title: Evaluation of the anti-inflammatory, anti-catabolic and pro-anabolic effects of E-caryophyllene, myrcene and limonene in a cell model of osteoarthritis.
abstract: Osteoarthritis is a progressive joint disease and a major cause of disability for which no curative therapies are yet available. To identify compounds with potential anti-osteoarthritic properties, in this study, we screened one sesquiterpene, E-caryophyllene, and two monoterpenes, myrcene and limonene, hydrocarbon compounds for anti-inflammatory, anti-catabolic and pro-anabolic activities in human chondrocytes. At non-cytotoxic concentrations, myrcene and limonene inhibited IL-1β-induced nitric oxide production (IC50=37.3μg/ml and 85.3µg/ml, respectively), but E-caryophyllene was inactive. Myrcene, and limonene to a lesser extent, also decreased IL-1β-induced NF-κB, JNK and p38 activation and the expression of inflammatory (iNOS) and catabolic (MMP-1 and MMP-13) genes, while increasing the expression of anti-catabolic genes (TIMP-1 and -3 by myrcene and TIMP-1 by limonene). Limonene increased ERK1/2 activation by 30%, while myrcene decreased it by 26%, relative to IL-1β-treated cells. None of the compounds tested was able to increase the expression of cartilage matrix-specific genes (collagen II and aggrecan), but both compounds prevented the increased expression of the non-cartilage specific, collagen I, induced by IL-1β. These data show that myrcene has significant anti-inflammatory and anti-catabolic effects in human chondrocytes and, thus, its ability to halt or, at least, slow down cartilage destruction and osteoarthritis progression warrants further investigation.
authors.affiliation: Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal. Electronic address: ana.t.rufino@gmail.com.
authors.forename: Ana Teresa
authors.initials: AT
authors.lastname: Rufino
authors.affiliation: Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal. Electronic address: madalena_ribeiro8@hotmail.com.
authors.forename: Madalena
authors.initials: M
authors.lastname: Ribeiro
authors.affiliation: Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal. Electronic address: catota_coura@hotmail.com.
authors.forename: Cátia
authors.initials: C
authors.lastname: Sousa
authors.affiliation: Orthopedics Department and Bone Bank, University and Hospital Center of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Electronic address: fernandojudas@gmail.com.
authors.forename: Fernando
authors.initials: F
authors.lastname: Judas
authors.affiliation: Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Centro de Estudos Farmacêuticos, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal. Electronic address: ligia@ff.uc.pt.
authors.forename: Lígia
authors.initials: L
authors.lastname: Salgueiro
authors.affiliation: Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Centro de Estudos Farmacêuticos, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal. Electronic address: Cavaleir@ff.uc.pt.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cavaleiro
authors.affiliation: Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal. Electronic address: afmendes@ff.uc.pt.
authors.forename: Alexandrina Ferreira
authors.initials: AF
authors.lastname: Mendes
mesh_terms: D000080462:Acyclic Monoterpenes; D000328:Adult; D000368:Aged; D053674:Aggrecans / Q000235:genetics; D000475:Alkenes / Q000494:pharmacology*; D045930:Anabolic Agents / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D019902:Chondrocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics; D024043:Collagen Type II / Q000235:genetics; D053138:Cyclohexenes / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000077222:Limonene; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D053509:Matrix Metalloproteinase 13 / Q000235:genetics; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D039821:Monoterpenes / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D010003:Osteoarthritis / Q000473:pathology*; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes / Q000494:pharmacology*; D013729:Terpenes / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics; D055815:Young Adult
chemical_list: D000080462:Acyclic Monoterpenes; D053674:Aggrecans; D000475:Alkenes; D045930:Anabolic Agents; D000893:Anti-Inflammatory Agents; D024042:Collagen Type I; D024043:Collagen Type II; D053138:Cyclohexenes; D053583:Interleukin-1beta; D039821:Monoterpenes; D016328:NF-kappa B; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes; C560822:TIMP1 protein, human; D013729:Terpenes; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D009569:Nitric Oxide; C509595:myrcene; D000077222:Limonene; C024714:caryophyllene; D052247:Nitric Oxide Synthase Type II; D020928:Mitogen-Activated Protein Kinases; D053509:Matrix Metalloproteinase 13; D020781:Matrix Metalloproteinase 1
keywords: Chronic inflammation; MAPK; NF-κB; Natural products; Osteoarthritis