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Review article: Biomedical intelligence

Vol. 144 No. 4950 (2014)

Adopted orphans as regulators of inflammation, immunity and skeletal homeostasis

  • Natacha Ipseiz
  • Carina Scholtysek
  • Stephan Culemann
  • Gerhard Krönke
DOI
https://doi.org/10.4414/smw.2014.14055
Cite this as:
Swiss Med Wkly. 2014;144:w14055
Published
30.11.2014

Summary

Adopted orphan nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs) and liver X receptors (LXRs), have emerged as key regulators of inflammation and immunity and likewise control skeletal homeostasis. These properties render them attractive targets for the therapy of various inflammatory and autoimmune diseases affecting the musculoskeletal system. This review summarises the current knowledge on the role of these families of receptors during innate and adaptive immunity as well as during the control of bone turnover and discuss the potential use of targeting these molecules during the treatment of chronic diseases such as osteoarthritis, rheumatoid arthritis and osteoporosis.

References

  1. Baschant U, Lane NE, Tuckermann J. The multiple facets of glucocorticoid action in rheumatoid arthritis. Nat Rev Rheumatol. 2012;8:645–55.
  2. Evans RM, Mangelsdorf DJ. Nuclear Receptors, RXR, and the Big Bang. Cell. 2014;157:255–66.
  3. Sever R, Glass CK. Signaling by nuclear receptors. Cold Spring Harb Perspect Biol. 2013;5:a016709.
  4. Kadmiel M, Cidlowski JA. Glucocorticoid receptor signaling in health and disease. Trends Pharmacol Sci. 2013;34:518–30.
  5. Baschant U, Culemann S, Tuckermann J. Molecular determinants of glucocorticoid actions in inflammatory joint diseases. Mol Cell Endocrinol. 2013;380:108–18.
  6. Kronke G, Kadl A, Ikonomu E, Bluml S, Furnkranz A, Sarembock IJ, et al. Expression of heme oxygenase-1 in human vascular cells is regulated by peroxisome proliferator-activated receptors. Arterioscler Thromb Vasc Biol. 2007;27:1276–82.
  7. Kiss M, Czimmerer Z, Nagy L. The role of lipid-activated nuclear receptors in shaping macrophage and dendritic cell function: From physiology to pathology. J Allergy Clin Immunol. 2013;132:264–86.
  8. Adhikary T, Kaddatz K, Finkernagel F, Schonbauer A, Meissner W, Scharfe M, et al. Genomewide analyses define different modes of transcriptional regulation by peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta). PLoS One 2011;6:e16344.
  9. Glass CK, Saijo K. Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat Rev Immunol. 2010;10:365–76.
  10. Perissi V, Jepsen K, Glass CK, Rosenfeld MG. Deconstructing repression: evolving models of co-repressor action. Nat Rev Genet. 2010;11:109–23.
  11. Pascual G, Fong AL, Ogawa S, Gamliel A, Li AC, Perissi V, et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature. 2005;437:759–63.
  12. Ghisletti S, Huang W, Jepsen K, Benner C, Hardiman G, Rosenfeld MG, et al. Cooperative NCoR/SMRT interactions establish a corepressor-based strategy for integration of inflammatory and anti-inflammatory signaling pathways. Genes Dev. 2009;23:681–93.
  13. Ghisletti S, Huang W, Ogawa S, Pascual G, Lin ME, Willson TM, et al. Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARgamma. Mol Cell. 2007;25:57–70.
  14. Straus DS, Glass CK. Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol. 2007;28:551–8.
  15. Mulholland DJ, Dedhar S, Coetzee GA, Nelson CC. Interaction of nuclear receptors with the Wnt/beta-catenin/Tcf signaling axis: Wnt you like to know? Endocr Rev. 2005;26:898–915.
  16. Scholtysek C, Katzenbeisser J, Fu H, Uderhardt S, Ipseiz N, Stoll C, et al. PPARbeta/delta governs Wnt signaling and bone turnover. Nature medicine. 2013;19:608–13.
  17. Flammer JR, Rogatsky I. Minireview: Glucocorticoids in autoimmunity: unexpected targets and mechanisms. Mol Endocrinol. 2011;25:1075–86.
  18. Taubert S, Ward JD, Yamamoto KR. Nuclear hormone receptors in nematodes: evolution and function. Mol Cell Endocrinol. 2011;334:49–55.
  19. Evans RM, Barish GD, Wang YX. PPARs and the complex journey to obesity. Nat Med. 2004;10:355–61.
  20. Glass CK, Ogawa S. Combinatorial roles of nuclear receptors in inflammation and immunity. Nat Rev Immunol. 2006;6:44–55.
  21. Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 1998;391:82–6.
  22. Straus DS, Pascual G, Li M, Welch JS, Ricote M, Hsiang CH, et al. 15–deoxy-delta 12,14–prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway. Proc Natl Acad Sci U S A. 2000;97:4844–9.
  23. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998;391:79–82.
  24. Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RMPPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med. 2001;7:48–52.
  25. Ogawa S, Lozach J, Benner C, Pascual G, Tangirala RK, Westin S, et al. Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell. 2005;122:707–21.
  26. Ricote M, Glass CK. PPARs and molecular mechanisms of transrepression. Biochim Biophys Acta. 2007;1771:926–35.
  27. Pyper SR, Viswakarma N, Yu S, Reddy JK. PPARalpha: energy combustion, hypolipidemia, inflammation and cancer. Nuclear receptor signaling. 2010;8:e002.
  28. Staels B, Koenig W, Habib A, Merval R, Lebret M, Torra IP, et al. Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. Nature. 1998;393:790–3.
  29. Delerive P, De Bosscher K, Besnard S, Vanden Berghe W, Peters JM, Gonzalez FJ, et al. Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. J Biol Chem. 1999;274:32048–54.
  30. Delerive P, Gervois P, Fruchart JC, Staels B. Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators. J Biol Chem. 2000;275:36703–7.
  31. Xu X, Otsuki M, Saito H, Sumitani S, Yamamoto H, Asanuma N, et al. PPARalpha and GR differentially down-regulate the expression of nuclear factor-kappaB-responsive genes in vascular endothelial cells. Endocrinology. 2001;142:3332–9.
  32. Barish GD, Atkins AR, Downes M, Olson P, Chong LW, Nelson M, et al. PPARdelta regulates multiple proinflammatory pathways to suppress atherosclerosis. Proc Natl Acad Sci U S A. 2008;105:4271–6.
  33. Bishop-Bailey D, Bystrom J. Emerging roles of peroxisome proliferator-activated receptor-beta/delta in inflammation. Pharmacol Ther. 2009;124:141–50.
  34. Lee CH, Chawla A, Urbiztondo N, Liao D, Boisvert WA, Evans RM, et al. Transcriptional repression of atherogenic inflammation: modulation by PPARdelta. Science. 2003;302:453–7.
  35. Shah YM, Morimura K, Gonzalez FJ. Expression of peroxisome proliferator-activated receptor-gamma in macrophage suppresses experimentally induced colitis. Am J Physiol Gastrointest Liver Physiol. 2007;292:G657–666.
  36. Adachi M, Kurotani R, Morimura K, Shah Y, Sanford M, Madison BB, et al. Peroxisome proliferator activated receptor gamma in colonic epithelial cells protects against experimental inflammatory bowel disease. Gut. 2006;55:1104–13.
  37. Dubrac S, Elentner A, Schoonjans K, Auwerx J, Schmuth M. Lack of IL-2 in PPAR-alpha-deficient mice triggers allergic contact dermatitis by affecting regulatory T cells. Eur J Immunol. 2011;41:1980–91.
  38. Man MQ, Barish GD, Schmuth M, Crumrine D, Barak Y, Chang S, et al. Deficiency of PPARbeta/delta in the epidermis results in defective cutaneous permeability barrier homeostasis and increased inflammation. J Invest Dermatol. 2008;128:370–7.
  39. Delayre-Orthez C, Becker J, Guenon I, Lagente V, Auwerx J, Frossard N, et al. PPARalpha downregulates airway inflammation induced by lipopolysaccharide in the mouse. Respir Res. 2005;6:91.
  40. Stienstra R, Mandard S, Patsouris D, Maass C, Kersten S, Muller M. Peroxisome proliferator-activated receptor alpha protects against obesity-induced hepatic inflammation. Endocrinology. 2007;148:2753–63.
  41. Tanaka T, Kohno H, Yoshitani S, Takashima S, Okumura A, Murakami A, et al. Ligands for peroxisome proliferator-activated receptors alpha and gamma inhibit chemically induced colitis and formation of aberrant crypt foci in rats. Cancer Res. 2001;61:2424–8.
  42. Esposito E, Mazzon E, Paterniti I, Dal Toso R, Pressi G, Caminiti R, Cuzzocrea S. PPAR-alpha Contributes to the Anti-Inflammatory Activity of Verbascoside in a Model of Inflammatory Bowel Disease in Mice. PPAR Res. 2010: 917312.
  43. Su CG, Wen X, Bailey ST, Jiang W, Rangwala SM, Keilbaugh SA, et al. A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response. J Clin Invest. 1999;104:383–9.
  44. Woerly G, Honda K, Loyens M, Papin JP, Auwerx J, Staels B, et al. Peroxisome proliferator-activated receptors alpha and gamma down-regulate allergic inflammation and eosinophil activation. J Exp Med. 2003;198:411–21.
  45. Trifilieff A, Bench A, Hanley M, Bayley D, Campbell E, Whittaker P. PPAR-alpha and -gamma but not -delta agonists inhibit airway inflammation in a murine model of asthma: in vitro evidence for an NF-kappaB-independent effect. Br J Pharmacol. 2003;139:163–71.
  46. Marx N, Sukhova GK, Collins T, Libby P, Plutzky J. PPARalpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation. 1999;99:3125–31.
  47. Israelian-Konaraki Z, Reaven PD. Peroxisome proliferator-activated receptor-alpha and atherosclerosis: from basic mechanisms to clinical implications. Cardiology. 2005;103:1–9.
  48. Li AC, Glass CK. PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis. J Lipid Res. 2004;45:2161–73.
  49. Li AC, Binder CJ, Gutierrez A, Brown KK, Plotkin CR, Pattison JW, et al. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma. J Clin Invest. 2004;114:1564–76.
  50. Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, et al. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Molecular Cell. 2001;7:161–71.
  51. Tordjman K, Bernal-Mizrachi C, Zemany L, Weng S, Feng C, Zhang F, et al. PPARalpha deficiency reduces insulin resistance and atherosclerosis in apoE-null mice. J Clin Invest. 2001;107:1025–34.
  52. Brown JD, Plutzky J. Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets. Circulation. 2007;115:518–33.
  53. Jennewein C, Kuhn AM, Schmidt MV, Meilladec-Jullig V, von Knethen A, Gonzalez FJ, et al. Sumoylation of peroxisome proliferator-activated receptor gamma by apoptotic cells prevents lipopolysaccharide-induced NCoR removal from kappaB binding sites mediating transrepression of proinflammatory cytokines. J Immunol. 2008;181:5646–52.
  54. Mukundan L, Odegaard JI, Morel CR, JHeredia E, Mwangi JW, Ricardo-Gonzalez RR, et al. PPAR-delta senses and orchestrates clearance of apoptotic cells to promote tolerance. Nat Med. 2009;15:1266–72.
  55. Gosset P, Charbonnier AS, Delerive P, Fontaine J, Staels B, Pestel J, et al. Peroxisome proliferator-activated receptor gamma activators affect the maturation of human monocyte-derived dendritic cells. Eur J Immunol. 2001;31:2857–65.
  56. Faveeuw C, Fougeray S, Angeli V, Fontaine J, Chinetti G, Gosset P, et al. Peroxisome proliferator-activated receptor gamma activators inhibit interleukin-12 production in murine dendritic cells. FEBS Lett. 2000;486:261–6.
  57. Szatmari I, Gogolak P, Im JS, Dezso B, Rajnavolgyi E, Nagy L. Activation of PPARgamma specifies a dendritic cell subtype capable of enhanced induction of iNKT cell expansion. Immunity. 2004;21:95–106.
  58. Szanto A, Balint BL, Nagy ZS, Barta E, Dezso B, Pap A, et al. STAT6 transcription factor is a facilitator of the nuclear receptor PPARgamma-regulated gene expression in macrophages and dendritic cells. Immunity. 2010;33:699–712.
  59. Nencioni A, Grunebach F, Zobywlaski A, Denzlinger C, Brugger W, Brossart P. Dendritic cell immunogenicity is regulated by peroxisome proliferator-activated receptor gamma. J Immunol. 2002;169:1228–35.
  60. Appel S, Mirakaj V, Bringmann A, Weck MM, Grunebach F, Brossart P. PPAR-gamma agonists inhibit toll-like receptor-mediated activation of dendritic cells via the MAP kinase and NF-kappaB pathways. Blood. 2005;106:3888–94.
  61. Angeli V, Hammad H, Staels B, Capron M, Lambrecht BN, Trottein F. Peroxisome proliferator-activated receptor gamma inhibits the migration of dendritic cells: consequences for the immune response. J Immunol. 2003;170:5295–301.
  62. Klotz L, Dani I, Edenhofer F, Nolden L, Evert B, Paul B, et al. Peroxisome proliferator-activated receptor gamma control of dendritic cell function contributes to development of CD4+ T cell anergy. J Immunol. 2007;178:2122–31.
  63. Jakobsen MA, Petersen RK, Kristiansen K, Lange M, Lillevang ST. Peroxisome proliferator-activated receptor alpha, delta, gamma1 and gamma2 expressions are present in human monocyte-derived dendritic cells and modulate dendritic cell maturation by addition of subtype-specific ligands. Scand J Immunol. 2006;63:330–7.
  64. Dubrac S, Stoitzner P, Pirkebner D, Elentner A, Schoonjans K, Auwerx J, et al. Peroxisome proliferator-activated receptor-alpha activation inhibits Langerhans cell function. J Immunol. 2007;178:4362–72.
  65. Szatmari I, Torocsik D, Agostini M, Nagy T, Gurnell M, Barta E, et al. PPARgamma regulates the function of human dendritic cells primarily by altering lipid metabolism. Blood. 2007;110:3271–80.
  66. Szatmari I, Pap A, Ruhl R, Ma JX, Illarionov PA, Besra GS, et al. PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006;203:2351–62.
  67. Gogolak P, Rethi B, Szatmari I, Lanyi A, Dezso B, Nagy L, Rajnavolgyi E. Differentiation of CD1a- and CD1a+ monocyte-derived dendritic cells is biased by lipid environment and PPARgamma. Blood. 2007;109:643–52.
  68. Setoguchi K, Misaki Y, Terauchi Y, Yamauchi T, Kawahata K, Kadowaki T, et al. Peroxisome proliferator-activated receptor-gamma haploinsufficiency enhances B cell proliferative responses and exacerbates experimentally induced arthritis. J Clin Invest. 2001;108:1667–75.
  69. Clark RB, Bishop-Bailey D, Estrada-Hernandez T, Hla T, Puddington L, Padula SJ. The nuclear receptor PPAR gamma and immunoregulation: PPAR gamma mediates inhibition of helper T cell responses. J Immunol. 2000;164:1364–71.
  70. Cunard R, DiCampli D, Archer DC, Stevenson JL, Ricote M, Glass CK, et al. WY14,643, a PPAR alpha ligand, has profound effects on immune responses in vivo. J Immunol. 2002;169:6806–12.
  71. Schlezinger JJ, Jensen BA, Mann KK, Ryu HY, Sherr DH. Peroxisome proliferator-activated receptor gamma-mediated NF-kappa B activation and apoptosis in pre-B cells. J Immunol. 2002;169:6831–41.
  72. Padilla J, Leung E, Phipps RP. Human B lymphocytes and B lymphomas express PPAR-gamma and are killed by PPAR-gamma agonists. Clin Immunol. 2002;103:22–33.
  73. Padilla J, Kaur K, Cao HJ, Smith TJ, Phipps RP. Peroxisome proliferator activator receptor-gamma agonists and 15–deoxy-Delta(12,14)(12,14)-PGJ(2) induce apoptosis in normal and malignant B-lineage cells. J Immunol. 2000;165:6941–8.
  74. Ray DM, Akbiyik F, Bernstein SH, Phipps RP. CD40 engagement prevents peroxisome proliferator-activated receptor gamma agonist-induced apoptosis of B lymphocytes and B lymphoma cells by an NF-kappaB-dependent mechanism. J Immunol. 2005;174:4060–9.
  75. Ramon S, Bancos S, Thatcher TH, Murant TI, Moshkani S, Sahler JM, et al. Peroxisome proliferator-activated receptor gamma B cell-specific-deficient mice have an impaired antibody response. J Immunol. 2012;189:4740–7.
  76. Schmidt S, Moric E, Schmidt M, Sastre M, Feinstein DL, Heneka MT. Anti-inflammatory and antiproliferative actions of PPAR-gamma agonists on T lymphocytes derived from MS patients. J Leukoc Biol. 2004;75:478–85.
  77. Zhang MA, Rego D, Moshkova M, Kebir H, Chruscinski A, Nguyen H, et al. Peroxisome proliferator-activated receptor (PPAR)alpha and -gamma regulate IFNgamma and IL-17A production by human T cells in a sex-specific way. Proc Natl Acad Sci U S A. 2012;109:9505–10.
  78. Dunn SE, Bhat R, Straus DS, Sobe RA l, Axtell R, Johnson A, et al. Peroxisome proliferator-activated receptor delta limits the expansion of pathogenic Th cells during central nervous system autoimmunity. J Exp Med. 2010;207:1599–608.
  79. Klotz L, Burgdorf S, Dani I, Saijo K, Flossdorf J, Hucke S, et al. The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. J Exp Med. 2009;206:2079–89.
  80. Gaffen SL, Jain R, Garg AV, Cua DJ. The IL-23–IL-17 immune axis: from mechanisms to therapeutic testing. Nature reviews. Immunology. 2014;14:585–600.
  81. Ohkura N, Kitagawa Y, Sakaguchi S. Development and maintenance of regulatory T cells. Immunity. 2013;38:414–23.
  82. Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson SE, et al. PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature. 2012;486:549–53.
  83. Housley WJ, O’Conor CA, Nichols F, Puddington L, Lingenheld EG, Zhu L, et al. PPARgamma regulates retinoic acid-mediated DC induction of Tregs. J Leukoc Biol. 2009;86:293–301.
  84. Kawahito Y, Kondo M, Tsubouchi Y, Hashiramoto A, Bishop-Bailey D, Inoue K, et al. 15–deoxy-delta(12,14)-PGJ(2) induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats. J Clin Invest. 2000;106:189–97.
  85. Cuzzocrea S, Mazzon E, Dugo L, Patel NS, Serraino I, Di Paola R, et al. Reduction in the evolution of murine type II collagen-induced arthritis by treatment with rosiglitazone, a ligand of the peroxisome proliferator-activated receptor gamma. Arthritis Rheum. 2003;48:3544–56.
  86. Tomita T, Kakiuchi Y, Tsao PS. THR0921, a novel peroxisome proliferator-activated receptor gamma agonist, reduces the severity of collagen-induced arthritis. Arthritis Res Ther. 2006;8:R7.
  87. Shirinsky I, Polovnikova O, Kalinovskaya N, Shirinsky V. The effects of fenofibrate on inflammation and cardiovascular markers in patients with active rheumatoid arthritis: a pilot study. Rheumatol Int. 2013;33:3045–8.
  88. Shahin D, Toraby EE, Abdel-Malek H, Boshra V, Elsamanoudy AZ, Shaheen D. Effect of peroxisome proliferator-activated receptor gamma agonist (pioglitazone) and methotrexate on disease activity in rheumatoid arthritis (experimental and clinical study). Clin Med Insights Arthritis Musculoskelet Disord. 2011;4:1–10.
  89. Okamoto H, Kamatani N. Successful treatment with fenofibrate, a peroxisome proliferator activated receptor alpha ligand, for a patient with rheumatoid arthritis. Ann Rheum Dis. 2004;63:1002–3.
  90. Bongartz T, Coras B, Vogt T, Scholmerich J, Muller-Ladner U. Treatment of active psoriatic arthritis with the PPARgamma ligand pioglitazone: an open-label pilot study. Rheumatology (Oxford). 2005;44:126–9.
  91. Sabatini M, Bardiot A, Lesur C, Moulharat N, Thomas M, Richard, I et al. Effects of agonists of peroxisome proliferator-activated receptor gamma on proteoglycan degradation and matrix metalloproteinase production in rat cartilage in vitro. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2002;10:673–9.
  92. Kobayashi T, Notoya K, Naito T, Unno S, Nakamura A, Martel-Pelletier J, et al. Pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, reduces the progression of experimental osteoarthritis in guinea pigs. Arthritis Rheum. 2005;52:479–87.
  93. Boileau C, Martel-Pelletier J, Fahmi H, Mineau F, Boily M, Pelletier JP. The peroxisome proliferator-activated receptor gamma agonist pioglitazone reduces the development of cartilage lesions in an experimental dog model of osteoarthritis: in vivo protective effects mediated through the inhibition of key signaling and catabolic pathways. Arthritis Rheum. 2007;56:2288–98.
  94. Fahmi H, Martel-Pelletier J, Pelletier JP, Kapoor M. Peroxisome proliferator-activated receptor gamma in osteoarthritis. Mod Rheumatol. 2011;21:1–9.
  95. Clockaerts S, Bastiaansen-Jenniskens YM, Feijt C, JVerhaar A, Somville J, De Clerck LS, et al. Peroxisome proliferator activated receptor alpha activation decreases inflammatory and destructive responses in osteoarthritic cartilage. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2011;19:895–902.
  96. Vasheghani F, Monemdjou R, Fahmi H, Zhang Y, Perez G, Blati M, et al. Adult cartilage-specific peroxisome proliferator-activated receptor gamma knockout mice exhibit the spontaneous osteoarthritis phenotype. Am J Pathol. 2013;182:1099–106.
  97. Monemdjou R, Vasheghani F, Fahmi H, Perez G, Blati M, Taniguchi N, et al. Association of cartilage-specific deletion of peroxisome proliferator-activated receptor gamma with abnormal endochondral ossification and impaired cartilage growth and development in a murine model. Arthritis Rheum. 2012;64:1551–61.
  98. Hong C, Tontonoz P. Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors. Current opinion in genetics & development. 2008;18:461–7.
  99. Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med. 2003;213–9.
  100. Castrillo A, Joseph SB, Vaidya SA, Haberland M, Fogelman AM, Cheng G, et al. Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism. Molecular cell. 2003;12:805–16.
  101. Joseph SB, Bradley MN, Castrillo A, Bruhn KW, Mak PA, Pei L, et al. LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell. 2004;119:299–309.
  102. Valledor AF, Hsu LC, Ogawa S, Sawka-Verhelle D, Karin M, Glass CK. Activation of liver X receptors and retinoid X receptors prevents bacterial-induced macrophage apoptosis. Proc Natl Acad Sci U S A. 2004;101:17813–8.
  103. N, A. G., Bensinger SJ, Hong C, Beceiro S, Bradley MN, Zelcer N, et al. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity. 2009;31:245–58.
  104. Hong C, Kidani Y, A. G. N, Phung T, Ito A, Rong X, Ericson K, et al. Coordinate regulation of neutrophil homeostasis by liver X receptors in mice. J Clin Invest. 2012;122:337–47.
  105. N, A. G., Guillen JA, Gallardo G, Diaz M, de la Rosa JV, Hernandez IH, et al. The nuclear receptor LXRalpha controls the functional specialization of splenic macrophages. Nat Immunol. 2013;14:831–9.
  106. Bensinger SJ, Bradley MN, Joseph SB, Zelcer N, Janssen EM, Hausner MA, et al. LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell. 2008;134:97–111.
  107. Joseph SB, McKilligin E, Pei L, Watson MA, Collins AR, Laffitte BA, et al. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci U S A. 2002;99:7604–9.
  108. Fowler AJ, Sheu MY, Schmuth M, Kao J, Fluhr JW, Rhein L, et al. Liver X receptor activators display anti-inflammatory activity in irritant and allergic contact dermatitis models: liver-X-receptor-specific inhibition of inflammation and primary cytokine production. J Invest Dermatol. 2003;120:246–55.
  109. Sheu MY, Fowler AJ, Kao J, Schmuth M, Schoonjans K, Auwerx J, et al. Topical peroxisome proliferator activated receptor-alpha activators reduce inflammation in irritant and allergic contact dermatitis models. J Invest Dermatol. 2002;118:94–101.
  110. Asquith DL, Miller AM, Hueber AJ, McKinnon HJ, Sattar N, Graham GJ, et al. Liver X receptor agonism promotes articular inflammation in murine collagen-induced arthritis. Arthritis Rheum. 2009;60:2655–65.
  111. Park MC, Kwon YJ, Chung SJ, Park YB, Lee SK. Liver X receptor agonist prevents the evolution of collagen-induced arthritis in mice. Rheumatology (Oxford). 2010;49:882–90.
  112. Asquith DL, Miller AM, Reilly J, Kerr S, Welsh P, Sattar N, et al. Simultaneous activation of the liver X receptors (LXRalpha and LXRbeta) drives murine collagen-induced arthritis disease pathology. Ann Rheum Dis. 2011;70:2225–8.
  113. Birrell MA, De Alba J, Catley MC, Hardaker E, Wong S, Collins M, et al. Liver X receptor agonists increase airway reactivity in a model of asthma via increasing airway smooth muscle growth. J Immunol. 2008;181:4265–71.
  114. Shi Y, Xu X, Tan Y, Mao S, Fang S, Gu W. A Liver-X-Receptor Ligand, T0901317, Attenuates IgE Production and Airway Remodeling in Chronic Asthma Model of Mice. PLoS One 2014;9:e92668.
  115. Collins-Racie LA, Yang Z, Arai M, Li N, Majumdar MK, Nagpal S, et al. Global analysis of nuclear receptor expression and dysregulation in human osteoarthritic articular cartilage: reduced LXR signaling contributes to catabolic metabolism typical of osteoarthritis. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2009;17:832–42.
  116. Li N, Rivera-Bermudez MA, Zhang M, Tejada J, Glasson SS, Collins-Racie LA, et al. LXR modulation blocks prostaglandin E2 production and matrix degradation in cartilage and alleviates pain in a rat osteoarthritis model. Proc Natl Acad Sci U S A. 2010;107:3734–9.
  117. McMorrow JP, Murphy EP. Inflammation: a role for NR4A orphan nuclear receptors? Biochem Soc Trans. 2011;39:688–93.
  118. Hamers AA, Hanna RN, Nowyhed H, Hedrick CC, de Vries CJ. NR4A nuclear receptors in immunity and atherosclerosis. Curr Opin Lipidol. 2013;24:381–5.
  119. Zhan Y, Du X, Chen H, Liu J, Zhao B, Huang D, et al. Cytosporone B is an agonist for nuclear orphan receptor Nur77. Nat Chem Biol. 2008;4:548–56.
  120. Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, et al. A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell. 2009;137:47–59.
  121. Hanna RN, Shaked I, Hubbeling HG, Punt JA, Wu R, Herrley E, et al. NR4A1 (Nur77) deletion polarizes macrophages toward an inflammatory phenotype and increases atherosclerosis. Circulation research. 2012;110:416–27.
  122. Hamers AA, M Vos, F Rassam, G Marinkovic, K Kurakula, PJ van Gorp, et al. Bone marrow-specific deficiency of nuclear receptor Nur77 enhances atherosclerosis. Circ Res. 2012;110:428–38.
  123. Ipseiz N, Uderhardt S, Scholtysek C, Steffen M, Schabbauer G, Bozec A, et al. The nuclear receptor Nr4a1 mediates anti-inflammatory effects of apoptotic cells. J Immunol. 2014;192:4852–8.
  124. Hanna RN, Carlin LM, Hubbeling HG, Nackiewicz D, Green AM, Punt JA, et al. The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C- monocytes. Nat Immunol. 2011;12:778–85.
  125. Sekiya T, Kashiwagi I, Yoshida R, Fukaya T, Morita R, Kimura A, et al. Nr4a receptors are essential for thymic regulatory T cell development and immune homeostasis. Nat Immunol. 2013;14:230–7.
  126. De Silva S, Han S, Zhang X, Huston DP, Winoto A, Zheng B. Reduction of the incidence and severity of collagen-induced arthritis by constitutive Nur77 expression in the T cell lineage. Arthritis Rheum. 2005;52:333–8.
  127. Mix KS, Attur MG, Al-Mussawir H, Abramson SB, Brinckerhoff CE, Murphy EP. Transcriptional repression of matrix metalloproteinase gene expression by the orphan nuclear receptor NURR1 in cartilage. J Biol Chem. 2007;282:9492–504.
  128. Imai Y, Youn MY, Inoue K, Takada I, Kouzmenko A, Kato S. Nuclear receptors in bone physiology and diseases. Physiol Rev. 2013;93:481–523.
  129. Warriner AH, Saag KG. Osteoporosis diagnosis and medical treatment. Orthop Clin North Am. 2013;44:125–35.
  130. Seibel MJ, Cooper MS, Zhou H. Glucocorticoid-induced osteoporosis: mechanisms, management, and future perspectives. The lancet. Diabetes & endocrinology. 2013;1:59–70.
  131. Schwartz AV, Sellmeyer DE, Vittinghoff E, Palermo L, Lecka-Czernik B, Feingold KR, et al. Thiazolidinedione use and bone loss in older diabetic adults. J Clin Endocrinol Metab. 2006;91:3349–54.
  132. Kahn SE, Zinman B, Lachin JM, Haffner SM, Herman WH, Holman RR, et al. Rosiglitazone-associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes care. 2008;31:845–51.
  133. Hu E, Tontonoz P, Spiegelman BM. Transdifferentiation of myoblasts by the adipogenic transcription factors PPAR gamma and C/EBP alpha. Proc Natl Acad Sci U S A. 1995;92:9856–60.
  134. Lecka-Czernik B, Moerman EJ, Grant DF, Lehmann JM, Manolagas SC, Jilka RL. Divergent effects of selective peroxisome proliferator-activated receptor-gamma 2 ligands on adipocyte versus osteoblast differentiation. Endocrinology. 2002;143:2376–84.
  135. Akune T, Ohba S, Kamekura S, Yamaguchi M, Chung UI, Kubota N, et al. PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest. 2004;113:846–55.
  136. Ali AA, Weinstein RS, Stewart SA, Parfitt AM, Manolagas SC, Jilka RL. Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation. Endocrinology. 2005;146:1226–35.
  137. Rzonca SO, Suva LJ, Gaddy D, Montague DC, Lecka-Czernik B. Bone is a target for the antidiabetic compound rosiglitazone. Endocrinology. 2004;145:401–6.
  138. Takada I, Kouzmenko AP, Kato S. Wnt and PPARgamma signaling in osteoblastogenesis and adipogenesis. Nat Rev Rheumatol. 2009;5:442–7.
  139. Takada I, Suzawa M, Matsumoto K, Kato S. Suppression of PPAR transactivation switches cell fate of bone marrow stem cells from adipocytes into osteoblasts. Ann N Y Acad Sci. 2007;1116:182–95.
  140. Okamura M, Kudo H, Wakabayashi K, Tanaka T, Nonaka A, Uchida A, et al. COUP-TFII acts downstream of Wnt/beta-catenin signal to silence PPARgamma gene expression and repress adipogenesis. Proc Natl Acad Sci U S A. 2009;106:5819–24.
  141. Kawai M, Rosen CJ. PPARgamma: a circadian transcription factor in adipogenesis and osteogenesis. Nat Rev Endocrinol. 6:629–36.
  142. Wan Y, Chong LW, Evans RM. PPAR-gamma regulates osteoclastogenesis in mice. Nat Med. 2007;13:1496–503.
  143. Still K, Grabowski P, Mackie I, Perry M, Bishop N. The peroxisome proliferator activator receptor alpha/delta agonists linoleic acid and bezafibrate upregulate osteoblast differentiation and induce periosteal bone formation in vivo. Calcif Tissue Int. 2008;83:285–92.
  144. Kim DH, Liu J, Bhat S, Benedict G, Lecka-Czernik B, Peterson SJ, et al. Peroxisome proliferator-activated receptor delta agonist attenuates nicotine suppression effect on human mesenchymal stem cell-derived osteogenesis and involves increased expression of heme oxygenase-1. J Bone Miner Metab. 2013;31:44–52.
  145. Chan BY, Gartland A, Wilson PJ, Buckley KA, Dillon JP, Fraser WD, et al. PPAR agonists modulate human osteoclast formation and activity in vitro. Bone. 2007;40:149–59.
  146. Mosti M, Stunes A, Ericsson M, Pullisaar H, Reseland J, Shabestari M, et al. Effects of the peroxisome proliferator-activated receptor (PPAR) delta agonist GW501516 on bone and muscle in ovariectomized rats. Endocrinology: 2014. en20131166.
  147. Ye JM, Tid-Ang J, Turner N, Zeng XY, Li HY, Cooney GJ, et al. PPARdelta agonists have opposing effects on insulin resistance in high fat-fed rats and mice due to different metabolic responses in muscle. Br J Pharmacol. 2011;163:556–66.
  148. Wu X, Peters JM, Gonzalez FJ, Prasad HS, Rohrer MD, Gimble JM. Frequency of stromal lineage colony forming units in bone marrow of peroxisome proliferator-activated receptor-alpha-null mice. Bone. 2000;6:21–6.
  149. Meier CR, Schlienger RG, Kraenzlin ME, Schlegel B, Jick H. HMG-CoA reductase inhibitors and the risk of fractures. JAMA. 2000;283:3205–10.
  150. Remen KM, Henning P, Lerner UH, Gustafsson JA, Andersson G. Activation of liver X receptor (LXR) inhibits receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast differentiation in an LXRbeta-dependent mechanism. J Biol Chem. 2011;286:33084–94.
  151. Kleyer A, Scholtysek C, Bottesch E, Hillienhof U, Beyer C, Distler JH, et al. Liver X receptors orchestrate osteoblast/osteoclast crosstalk and counteract pathologic bone loss. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research. 2012;27:2442–51.
  152. Robertson KM, Norgard M, Windahl SH, Hultenby K, Ohlsson C, Andersson G, et al. Cholesterol-sensing receptors, liver X receptor alpha and beta, have novel and distinct roles in osteoclast differentiation and activation. J Bone Miner Res. 2006;21:1276–87.
  153. Prawitt J, Beil FT, Marshall RP, Bartelt A, Ruether W, Heeren J, et al. Short-term activation of liver X receptors inhibits osteoblasts but long-term activation does not have an impact on murine bone in vivo. Bone. 2011;48:339–46.
  154. Kim HJ, Yoon KA, Yoon HJ, Hong JM, Lee MJ, Lee IK, et al. Liver X receptor activation inhibits osteoclastogenesis by suppressing NF-kappaB activity and c-Fos induction and prevents inflammatory bone loss in mice. J Leukoc Biol. 2013;94:99–107.
  155. Lammi J, Huppunen J, Aarnisalo P. Regulation of the osteopontin gene by the orphan nuclear receptor NURR1 in osteoblasts. Mol Endocrinol. 2004;18:1546–57.
  156. Lee MK, Choi H, Gil M, Nikodem VM. Regulation of osteoblast differentiation by Nurr1 in MC3T3–E1 cell line and mouse calvarial osteoblasts. J Cell Biochem. 2006;99:986–94.
  157. Pirih FQ, Tang A, Ozkurt IC, Nervina JM, Tetradis S. Nuclear orphan receptor Nurr1 directly transactivates the osteocalcin gene in osteoblasts. J Biol Chem. 2004;279:53167–74.