title: Cytoskeletal dissolution blocks oxidant release and cell death in injured cartilage.
abstract: The mechanisms by which articular surface impact causes post-traumatic osteoarthritis are not well understood, but studies of cartilage explants implicate the mitochondrial electron transport chain as a source of oxidants that cause chondrocyte death from mechanical injury. The linkage of mitochondria to the cytoskeleton suggests that they might release oxidants in response to mechanical strain, an effect that disrupting the cytoskeleton would prevent. To test this we investigated the effects of agents that promote the dissolution of microfilaments (cytochalasin B) or microtubules (nocodazole) on oxidant production and chondrocyte death following impact injury. Osteochondral explants treated with cytochalasin B or nocodazole for 4 h were impacted (7 J/cm(2)) and stained for oxidant production directly after impact and for cell viability 24 h after impact. Surfaces within and outside impact sites were then imaged by confocal microscopy. Both agents significantly reduced impact-induced oxidant release (p < 0.05); however, cytochalasin B was more effective than nocodazole (>60% reduction vs. 40% reduction, respectively). Both agents also prevented impact induced cell death. Dissolution of the cytoskeleton by both drugs was confirmed by phalloidin staining and confocal microscopy. These findings show that chondrocyte mortality from impact injury depends substantially on mitochondrial-cytoskeletal linkage, suggesting new approaches to stem mechanically induced cartilage degeneration.
authors.affiliation: University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Sauter
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Buckwalter
authors.forename: Todd O
authors.initials: TO
authors.lastname: McKinley
authors.forename: James A
authors.initials: JA
authors.lastname: Martin
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002417:Cattle; D016923:Cell Death / Q000502:physiology*; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D003571:Cytochalasin B / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D008592:Menisci, Tibial / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism; D015739:Nocodazole / Q000494:pharmacology; D016877:Oxidants / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000070600:Tibial Meniscus Injuries; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D000199:Actins; D016877:Oxidants; D017382:Reactive Oxygen Species; D050257:Tubulin Modulators; D003571:Cytochalasin B; D015739:Nocodazole