title: Biological effects of the plant-derived polyphenol resveratrol in human articular cartilage and chondrosarcoma cells.
abstract: The natural phytoestrogen resveratrol (RSV) may have therapeutic potential for arthritic conditions. RSV is chondroprotective for articular cartilage in rabbit models for arthritis, but its biological effects on human articular cartilage and chondrosarcoma cells are unknown. Effects of RSV on human articular cartilage homeostasis were studied by assessing production of matrix-degrading enzymes (MMP-13, ADAMTS4, and ADAMTS5), as well as proteoglycan production and synthesis. The counteractions of RSV against catabolic factors (e.g., FGF-2 or IL-1β) were examined by in vitro and ex vivo using monolayer, three-dimensional alginate beads and cartilage explants cultures, respectively. RSV improves cell viability of articular chondrocytes and effectively antagonizes cartilage-degrading protease production that was initiated by catabolic and/or anti-anabolic cytokines in human articular chondrocytes. RSV significantly also enhances BMP7-promoted proteoglycan synthesis as assessed by (35) S-sulfate incorporation. Protein-DNA interaction arrays suggest that RSV inhibits the activation of transcription factors involved in inflammation and cartilage catabolic signaling pathways, including direct downstream regulators of MAPK (e.g., AP-1, PEA3) and NFκB. RSV selectively compromises survival of human chondrosarcoma cells, but not primary articular chondrocytes, revealing cell-specific activity of RSV on non-tumorigenic versus tumor-derived cells. We propose that RSV exerts its chondroprotective functions, in part, by deactivating p53-induced apoptosis in human primary chondrocytes, but not human chondrosarcoma. Our findings suggest that RSV has potential as a unique biologic treatment for both prevention and treatment of cartilage degenerative diseases.
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA. hee-jeong_sampen@rush.edu
authors.forename: Hee-Jeong
authors.initials: HJ
authors.lastname: Im
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.forename: Dongyao
authors.initials: D
authors.lastname: Yan
authors.forename: Jaesung
authors.initials: J
authors.lastname: Kim
authors.forename: Michael B
authors.initials: MB
authors.lastname: Ellman
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.forename: Brian
authors.initials: B
authors.lastname: Cole
authors.forename: Ranjan
authors.initials: R
authors.lastname: Kc
authors.forename: Gabriella
authors.initials: G
authors.lastname: Cs-Szabo
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D002813:Chondrosarcoma / Q000188:drug therapy* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008660:Metabolism / Q000187:drug effects; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D010944:Plants / Q000737:chemistry; D059808:Polyphenols / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D016207:Cytokines; D004268:DNA-Binding Proteins; D053583:Interleukin-1beta; C121623:PSMF1 protein, human; D059808:Polyphenols; D011506:Proteins; D013267:Stilbenes; D014157:Transcription Factors; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; D000077185:Resveratrol