev. Oral Biol. Med.2, 297–322 (1991).
R. A. Greenwald, S. A. Moak, N. S. Ramamurthy and L. M. Golub,Tetracyclines supress matrix metalloproteinase activity in adjuvant arthritis and in combination with flurbiprofen, ameliorate bone damage. J. Rheumatol.19, 927–938 (1992).
L. M. Golub, N. S. Ramamurthy, H. Kaneko, T. Sasaki, B. Rifkin and T. F. McNamara,Tetracycline administration prevents diabetes-induced osteopenia in the rat: Initial observations. Res. Commun Chem. Pathol. Pharmacol.68, 27–40 (1990).
B. R. Rifkin, L. M. Golub, F. Sanavi, A. T. Vernillo, A. P. Kleckner, T. F. McNamara, J. M. Auszmann and N. S. Ramamurthy,Effects of tetracyclines on rat osteoblast collagenase activity and bone resorption in vitro. InThe Biological Mechanisms of Tooth Movement and Craniofacial Adaptation. (Ed. Z. Davidovitch) pp. 261–267, EBSCO Media, Birmingham, AL 1991.
T. Sasaki, H. Kaneko, N. S. Ramamurthy and L. M. Golub,Tetracycline administration restores osteoblast structure and function during experimental diabetes. Anat. Rec.231, 25–34 (1991).
H. Kaneko, T. Sasaki, N. S. Ramamurthy and L. M. Golub,Tetracycline administration normalizes the structure and acid phosphatase activity of osteoclasts in streptozotocin-induced diabetic rats. Anat. Rec.227, 427–436 (1990).
T. Sasaki, N. S. Ramamurthy and L. M. Golub,Tetracycline administration increases collagen synthesis in osteoblasts of streptozotocin-induced diabetic rats: A quantitative autoradiographic study. Calcif. Tissue Int.50, 411–419 (1992).
L. M. Golub, T. F. McNamara, G. D'Angelo, R. A. Greenwald and N. S. Ramamurthy,A non-antibacterial chemically modified tetracycline inhibits mammalian collagenase activity. J. Dent. Res.66, 1310–1314 (1987).
A. Boyde, N. N. Ali and S. J. Jones,Resorption of dentine by isolated osteoclasts in vitro. Br. Dental J.156, 210–220 (1984).
T. J. Chambers, P. M. J. McSheehy, B. M. Thomson and K. Fuller,The effect of calcium regulating hormones and prostaglandins on bone resorption by osteoclasts disaggregated from neonatal rabbit bones. Endocrinology116, 234–239 (1985).
D. W. Dempster, R. J. Murrills, W. R. Horbert and T. R. Arnett,Biologic activity of chicken calcitonin: Effects on neonatal rat and embryonic chick osteoclasts. J. Bone Mineral Res.2, 443–448 (1987).
K. M. Wilbur and N. G. Anderson,Electrometric and colorimetric determination of carbonic anhydrase. J. Biol. Chem.176, 147–154 (1948).
R. Baron, Y. Eeckhout, L. Neff, C. Francois-Gillet, P. Henriet, J. M. Delaisse and G. Vaes,Affinity purified antibodies reveal the presence of (pro) collagenase in the subosteoclastic bone resorbing compartment. J. Bone Mineral Res.5 (Suppl. 2), 519 (1990).
V. Everts, J. M. Delaisse, W. Korper, A. Niehof, G. Vaes and W. Beertsen,Degradation of collagen in the bone resorbing compartment underlying the osteoclast involves both cysteine-proteinases and matrix metalloproteinase. J. Cell. Physiol.150, 221–231 (1992).
B. C. Gomes, L. M. Golub and N. S. Ramamurthy,Tetracyclines inhibit parathyroid hormone induced bone resorption in organ culture. Experientia40, 1273–1275 (1984).
G. C. Griffith, G. Nichols and J. D. Asher,Heparin osteoporosis. J. Am. Med. Assoc.193, 85–88 (1965).
T. Matzsch, D. Bergqvist, U. Hedner and B. Nilsson,Heparin induced osteoporosis in rats. Thromb. Haemostasis56, 293–294 (1986).
P. Goldhaber,Heparin enhancement of factors stimulating bone resorption in tissue culture. Science147, 407–408 (1965).
M. H. Chowdhury, C. Hamada and D. W. Dempster,Effect of heparin on osteoclast activity. J. Bone Mineral Res.7, 771–777 (1992).
K. Fuller, T. J. Chambers and A. C. Gallagher,Heparin augments osteoclast resorption-stimulating activity in serum. J. Cell Physiol.147, 208–214 (1991).
S. Sakamoto, M. Sakamoto, L. Goldberg, L. Colarusso and Y. Gotoh,Mineralization induced by beta-glycerophosphate in cultures leads to a marked increase in collagenase synthesis by mouse osteogenic MC3T3-E1 cells under subsequent stimulation with heparin. Biochem. Biophys. Res. Commun.162, 773–780 (1989).
N. S. Ramamurthy, A. T. Vernillo, H. M. Lee, L. M. Golub and B. R. Rifkin,The effect of tetracyclines on collagenase activity in UMR 106-01 rat osteoblastic osteosarcoma cells. Res. Commun Chem. Pathol. Pharmacol.70, 323–335 (1990).
K. H. Ibsen,Studies on the association of the tetracyclines with mineralized tissue. Clin. Orthop. Rel. Res.200, 85–86 (1985).
L. Saxen,Tetracyclines: Effect on osteogenesis in vitro. Sci.149, 870–872 (1965).
L. B. Engesaeter, T. Underdal and N. Langeland,Effects of oxytetracycline on mineralization of bone in young rats. Acta Orthop. Scand.51, 459–465 (1980).
D. J. Simmons, S. L. Chang, J. E. Russell, B. Grazman, D. Webster and C. Oloff,The effect of protracted tetracycline treatment on bone growth and maturation. Clin. Orthop. Rel. Res.180, 253–259 (1983).
J. Auszmann, A. Kleckner, A. Vernillo and B. R. Rifkin,Effect of tetracycline on osteoclast cathepsin L activity. J. Dent. Res.72, abstract no. 1928A (1992).
G. Vaes,Cellular biology and biochemical mechanism of bone resorption: A review of recent developments in the formation, activation and mode of action of osteoclasts. Clin. Orthop. Rel. Res.231, 239–271 (1988).
T. Ikamura, H. Shimokawa, Y. Takagi, H. Ono and S. Sasaki,Detection of collagenase mRNA in odontoclasts of bovine root resorbing tissue by in situ hybridization. Calcif. Tissue Int.52, 325–330 (1993).
Author information
Authors and Affiliations
Additional information
The Long Island Campus for the Albert Einstein College of Medicine
Rights and permissions
About this article
Cite this article
Chowdhury, M.H., Moak, S.A., Rifkin, B.R. et al. Effect of tetracyclines which have metalloproteinase inhibitory capacity on basal and heparin-stimulated bone resorption by chick osteoclasts. Agents and Actions 40, 124–128 (1993). https://doi.org/10.1007/BF01976761
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01976761