title: A preliminary in vitro and in vivo study of the effects of new anthraquinones on neutrophils and bone remodeling.
abstract: Osteolysis, that is, progressive periprosthetic bone loss, is responsible for approximately 70% of aseptic loosening and implant failure. Usually, it is due to a granulomatous reaction wear-induced, leading to macrophage and osteoclast-mediated bone resorption. At present, there is no established prophylaxis or treatment for this process. For this purpose, as a preliminary investigation, we aimed to study the effects in two directions, inhibition of proinflammatory signals, and bone remodeling activity, of two newly synthesized anthraquinone molecules [N,N'-Diethylamino-2,6-anthraquinone-disulfonamide (GR375) and N,N'-(p-ethoxyphenyl)-2,6-anthraquinone-disulfon amide (GR377)]. Among the pro-inflammatory signals, the ability of the two anthraquinones to interfere with the production of superoxide anion (O(2) (-)), which was assumed as a marker of reactive oxygen species (ROS), was evaluated in an in vitro cell model by testing phagocytes, such as human neutrophils, challenged by the chemotactic agent N-formylmethionyl-leucyl-phenylalanine (FMLP). Both compounds inhibited O(2) (-) production, in a dose-dependent way, without exerting scavenger effects. An in vivo model was applied to investigate their effect on bone remodeling. Fifty-four female Wistar rats were divided into eight groups of six animals each, and a 4-week treatment was applied in two phases. A 25 mg/kg/os dose in the first phase and 12.5-6.25 mg/kg/os doses in the second one were employed. The tibia trabecular bone at the secondary spongiosa level was analyzed, and trabecular bone volume (%TBV), trabecular thickness (TbTh), and apatite lattice parameters were measured. At the highest doses of GR375 and GR377 the %TBV and the TbTh increased by 33.2, 34.6%, and 3.6 and 9.1%, respectively, whereas crystallographic parameters were not significantly different from the untreated group. Our results suggest a simultaneous antiinflammatory and antiosteoclastic activity of both drugs that encourages to perform further research. If it will be confirmed, they could be proposed in a variety of bone diseases, in particular, when acute inflammation is associated to osteolytic processes and, eventually, in the prevention and treatment of periprosthetic osteolysis.
authors.affiliation: Laboratory for Pathophysiology of Orthopaedic Implants, Istituti Ortopedici Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy. lucia.savarino@ior.it
authors.forename: L
authors.initials: L
authors.lastname: Savarino
authors.forename: D
authors.initials: D
authors.lastname: Benetti
authors.forename: N
authors.initials: N
authors.lastname: Baldini
authors.forename: C
authors.initials: C
authors.lastname: Tarabusi
authors.forename: M
authors.initials: M
authors.lastname: Greco
authors.forename: R
authors.initials: R
authors.lastname: Aloisi
authors.forename: S
authors.initials: S
authors.lastname: Frascarelli
authors.forename: R
authors.initials: R
authors.lastname: Fantozzi
authors.forename: C
authors.initials: C
authors.lastname: Dianzani
authors.forename: M
authors.initials: M
authors.lastname: Mian
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology*; D016723:Bone Remodeling / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006801:Humans; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010014:Osteolysis / Q000503:physiopathology; D011475:Prosthesis Failure; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013977:Tibia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014961:X-Ray Diffraction
chemical_list: D000880:Anthraquinones; D017382:Reactive Oxygen Species; D013481:Superoxides