title: Palmitate has proapoptotic and proinflammatory effects on articular cartilage and synergizes with interleukin-1.
abstract: OBJECTIVE
  Obesity is a major risk factor for the development of osteoarthritis (OA) that is associated with a state of low-grade inflammation and increased circulating levels of adipokines and free fatty acids (FFAs). The aim of this study was to analyze the effects of saturated (palmitate) and monounsaturated (oleate) FFAs on articular chondrocytes, synoviocytes, and cartilage.
  
  
  METHODS
  Human articular chondrocytes and fibroblast-like synoviocytes obtained from young healthy donors and OA chondrocytes from patients undergoing total knee replacement surgery were treated with palmitate or oleate alone or in combination with interleukin-1β (IL-1β). Cell viability, caspase activation, and gene expression of proinflammatory factors, extracellular matrix (ECM) proteins, and proteases were studied. In addition, chondrocyte viability, IL-6 production, and matrix damage were assessed in bovine and human articular cartilage explants cultured with FFAs in the presence or absence of IL-1β.
  
  
  RESULTS
  Palmitate, but not oleate, induced caspase activation and cell death in IL-1β-stimulated normal chondrocytes, and up-regulated the expression of IL-6 and cyclooxygenase 2 in chondrocytes and fibroblast-like synoviocytes through Toll-like receptor 4 (TLR-4) signaling. In cartilage explants, palmitate induced chondrocyte death, IL-6 release, and ECM degradation. Palmitate synergized with IL-1β in stimulating proapoptotic and proinflammatory cellular responses. Pharmacologic inhibition of caspases or TLR-4 signaling reduced palmitate and IL-1β induced cartilage damage.
  
  
  CONCLUSIONS
  Palmitate acts as a proinflammatory and catabolic factor that, in synergy with IL-1β, induces chondrocyte apoptosis and articular cartilage breakdown. Collectively, our data suggest that elevated levels of saturated FFAs that are often found in patients who are obese may contribute to the pathogenesis of OA.
authors.affiliation: The Scripps Research Institute, La Jolla, California.
authors.forename: Oscar
authors.initials: O
authors.lastname: Alvarez-Garcia
authors.forename: Nicole H
authors.initials: NH
authors.lastname: Rogers
authors.forename: Roy G
authors.initials: RG
authors.lastname: Smith
authors.forename: Martin K
authors.initials: MK
authors.lastname: Lotz
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D002358:Cartilage, Articular / Q000187:drug effects* / Q000276:immunology; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000276:immunology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology; D004357:Drug Synergism; D005109:Extracellular Matrix / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D053583:Interleukin-1beta / Q000276:immunology / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008875:Middle Aged; D019301:Oleic Acid / Q000276:immunology / Q000494:pharmacology; D020370:Osteoarthritis, Knee / Q000188:drug therapy* / Q000276:immunology; D010168:Palmitates / Q000276:immunology / Q000494:pharmacology*; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
chemical_list: D005230:Fatty Acids, Nonesterified; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D010168:Palmitates; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D019301:Oleic Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human