title: Osteocytic cell necrosis is caused by a combination of glucocorticoid-induced Dickkopf-1 and hypoxia.
abstract: Osteonecrosis is a major glucocorticoid-induced complication in the orthopedics field. Despite the extensive researches, mechanisms underlining the glucocorticoid-induced osteonecrosis are largely unknown. Here, we first provide the evidence that a combined treatment of cultured osteocytic cells with glucocorticoid and hypoxia caused necrotic cell death, which is assumed to occur in the acute bone injuries induced by glucocorticoids. We cultured MLO-Y4 murine osteocytic cells under hypoxia in the presence or absence of Dexamethasone (Dex) and examined the rates of apoptotic and necrotic cell death. Dex or hypoxia alone increased apoptotic cells, but not necrotic cells. The combination of Dex and hypoxia dramatically increased osteocytic cell death, notably necrotic cell death. The expression of Dickkopf-1 (Dkk-1), an inhibitor of Wnt/β-catenin signal, was scarcely expressed in the control and hypoxic cells, but a dramatic increase of the Dkk-1 expression was detected in Dex-treated cells. siRNA-mediated knockdown of Dkk-1 in Dex and hypoxia-treated osteocytic cells showed the significant decreases in both apoptotic and necrotic cells. The results indicated that the combination of Dkk-1 overexpression by Dex and hypoxia causes the necrotic osteocytic cell death. The results also indicated that blocking of Dkk-1 can protect bone cells from glucocorticoid and hypoxia-induced cell injury.
authors.affiliation: Department of Orthopaedic Surgery, Kanazawa Medical University, Daigaku 1-1, Uchinada-machi, Kahoku-gun, Ishikawa, 920-0293, Japan.
authors.forename: Shusuke
authors.initials: S
authors.lastname: Ueda
authors.forename: Toru
authors.initials: T
authors.lastname: Ichiseki
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yoshitomi
authors.forename: Hideto
authors.initials: H
authors.lastname: Yonekura
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Ueda
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kaneuji
authors.forename: Tadami
authors.initials: T
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003907:Dexamethasone / Q000009:adverse effects; D005938:Glucocorticoids / Q000378:metabolism; D000860:Hypoxia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D009336:Necrosis / Q000139:chemically induced / Q000378:metabolism*; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: C501127:Dkk1 protein, mouse; D005938:Glucocorticoids; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D003907:Dexamethasone