title: Haem oxygenase-1 counteracts the effects of interleukin-1β on inflammatory and senescence markers in cartilage-subchondral bone explants from osteoarthritic patients.
abstract: IL (interleukin)-1β plays an important role in cartilage extracellular matrix degradation and bone resorption in OA (osteoarthritis) through the induction of degradative enzymes and pro-inflammatory mediators. In the present study, we have determined the consequences of HO-1 (haem oxygenase-1) induction on markers of inflammation and senescence in the functional unit cartilage-subchondral bone stimulated with IL-1β. Cartilage-subchondral bone specimens were obtained from the knees of osteoarthritic patients. Treatment with the HO-1 inducer CoPP (cobalt protoporphyrin IX) counteracted the stimulatory effects of IL-1β on IL-6, nitrite, PGE2 (prostaglandin E2), TGF (transforming growth factor) β2, TGFβ3 and osteocalcin. Immunohistochemical analyses indicated that CoPP treatment of explants down-regulated iNOS (inducible nitric oxide synthase), COX-2 (cyclooxygenase-2) and mPGES-1 (microsomal prostaglandin E synthase-1) induced by IL-1β. In contrast, the expression of HMGB1 (high-mobility group box 1) was not significantly modified. In addition, CoPP decreased the expression of iNOS and mPGES-1 in cells isolated from the explants and stimulated with IL-1β, which was counteracted by an siRNA (small interfering RNA) specific for human HO-1. In isolated primary chondrocytes, we determined senescence-associated β-galactosidase activity and the expression of senescence markers by real-time PCR. We have found that HO-1 induction could regulate senescence markers in the presence of IL-1β and significantly affected telomerase expression, as well as β-galactosidase activity and hTERT (human telomerase reverse transcriptase) and p21 expression in chondrocytes. The findings of the present study support the view that HO-1 induction results in the down-regulation of inflammatory and senescence responses in OA articular tissues.
authors.affiliation: Department of Pharmacology, University of Valencia, and IDM, Av. Vicent A. Estellés s/n, 46100 Burjasot, Valencia, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Clérigues
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Guillén
authors.forename: Francisco
authors.initials: F
authors.lastname: Gomar
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Alcaraz
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D001862:Bone Resorption; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D016922:Cellular Senescence; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D015536:Down-Regulation; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D000071876:Prostaglandin-E Synthases; D011524:Protoporphyrins / Q000494:pharmacology; D034741:RNA, Small Interfering
chemical_list: D015415:Biomarkers; D053583:Interleukin-1beta; D015850:Interleukin-6; D011524:Protoporphyrins; D034741:RNA, Small Interfering; C007095:cobaltiprotoporphyrin; D052247:Nitric Oxide Synthase Type II; D006419:Heme Oxygenase (Decyclizing); D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone