Inhibition of matrix metalloproteinase-9 activity by doxycycline ameliorates RANK ligand-induced osteoclast differentiation in vitro and in vivo

Journal Article · Fri Jun 10 00:00:00 EDT 2011 · Experimental Cell Research

DOI:https://doi.org/10.1016/J.YEXCR.2011.03.014· OSTI ID:22212144

Franco, Gilson C.N. ^[1]; Kajiya, Mikihito ^[1]; Nakanishi, Tadashi ^[1]; Ohta, Kouji ^[1]; Rosalen, Pedro L.; Groppo, Francisco C. ^[2]; Ernst, Cory W.O.; Boyesen, Janie L. ^[1]; Bartlett, John D.; Stashenko, Philip ^[3]; Taubman, Martin A. ^[1]; Kawai, Toshihisa ^[1]

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1. Department of Immunology, Forsyth Institute, Cambridge, MA (United States)
2. Department of Pharmacology, FOP/UNICAMP, Piracicaba, SP (Brazil)
3. Department of Cytokine Biology, Forsyth Institute, Cambridge, MA (United States)

Tetracycline antibiotics, including doxycycli/e (DOX), have been used to treat bone resorptive diseases, partially because of their activity to suppress osteoclastogenesis induced by receptor activator of nuclear factor kappa B ligand (RANKL). However, their precise inhibitory mechanism remains unclear. Therefore, the present study examined the effect of Dox on osteoclastogenesis signaling induced by RANKL, both in vitro and in vivo. Although Dox inhibited RANKL-induced osteoclastogenesis and down-modulated the mRNA expression of functional osteoclast markers, including tartrate-resistant acid phosphatase (TRAP) and cathepsin K, Dox neither affected RANKL-induced MAPKs phosphorylation nor NFATc1 gene expression in RAW264.7 murine monocytic cells. Gelatin zymography and Western blot analyses showed that Dox down-regulated the enzyme activity of RANKL-induced MMP-9, but without affecting its protein expression. Furthermore, MMP-9 enzyme inhibitor also attenuated both RANKL-induced osteoclastogenesis and up-regulation of TRAP and cathepsin K mRNA expression, indicating that MMP-9 enzyme action is engaged in the promotion of RANKL-induced osteoclastogenesis. Finally, Dox treatment abrogated RANKL-induced osteoclastogenesis and TRAP activity in mouse calvaria along with the suppression of MMP9 enzyme activity, again without affecting the expression of MMP9 protein. These findings suggested that Dox inhibits RANKL-induced osteoclastogenesis by its inhibitory effect on MMP-9 enzyme activity independent of the MAPK-NFATc1 signaling cascade.

• OSTI ID: 22212144
• Journal Information: Experimental Cell Research, Vol. 317, Issue 10; Other Information: Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0014-4827
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACID PHOSPHATASE
CATHEPSINS
ENZYME ACTIVITY
ENZYME INHIBITORS
GELATIN
IN VITRO
IN VIVO
INHIBITION
LIGANDS
MESSENGER-RNA
MICE
PHOSPHORYLATION
RECEPTORS
SKELETON
TETRACYCLINES