title: Protection against titanium particle-induced inflammatory osteolysis by the proteasome inhibitor bortezomib in vivo.
abstract: Wear particle-induced vascularized granulomatous inflammation and subsequent inflammatory osteolysis is the most common cause of aseptic loosening after total joint replacement (TJR); however, the precise mechanism by which this occurs is unclear. This study investigates the effects of the proteasome inhibitor bortezomib (Bzb) on the expression of key biochemical markers of bone metabolism and vascularised granulomatous tissues, such as receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), vascular endothelial growth factor (VEGF) and tumor necrosis factor receptor-associated factor 6 (TRAF6). In addition, the effect of Bzb on apoptosis of CD68+ cells was examined. A total of 32 female BALB/C mice were randomly divided into four groups. After implantation of calvaria bone from syngeneic littermates, titanium (Ti) particles were injected into established air pouches for all mice (excluding negative controls) to provoke inflammatory osteolysis. Subsequently, Bzb was administered at a ratio of 0, 0.1, or 0.5 mg/kg on day 1, 4, 8, and 11 post-surgery to alleviate this response. All of the air pouches were harvested 14 days after the surgical procedure and were processed for molecular and histological analysis. The results demonstrated that Ti injection elevated the expression of RANKL, OPG, VEGF, and TRAF6 at both the gene and protein levels, increased counts of infiltrated cells and thickness of air pouch membranes, and elevated the apoptosis index (AI) of CD68+ cells. Bzb treatment significantly improved Ti particle-induced implanted bone osteolysis, attenuated vascularised granulomatous tissues and elevated AI of CD68+ cells. Therefore, the proteasome pathway may represent an effective therapeutic target for the prevention and treatment of aseptic loosening.
authors.affiliation: Department of Orthopaedics, Sixth Affiliated People's Hospital, Shanghai Jiaotong University School of Medicine, 600 Yishan Road, Shanghai, 200233, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Mao
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Pan
authors.forename: Song
authors.initials: S
authors.lastname: Zhao
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Peng
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
authors.forename: Xianlong
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000187:drug effects; D015214:Antigens, Differentiation, Myelomonocytic / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D019643:Arthroplasty, Replacement / Q000009:adverse effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D005260:Female; D007249:Inflammation / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D010014:Osteolysis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control*; D053244:Osteoprotegerin / Q000096:biosynthesis; D011475:Prosthesis Failure / Q000187:drug effects; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D053245:RANK Ligand / Q000096:biosynthesis; D011897:Random Allocation; D048029:TNF Receptor-Associated Factor 6 / Q000096:biosynthesis; D014025:Titanium; D042442:Vascular Endothelial Growth Factors / Q000096:biosynthesis; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001897:Boronic Acids; D000069286:Bortezomib; D053244:Osteoprotegerin; D061988:Proteasome Inhibitors; D011719:Pyrazines; D053245:RANK Ligand; D048029:TNF Receptor-Associated Factor 6; D014025:Titanium; D042442:Vascular Endothelial Growth Factors; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C505689:Tnfsf11 protein, mouse