Hair follicle stem cell-specific PPARgamma deletion causes scarring alopecia.

Primary cicatricial or scarring alopecias (CA) are a group of inflammatory hair disorders of unknown pathogenesis characterized by the permanent destruction of the hair follicle. The current treatment options are ineffective in controlling disease progression largely because the molecular basis for CA is not understood. Microarray analysis of the lymphocytic CA, Lichen planopilaris (LPP), compared to normal scalp biopsies identified decreased expression of genes required for lipid metabolism and peroxisome biogenesis. Immunohistochemical analysis showed progressive loss of peroxisomes, proinflammatory lipid accumulation, and infiltration of inflammatory cells followed by destruction of the pilosebaceous unit. The expression of peroxisome proliferator-activated receptor (PPAR) gamma, a transcription factor that regulates these processes, is significantly decreased in LPP. Specific agonists of PPARgamma are effective in inducing peroxisomal and lipid metabolic gene expression in human keratinocytes. Finally, targeted deletion of PPARgamma in follicular stem cells in mice causes a skin and hair phenotype that emulates scarring alopecia. These studies suggest that PPARgamma is crucial for healthy pilosebaceous units and it is the loss of this function that triggers the pathogenesis of LPP. We propose that PPARgamma-targeted therapy may represent a new strategy in the treatment of these disorders.

[1]  S. Muller,et al.  Lichen planopilaris: clinical and pathologic study of forty-five patients. , 1992, Journal of the American Academy of Dermatology.

[2]  P. Chambon,et al.  Peroxisome-proliferator-activated receptor (PPAR)-gamma activation stimulates keratinocyte differentiation. , 2004, The Journal of investigative dermatology.

[3]  C. Jefcoate,et al.  TCDD administration after the pro-adipogenic differentiation stimulus inhibits PPARgamma through a MEK-dependent process but less effectively suppresses adipogenesis. , 2004, Toxicology and applied pharmacology.

[4]  Weimin He,et al.  Adipose-specific peroxisome proliferator-activated receptor γ knockout causes insulin resistance in fat and liver but not in muscle , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[5]  T. McCalmont,et al.  Primary cicatricial alopecia: histopathologic findings do not distinguish clinical variants. , 2005, Journal of the American Academy of Dermatology.

[6]  J. Folch,et al.  A simple method for the isolation and purification of total lipides from animal tissues. , 1957, The Journal of biological chemistry.

[7]  X. Chen,et al.  Structural organization of mouse peroxisome proliferator-activated receptor gamma (mPPAR gamma) gene: alternative promoter use and different splicing yield two mPPAR gamma isoforms. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Alberto Riva,et al.  MAPPER: a search engine for the computational identification of putative transcription factor binding sites in multiple genomes , 2005, BMC Bioinformatics.

[9]  J. Sundberg,et al.  Hair follicle biology, the sebaceous gland, and scarring alopecias. , 1999, Archives of dermatology.

[10]  A. Saghatelian,et al.  Maternal PPARγ protects nursing neonates by suppressing the production of inflammatory milk , 2007 .

[11]  W. Schliebs,et al.  Peroxisome Membrane Biogenesis: The Stage Is Set , 2004, Current Biology.

[12]  I. Heiland,et al.  Biogenesis of peroxisomes. Topogenesis of the peroxisomal membrane and matrix proteins. , 2005, The FEBS journal.

[13]  R. Wanders,et al.  Peroxisomes, lipid metabolism, and peroxisomal disorders. , 2004, Molecular genetics and metabolism.

[14]  J. Sundberg,et al.  Asebia-2J (Scd1(ab2J)): a new allele and a model for scarring alopecia. , 2000, The American journal of pathology.

[15]  J. Gordon,et al.  Identification of the Δ-6 Desaturase of Human Sebaceous Glands: Expression and Enzyme Activity , 2003 .

[16]  S. Millar,et al.  Towards a molecular understanding of hair loss and its treatment. , 2001, Trends in molecular medicine.

[17]  C. Jefcoate,et al.  2,3,7,8-Tetrachlorodibenzo-p-dioxin and Epidermal Growth Factor Cooperatively Suppress Peroxisome Proliferator-Activated Receptor-γ1 Stimulation and Restore Focal Adhesion Complexes during Adipogenesis: Selective Contributions of Src, Rho, and Erk Distinguish These Overlapping Processes in C3H10T1/2 , 2006, Molecular Pharmacology.

[18]  P. Baeuerle,et al.  Function and activation of NF-kappa B in the immune system. , 1994, Annual review of immunology.

[19]  K. Ghaedi,et al.  Identification of PEX3 as the gene mutated in a Zellweger syndrome patient lacking peroxisomal remnant structures. , 2000, Human molecular genetics.

[20]  H. Kamino,et al.  Possible role of the bulge region in the pathogenesis of inflammatory scarring alopecia: lichen planopilaris as the prototype , 2005, Journal of cutaneous pathology.

[21]  M. H. Hardy,et al.  The expression of the gene asebia in the laboratory mouse. I. Epidermis and dermis. , 1978, Genetical research.

[22]  D. Valle,et al.  Peroxisome biogenesis disorders: genetics and cell biology. , 2000, Trends in genetics : TIG.

[23]  E. Lane,et al.  Defolliculated (dfl): a dominant mouse mutation leading to poor sebaceous gland differentiation and total elimination of pelage follicles. , 2002, The Journal of investigative dermatology.

[24]  J. Saurat,et al.  Peroxisome proliferator‐activated receptors in cutaneous biology , 2003, The British journal of dermatology.

[25]  S. Lyle,et al.  Keratin 15 promoter targets putative epithelial stem cells in the hair follicle bulge. , 2003, The Journal of investigative dermatology.

[26]  J. Gordon,et al.  Identification of the delta-6 desaturase of human sebaceous glands: expression and enzyme activity. , 2003, The Journal of investigative dermatology.

[27]  V. Price.  The medical treatment of cicatricial alopecia. , 2006, Seminars in cutaneous medicine and surgery.

[28]  L. Landmann.  Epidermis and Dermis , 1986 .

[29]  J. Berger,et al.  PPARs: therapeutic targets for metabolic disease. , 2005, Trends in pharmacological sciences.

[30]  A. Cabrero,et al.  Peroxisome proliferator-activated receptors and the control of inflammation. , 2002, Current drug targets. Inflammation and allergy.

[31]  A. Kentsis,et al.  Rat preputial sebocyte differentiation involves peroxisome proliferator-activated receptors. , 1999, The Journal of investigative dermatology.

[32]  I. Heiland,et al.  Biogenesis of peroxisomes , 2005 .

[33]  C. Jefcoate,et al.  AhR- and ERK-dependent pathways function synergistically to mediate 2,3,7,8-tetrachlorodibenzo-p-dioxin suppression of peroxisome proliferator-activated receptor-gamma1 expression and subsequent adipocyte differentiation. , 2003, Toxicology and applied pharmacology.

[34]  M. Sumida,et al.  Expression of perilipin A on the surface of lipid droplets increases along with the differentiation of hamster sebocytes in vivo and in vitro. , 2005, The Journal of investigative dermatology.

[35]  A. Saghatelian,et al.  Maternal PPAR gamma protects nursing neonates by suppressing the production of inflammatory milk. , 2007, Genes & development.

[36]  M. Karasek,et al.  Skin lipids of a normal and mutant (asebic) mouse strain. , 1966, The Journal of investigative dermatology.

[37]  P. Elias,et al.  Series : Skin Lipids Peroxisome proliferator-activated receptors and liver X receptors in epidermal biology , 2008 .

[38]  W. R. Morrison,et al.  PREPARATION OF FATTY ACID METHYL ESTERS AND DIMETHYLACETALS FROM LIPIDS WITH BORON FLUORIDE--METHANOL. , 1964, Journal of lipid research.

[39]  M. Martinka,et al.  Primary cicatricial alopecias: clinicopathology of 112 cases. , 2004, Journal of the American Academy of Dermatology.

[40]  N. Bunce,et al.  Linking dioxins to diabetes: epidemiology and biologic plausibility. , 2002, Environmental health perspectives.

[41]  J. Shapiro,et al.  Diagnosis and management of primary cicatricial alopecia: part I. , 2008, Skinmed.

[42]  C. Bradfield,et al.  Ah receptor signaling pathways. , 1996, Annual review of cell and developmental biology.

[43]  T. Kealey,et al.  Lipogenesis in the human sebaceous gland: glycogen and glycerophosphate are substrates for the synthesis of sebum lipids. , 1998, The Journal of investigative dermatology.

[44]  W. Wahli,et al.  Peroxisome proliferator-activated receptors (PPARs): from metabolic control to epidermal wound healing. , 2002, Swiss medical weekly.

[45]  M. H. Hardy,et al.  A hypothesis on the cause of chronic epidermal hyperproliferation in asebia mice , 1988, Clinical and experimental dermatology.