Inhibition of matrix metalloproteinase-9 activity by doxycycline ameliorates RANK ligand-induced osteoclast differentiation in vitro and in vivo.
Inhibition of matrix metalloproteinase-9 activity by doxycycline ameliorates RANK ligand-induced osteoclast differentiation in vitro and in vivo.
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DOI：
10.1016/j.yexcr.2011.03.014
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发表时间：
2011-06-10
影响因子：
3.7
通讯作者：
Kawai, Toshihisa
中科院分区：
文献类型：
--
作者：
Franco, Gilson C. N.;Kajiya, Mikihito;Nakanishi, Tadashi;Ohta, Kouji;Rosalen, Pedro L.;Groppo, Francisco C.;Ernst, Cory W. O.;Boyesen, Janie L.;Bartlett, John D.;Stashenko, Philip;Taubman, Martin A.;Kawai, Toshihisa
四环素抗生素，包括强力霉素 (DOX)，已被用于治疗骨吸收疾病，部分原因是它们具有抑制核因子 kappa B 配体受体激活剂 (RANKL) 诱导的破骨细胞生成的活性。然而，它们的精确抑制机制仍不清楚。因此，本研究在体外和体内检查了 Dox 对 RANKL 诱导的破骨细胞生成信号传导的影响。尽管Dox抑制RANKL诱导的破骨细胞生成并下调功能性破骨细胞标志物的mRNA表达，包括抗酒石酸酸性磷酸酶（TRAP）和组织蛋白酶K，但Dox既不影响RAW264.7小鼠单核细胞中RANKL诱导的MAPK磷酸化也不影响NFATc1基因表达。明胶酶谱和蛋白质印迹分析表明，Dox 下调 RANKL 诱导的 MMP-9 的酶活性，但不影响其蛋白表达。此外，MMP-9酶抑制剂还减弱RANKL诱导的破骨细胞生成以及TRAP和组织蛋白酶K mRNA表达的上调，表明MMP-9酶的作用参与促进RANKL诱导的破骨细胞生成。最后，Dox 治疗消除了 RANKL 诱导的小鼠颅骨破骨细胞生成和 TRAP 活性，同时抑制了 MMP9 酶活性，同样不影响 MMP9 蛋白的表达。这些发现表明，Dox 通过对 MMP-9 酶活性的抑制作用来抑制 RANKL 诱导的破骨细胞生成，而与 MAPK-NFATc1 信号级联无关。
Tetracycline antibiotics, including Doxycycline (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 osteoclstogenesis. 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.
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影响因子：
4.3
作者：
Crout, RJ;Lee, HM;Golub, LM
通讯作者：
Golub, LM
影响因子：
3.1
作者：
Li, L;Khansari, A;Amar, S
通讯作者：
Amar, S
影响因子：
4.4
作者：
Hayashi, SI;Yamada, T;Yamazaki, H
通讯作者：
Yamazaki, H
影响因子：
4.7
作者：
George, Saby;Brenner, Andrew;Bukowski, Ronald M.
通讯作者：
Bukowski, Ronald M.
DOI：
10.1111/j.1749-6632.1994.tb24733.x
发表时间：
1994-01-01
期刊：
INHIBITION OF MATRIX METALLOPROTEINASES: THERAPEUTIC POTENTIAL
影响因子：
--
作者：
RIFKIN, BR;VERNILLO, AT;RAMAMURTHY, NS
通讯作者：
RAMAMURTHY, NS