title: Free fatty acid palmitate activates unfolded protein response pathway and promotes apoptosis in meniscus cells.
abstract: BACKGROUND
  Obesity is the major risk factor for the development of osteoarthritis (OA); however, the mechanisms involved are not clearly understood. Obesity is associated with increased production of adipokine and elevated levels of circulating free fatty acids (FFA). A recent study has shown that saturated fatty acid palmitate induced pro-inflammatory and pro-apoptotic pathways in chondrocytes. Meniscus has been shown to be more susceptible than articular cartilage to catabolic stimuli. Thus, the aim of this study was to determine the effect of FFA (specifically, palmitate) on meniscus cells.
  
  
  METHODS
  Cultured primary porcine meniscus cells were stimulated with 500 μM FFA (palmitate and oleate) for 24 h to induce endoplasmic reticulum (ER) stress. After treatment, cell lysates were prepared and immunoblotted for C/EBP homologous protein (CHOP). To determine the activation of unfolded protein response (UPR) signaling, cell lysates were probed for cJun n-terminal kinase (JNK), cleaved caspase -3 and Xbp-1s, an alternative mRNA splicing product generated due to Ire1α activation.
  
  
  RESULTS
  Treatment of isolated primary meniscus cells with palmitate but not oleate induced expression of CHOP and Xbp-1s. Palmitate treatment of meniscus cells also activated JNK and increased expression of caspase-3, thus promoting apoptosis in meniscus cells.
  
  
  CONCLUSIONS
  Palmitate induces ER stress and promotes apoptotic pathways in meniscus cells. This is the first study to establish ER stress as a key metabolic mechanistic link between obesity and OA, in addition to (or operating with) biomechanical factors.
authors.affiliation: Section of Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA. Electronic address: jhaywood@wakehealth.edu.
authors.forename: J
authors.initials: J
authors.lastname: Haywood
authors.affiliation: Section of Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA. Electronic address: ryammani@wakehealth.edu.
authors.forename: R R
authors.initials: RR
authors.lastname: Yammani
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology; D000072600:Meniscus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010168:Palmitates / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D034421:Sus scrofa; D056811:Unfolded Protein Response / Q000187:drug effects* / Q000502:physiology
chemical_list: D010168:Palmitates
keywords: Apoptosis; Endoplasmic reticulum stress; Free fatty acids; Meniscus; Unfolded protein response (UPR)