title: MMP-9 inhibition suppresses wear debris-induced inflammatory osteolysis             through downregulation of RANK/RANKL in a murine osteolysis model.
abstract: Wear debris-induced osteolysis in periprosthetic tissue with aseptic loosening is a serious problem after total joint arthroplasty. Matrix metalloproteinase-9 (MMP-9) is expressed in osteoclast cells that surround loosening peri-implant tissue, but the molecular mechanism of MMP-9 action in wear debris-induced osteolysis remains ambiguous. We used a murine osteolysis model to examine the hypothesis that administration of an MMP-9 inhibitor reduces the expression of receptor activator of nuclear factor-κB (RANK) and nuclear factor-κB ligand (RANKL) and, thereby, suppressesdebris-induced inflammatory osteolysis. Experiments were performed in 3 groups of 15 mice: a control, a titanium (Ti) and a Ti plus tetracycline group. To provoke inflammatory osteolysis, calvarial bone was implanted from syngeneic littermates, followed by injection of Ti particles into established air pouches for all groups except the control. Tetracycline was administered daily by intraperitoneal (i.p.) injection, and PBS was administered by i.p. injection to the control and Ti groups. Mice were sacrificed 14 days after bone-Ti implantation. Pouch membranes with the intact bone implants were collected for histological and molecular analysis. Tetracycline had minimum effect on the expression of MMP-9 and tumor necrosis factor-α (TNF-α) but it decreased gene activation and inhibited the expression of RANK and RANKL, thereby inhibiting Ti-particle-induced inflammatory osteolysis. Tetracycline decreased the number of tartrate-resistant acid phosphatase (TRAP)-positive cells in the pouch tissues. Our results in the murine osteolysis model suggest that through the downregulation of RANK/RANKL, tetracycline significantly inhibits debris-induced inflammatory osteolysis. Its use in clinical practice may help prevent complications experienced by patients who have undergone total joint arthroplasty.
authors.affiliation: Department of Orthopaedics, The Sixth Affiliated People's Hospital,                     Shanghai Jiaotong University School of Medicine, Shanghai 200233, P.R.                     China.
authors.forename: Desheng
authors.initials: D
authors.lastname: Chen
authors.forename: Xianlong
authors.initials: X
authors.lastname: Zhang
authors.forename: Yongyuan
authors.initials: Y
authors.lastname: Guo
authors.forename: Sifeng
authors.initials: S
authors.lastname: Shi
authors.forename: Xin
authors.initials: X
authors.lastname: Mao
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Pan
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001178:Arthroplasty; D002454:Cell Differentiation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D010000:Osteitis / Q000188:drug therapy / Q000209:etiology; D010010:Osteoclasts / Q000502:physiology; D010014:Osteolysis / Q000209:etiology / Q000517:prevention & control*; D052638:Particulate Matter / Q000009:adverse effects; D011475:Prosthesis Failure; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism; D013752:Tetracycline / Q000494:pharmacology*; D014025:Titanium / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D052638:Particulate Matter; D011500:Protein Synthesis Inhibitors; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D014025:Titanium; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D013752:Tetracycline