title: Nuclear receptors regulate lipid metabolism and oxidative stress markers in chondrocytes.
abstract: Joint homeostasis failure can result in osteoarthritis (OA). Currently, there are no treatments to alter disease progression in OA, but targeting early changes in cellular behavior has great potential. Recent data show that nuclear receptors contribute to the pathogenesis of OA and could be viable therapeutic targets, but their molecular mechanisms in cartilage are incompletely understood. This study examines global changes in gene expression after treatment with agonists for four nuclear receptor implicated in OA (LXR, PPARδ, PPARγ, and RXR). Murine articular chondrocytes were treated with agonists for LXR, PPARδ, PPARγ, or RXR and underwent microarray, qPCR, and cellular lipid analyses to evaluate changes in gene expression and lipid profile. Immunohistochemistry was conducted to compare two differentially expressed targets (Txnip, Gsta4) in control and cartilage-specific PPARδ knockout mice subjected to surgical destabilization of the medial meniscus (DMM). Nuclear receptor agonists induced different gene expression profiles with many responses affecting lipid metabolism. LXR activation downregulated gene expression of proteases involved in OA, whereas RXR agonism decreased expression of ECM components and increased expression of Mmp13. Functional assays indicate increases in cell triglyceride accumulation after PPARγ, LXR, and RXR agonism but a decrease after PPARδ agonism. PPARδ and RXR downregulate the antioxidant Gsta4, and PPARδ upregulates Txnip. Wild-type, but not PPARδ-deficient mice, display increased staining for Txnip after DMM. Collectively, these data demonstrate that nuclear receptor activation in chondrocytes primarily affects lipid metabolism. In the case of PPARδ, this change might lead to increased oxidative stress, possibly contributing to OA-associated changes.
  
  
  
  Nuclear receptors regulate metabolic genes in chondrocytes. Nuclear receptors affect triglyceride levels. PPARδ mediates regulation of oxidative stress markers. Nuclear receptors are promising therapeutic targets for osteoarthritis.
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada.|Western Bone & Joint Institute, University of Western Ontario, London, ON, Canada.
authors.forename: Anusha
authors.initials: A
authors.lastname: Ratneswaran
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada.|Western Bone & Joint Institute, University of Western Ontario, London, ON, Canada.
authors.forename: Margaret Man-Ger
authors.initials: MM
authors.lastname: Sun
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada.|Western Bone & Joint Institute, University of Western Ontario, London, ON, Canada.
authors.forename: Holly
authors.initials: H
authors.lastname: Dupuis
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Sawyez
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada.
authors.forename: Nica
authors.initials: N
authors.lastname: Borradaile
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada. fbeier@uwo.ca.|Western Bone & Joint Institute, University of Western Ontario, London, ON, Canada. fbeier@uwo.ca.
authors.forename: Frank
authors.initials: F
authors.lastname: Beier
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D050356:Lipid Metabolism; D000071518:Liver X Receptors / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D047494:PPAR delta / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000378:metabolism
chemical_list: D000071518:Liver X Receptors; D047494:PPAR delta; D047495:PPAR gamma; D018160:Receptors, Cytoplasmic and Nuclear; D047488:Retinoid X Receptors
keywords: Cartilage; Chondrocyte; Lipid metabolism; Osteoarthritis; Oxidative stress