The mitochondrial inhibitor oligomycin induces an inflammatory response in the rat knee jointReport as inadecuate




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BMC Musculoskeletal Disorders

, 18:254

Pathophysiology of musculoskeletal disorders

Abstract

BackgroundRecent findings support a connection between mitochondrial dysfunction and activation of inflammatory pathways in articular cells. This study investigates in vivo in an acute model whether intra-articular administration of oligomycin, an inhibitor of mitochondrial function, induces an oxidative and inflammatory response in rat knee joints.

MethodsOligomycin was injected into the rat left knee joint on days 0, 2, and 5 before joint tissues were obtained on day 6. The right knee joint served as control. Results were evaluated by macroscopy and histopathology and by measuring cellular and mitochondrial reactive oxygen species ROS, 4-hydroxy-2-nonenal 4-HNE, a marker of lipid peroxidation, nuclear factor erythroid 2-related factor 2 Nrf2, and CD68 macrophages and chemokine levels. The marker of mitochondrial mass COX-IV was also evaluated.

ResultsThe macroscopic findings showed significantly greater swelling in oligomycin-injected knees than in control knees. Likewise, the histological score of synovial damage was also increased significantly. Immunohistochemical studies showed high expression of IL-8, coinciding with a marked infiltration of polymorphonuclears and CD68+ cells in the synovium. Mitochondrial mass was increased in the synovium of oligomycin-injected joints, as well as cellular and mitochondrial ROS production, and 4-HNE. Relatedly, expression of the oxidative stress-related transcription factor Nrf2 was also increased. As expected, no histological differences were observed in the cartilage; however, cytokine-induced neutrophil chemoattractant-1 mRNA and protein expression were up-regulated in this tissue.

ConclusionsMitochondrial failure in the joint is able to reproduce the oxidative and inflammatory status observed in arthritic joints.

KeywordsMitochondria Inflammation Oxidative stress Synovial tissue Cartilage Abbreviations4-HNE4-hydroxy-2-nonenal

BSABovine serum albumin

CINC-1Cytokine-induced neutrophil chemoattractant-1

COX-IVCytochrome c oxidase subunit IV

DAPI4′,6-diamidino-2-phenylindole

DHEDihydroethidium

DMSODimethyl sulfoxide

HPRTHypoxanthine phosphoribosyltransferase

ILInterleukin

JIAJuvenile idiopathic arthritis

MitoSOXmitoSOX™ red mitochondrial superoxide indicator

MRCMitochondrial respiratory chain

mtDNAmitochondrial DNA

Nrf2Nuclear factor erythroid 2-related factor 2

OAOsteoarthritis

PBSPhosphate buffered saline

PMNPolymorphonuclear leukocytes

RARheumatoid arthritis

ROSReactive oxygen species

SODSuperoxide dismutase

Electronic supplementary materialThe online version of this article doi:10.1186-s12891-017-1621-2 contains supplementary material, which is available to authorized users.





Author: Carlos Vaamonde-García - Jesús Loureiro - Marta N. Valcárcel-Ares - Romina R. Riveiro-Naveira - Olalla Ramil-Gómez - La

Source: https://link.springer.com/







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