title: Carnosol Inhibits Pro-Inflammatory and Catabolic Mediators of Cartilage Breakdown in Human Osteoarthritic Chondrocytes and Mediates Cross-Talk between Subchondral Bone Osteoblasts and Chondrocytes.
abstract: OBJECTIVE
  The aim of this work was to evaluate the effects of carnosol, a rosemary polyphenol, on pro-inflammatory and catabolic mediators of cartilage breakdown in chondrocytes and via bone-cartilage crosstalk.
  
  
  METHODS
  Osteoarthritic (OA) human chondrocytes were cultured in alginate beads for 4 days in presence or absence of carnosol (6 nM to 9 μM). The production of aggrecan, matrix metalloproteinase (MMP)-3, tissue inhibitor of metalloproteinase (TIMP)-1, interleukin (IL)-6 and nitric oxide (NO) and the expression of type II collagen and ADAMTS-4 and -5 were analyzed. Human osteoblasts from sclerotic (SC) or non-sclerotic (NSC) subchondral bone were cultured for 3 days in presence or absence of carnosol before co-culture with chondrocytes. Chondrocyte gene expression was analyzed after 4 days of co-culture.
  
  
  RESULTS
  In chondrocytes, type II collagen expression was significantly enhanced in the presence of 3 μM carnosol (p = 0.008). MMP-3, IL-6, NO production and ADAMTS-4 expression were down-regulated in a concentration-dependent manner by carnosol (p<0.01). TIMP-1 production was slightly increased at 3 μM (p = 0.02) and ADAMTS-5 expression was decreased from 0.2 to 9 μM carnosol (p<0.05). IL-6 and PGE2 production was reduced in the presence of carnosol in both SC and NSC osteoblasts while alkaline phosphatase activity was not changed. In co-culture experiments preincubation of NSC and SC osteoblasts wih carnosol resulted in similar effects to incubation with anti-IL-6 antibody, namely a significant increase in aggrecan and decrease in MMP-3, ADAMTS-4 and -5 gene expression by chondrocytes.
  
  
  CONCLUSIONS
  Carnosol showed potent inhibition of pro-inflammatory and catabolic mediators of cartilage breakdown in chondrocytes. Inhibition of matrix degradation and enhancement of formation was observed in chondrocytes cocultured with subchondral osteoblasts preincubated with carnosol indicating a cross-talk between these two cellular compartments, potentially mediated via inhibition of IL-6 in osteoblasts as similar results were obtained with anti-IL-6 antibody.
authors: Bone and Cartilage Research Unit, Arthropôle Liège, University of Liège, Liège, Belgium.
authors: Christelle
authors: C
authors: Sanchez
authors: Nutrition and Health, Nestle Research Center, Vers- chez- les- Blanc, Lausanne, Switzerland.
authors: Marie-Noëlle
authors: MN
authors: Horcajada
authors: Nutrition and Health, Nestle Research Center, Vers- chez- les- Blanc, Lausanne, Switzerland.
authors: Fanny
authors: F
authors: Membrez Scalfo
authors: Nutrition and Health, Nestle Research Center, Vers- chez- les- Blanc, Lausanne, Switzerland.
authors: Laurent
authors: L
authors: Ameye
authors: Nutrition and Health, Nestle Research Center, Vers- chez- les- Blanc, Lausanne, Switzerland.
authors: Elizabeth
authors: E
authors: Offord
authors: Bone and Cartilage Research Unit, Arthropôle Liège, University of Liège, Liège, Belgium; Physical Therapy and Rehabilitation Department, Princess Paola Hospital, Marche-en-Famenne, Belgium.
authors: Yves
authors: Y
authors: Henrotin
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D053674:Aggrecans / Q000276:immunology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology*; D018920:Coculture Techniques; D015232:Dinoprostone / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology; D019278:Matrix Metalloproteinase 3 / Q000276:immunology; D010003:Osteoarthritis / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D010006:Osteoblasts / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000276:immunology
chemical_list: D045784:Abietanes; D053674:Aggrecans; D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D019715:Tissue Inhibitor of Metalloproteinase-1; C068623:carnosol; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; D015232:Dinoprostone