title: Potential involvement of p53 in ischemia/reperfusion-induced osteonecrosis.
abstract: Idiopathic osteonecrosis of the femoral head (ION) is a devastating pathological condition of unknown etiology. In this study, we developed a simple murine model of osteonecrosis and investigated the underlying molecular mechanisms. In this model, the central portion of the tails of male C57BL/6 mice were tightly ligated to produce ischemic regions at sites distal to the ligatures. The occlusive ligatures were maintained for the indicated periods and then removed to induce reperfusion. The tails were histologically examined, and gene expression was analyzed by PCR array. The effect of p53 expression on osteocytes apoptosis was examined using preosteocytic MLO-A5 cells. In addition, the expression of p53 was analyzed in the femoral head samples obtained from hip osteoarthritis (OA) patients and ION patients. Caudal vertebrae distal to the ligatures (distal region) exhibited histological changes mimicking those observed in ION. Expression of p53 was increased in the distal region, and overexpression of p53 induced apoptosis in MLO-A5 cells. Treatment with a p53 inhibitor suppressed osteocyte apoptosis in the distal region. Strong p53 immunostaining was observed in osteocytes, vascular endothelial cells, and bone marrow cells in the femoral heads from ION patients but not from OA patients. Ischemia/reperfusion of the caudal vertebrae is a useful murine model of osteonecrosis, mimicking the histological changes found in ION. Using this model, we found the possible involvement of p53 in the osteocyte apoptosis observed in ION. Therapeutics targeting p53 might be a useful approach to ameliorating or even preventing osteonecrosis in ION patients.
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Okuma
authors.forename: Takefumi
authors.initials: T
authors.lastname: Kaketa
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Hikita
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuda
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakamura
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Nagase
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Oshima
authors.forename: Mitsuyasu
authors.initials: M
authors.lastname: Iwasawa
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kurosawa
authors.forename: Kozo
authors.initials: K
authors.lastname: Nakamura
authors.forename: Sakae
authors.initials: S
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005270:Femur Head / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D016158:Genes, p53; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010020:Osteonecrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013623:Tail / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53