title: Involvement of necroptosis, a newly recognized cell death type, in steroid-induced osteonecrosis in a rabbit model.
abstract: We investigated the role of programmed necrosis (necroptosis), a newly recognized form of cell necrosis that has been implicated in the development of steroid-induced osteonecrosis. We used an osteonecrosis model in which 30 Japanese white rabbits each weighing 3.5kg were injected once with methylprednisolone at 20 mg/kg body weight into the right gluteal muscle. Ten animals killed 14 days thereafter were designated as S14d groups, while another 10 animals injected with necroptosis, a specific inhibitor of necrostatin-1 i.v. at 1.65mg/kg on the same day as the steroid were also killed on the 14thday and designated as SN14d group. As a control, 10 animals injected only with physiological saline were studied as N group. After the animals were sacrificed the bilateral femoral bone was examined histopathologically and the presence of osteonecrosis determined. Furthermore, animals subjected to the same treatment and killed on the 3rdday after drug administration were set up as S3d group and SN3d group, and Western blotting of Receptor-interacting protein ( RIP ) 1 and RIP3 in femoral bone performed. The osteonecrosis rate was 70% in S14d group, and 0% in both N and SN groups. In 2 of 10 animals in SN group fatty marrow was found. On Western blotting significantly increased expression of both RIP1 and RIP3 was noted in S3d group, confirming that Nec-1 was suppressed. Necroptosis mediated by RIP1 and RIP3 expression was thought to be implicated in the development of steroid-induced osteonecrosis. Also, by suppressing expression of RIP1 and 3 with the administration of Nec-1 the osteonecrosis rate was significantly decreased. These results suggest that necroptosis may have potential as a novel target for both elucidating the mechanisms underlying steroid-induced osteonecrosis and establishing more effective prophylactic countermeasures.
authors.affiliation: Department of Orthopaedic Surgery, Kanazawa Medical University, Daigaku 1-1, Uchinada, Kahoku-gun, Ishikawa, 920-0293, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Ichiseki
authors.affiliation: Department of Orthopaedic Surgery, Kanazawa Medical University, Daigaku 1-1, Uchinada, Kahoku-gun, Ishikawa, 920-0293, Japan.
authors.forename: Shusuke
authors.initials: S
authors.lastname: Ueda
authors.affiliation: Department of Pathology, Kanazawa Medical University, Daigaku 1-1, Uchinada, Kahoku-gun, Ishikawa, 920-0293, Japan.
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Department of Orthopaedic Surgery, Kanazawa Medical University, Daigaku 1-1, Uchinada, Kahoku-gun, Ishikawa, 920-0293, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Tuchiya
authors.affiliation: Department of Orthopaedic Surgery, Kanazawa Medical University, Daigaku 1-1, Uchinada, Kahoku-gun, Ishikawa, 920-0293, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kaneuji
authors.affiliation: Department of Orthopaedic Surgery, Kanazawa Medical University, Daigaku 1-1, Uchinada, Kahoku-gun, Ishikawa, 920-0293, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Kawahara
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D008297:Male; D009336:Necrosis / Q000378:metabolism* / Q000503:physiopathology*; D010020:Osteonecrosis / Q000378:metabolism* / Q000503:physiopathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011817:Rabbits; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D013256:Steroids / Q000494:pharmacology*
chemical_list: D013256:Steroids; D017346:Protein Serine-Threonine Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases
keywords: necroptosis; necrostatin-1 (nec-1).; receptor-interacting protein (RIP); steroid-induced osteonecrosis