Scarring Alopecia and the PPAR-γ Connection
2009; Elsevier BV; Volume: 129; Issue: 5 Linguagem: Inglês
10.1038/jid.2008.425
ISSN1523-1747
Autores Tópico(s)RNA regulation and disease
ResumoThe pathobiology of primary cicatricial ("scarring") alopecia (PCA) remains poorly understood and underinvestigated. In this issue, Karnik et al. identify a previously unsuspected player, peroxisome proliferator-activated receptor-γ (PPARγ), in the pathogenesis of the most frequent form of PCA, lichen planopilaris (LPP). The authors show that PPARγ is required for maintenance of a functional epithelial stem cell compartment in murine hair follicles, that the targeted deletion of PPARγ in the bulge/isthmus area of the hair follicle epithelium generates a skin pathology that resembles LPP, and that LPP patients show gene expression changes that indicate a defect in lipid metabolism and peroxisome biogenesis. This study invites the revisitation of many open questions in PCA pathobiology and the exploration of new avenues for future PCA management. The pathobiology of primary cicatricial ("scarring") alopecia (PCA) remains poorly understood and underinvestigated. In this issue, Karnik et al. identify a previously unsuspected player, peroxisome proliferator-activated receptor-γ (PPARγ), in the pathogenesis of the most frequent form of PCA, lichen planopilaris (LPP). The authors show that PPARγ is required for maintenance of a functional epithelial stem cell compartment in murine hair follicles, that the targeted deletion of PPARγ in the bulge/isthmus area of the hair follicle epithelium generates a skin pathology that resembles LPP, and that LPP patients show gene expression changes that indicate a defect in lipid metabolism and peroxisome biogenesis. This study invites the revisitation of many open questions in PCA pathobiology and the exploration of new avenues for future PCA management. Cicatricial ("scarring") alopecias may be primary, with the hair follicle being the main target of a detrimental inflammatory process, or secondary, with follicle damage occurring coincidentally during a more generalized destructive event within the skin (e.g., thermal burn, trauma, infection, ionizing irradiation). Primary cicatricial alopecia (PCA) is a diverse group of inflammatory scalp disorders that target and destroy hair follicles, eventually resulting in permanent alopecia. The reliable diagnosis and effective management of these infrequent but often psychologically devastating forms of irreversible hair loss have long constituted a major unmet clinical need (Harries et al., 2008bHarries M.J. Sinclair R. MacDonald-Hull S. Whiting D. Griffiths C.E. Paus R. Primary cicatricial alopecias—options for treatment.Br J Dermatol. 2008; 159: 1-22Crossref PubMed Scopus (80) Google Scholar; Olsen et al., 2003Olsen E. Stenn K. Bergfeld W. Cotsarelis G. Price V. Shapiro J. et al.Update on cicatricial alopecia.J Investig Dermatol Symp Proc. 2003; 8: 1-9Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar).The main diagnostic hallmarks of PCA are the loss of visible follicular ostia on clinical inspection and the destruction of follicles, with subsequent replacement by scar-like fibrous tissue on histopathological examination (Harries et al., 2009Harries M.J. Trueb R. Tosti A. Messenger A. Whiting D.A. Sinclair R. et al.How not to get scar(r)ed: pointers to the correct diagnosis in patients with suspected primary cicatricial alopecia.Br J Dermatol. 2009; 160: 482-501Crossref PubMed Scopus (69) Google Scholar). Unfortunately, the etiology and pathogenesis of PCA are still largely unknown (Harries et al., 2008aHarries M.J. Meyer K.C. Paus R. Hair loss as a result of cutaneous autoimmunity: frontiers in the immunopathogenesis of primary cicatricial alopecia.Autoimmun Rev. 2008Google Scholar) because a number of factors impede our understanding of these clinically frustrating yet important and biologically fascinating disorders that lie at the crossroads of immunopathology, stem cell biology, and hair biology. These factors include our poor knowledge of the natural progression of the disease (typically, PCA patients see a doctor only relatively late in the disease process) and the literature's inconsistent and often confusing definitions of the various PCA entities. Also, the commonly observed variation and overlap of clinical and histological features at different time points during disease evolution and between different PCA states, complicated by the lack of truly specific molecular markers, have further hampered PCA characterization and understanding. Thus, the diagnosis of patients with PCA is frequently challenging and subsequent management is frustrating because of commonly inconsistent responses to treatment and the generally poor evidence from which to draw when counseling patients (Harries et al., 2008bHarries M.J. Sinclair R. MacDonald-Hull S. Whiting D. Griffiths C.E. Paus R. Primary cicatricial alopecias—options for treatment.Br J Dermatol. 2008; 159: 1-22Crossref PubMed Scopus (80) Google Scholar). An important study by Karnik et al., 2009Karnik P. Tekeste Z. McCormick T.S. Gilliam A.C. Price V.H. et al.Hair follicle stem cell-specific PPARγ deletion causes scarring alopecia.J Invest Dermatol. 2009; 129: 1243-1257Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar in this issue shines new light on this poorly understood corner of the dermatological universe by calling attention to defective lipid metabolism and peroxisome biogenesis as previously unsuspected players in the pathogenesis of the most frequent form of PCA, lichen planopilaris (LPP). Specifically, the authors show that one of the peroxisome proliferator-activated receptors (PPAR), namely PPARγ, is required for maintenance of a functional epithelial stem cell compartment in murine hair follicles, that the targeted deletion of PPARγ in the bulge/isthmus area of the hair follicle epithelium generates a skin pathology that resembles LPP in several respects, and that LPP patients show gene expression changes that suggest that a defect in lipid metabolism and peroxisome biogenesis may contribute to LPP pathogenesis. This study invites us to revisit the many open questions in PCA pathobiology and explore new avenues in the management of this enigmatic and intriguing group of inflammatory dermatoses. When considering this study, it helps to recall some foundations on which this work and current hypotheses of PCA pathogenesis rest. Chiefly, it is now widely appreciated that the irreversible destruction of epithelial hair follicle stem cells (eHFSCs), which abolish a hair follicle's capacity to cycle and regenerate itself from resident stem cell pools (e.g., after destructive inflammatory cell attacks on this mini-organ), lies at the heart of PCA pathogenesis (Cotsarelis, 2006Cotsarelis G. Epithelial stem cells: a folliculocentric view.J Invest Dermatol. 2006; 126: 1459-1468Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar; Harries et al., 2008aHarries M.J. Meyer K.C. Paus R. Hair loss as a result of cutaneous autoimmunity: frontiers in the immunopathogenesis of primary cicatricial alopecia.Autoimmun Rev. 2008Google Scholar). Because functional eHFSCs, located in the bulge region of the hair follicle's outer root sheath (Figure 1), play a central role in hair follicle cycling and are vital for the maintenance of hair follicle integrity, it has been proposed that they are in some way destroyed by the inflammatory process, resulting in an acquired inability of the hair to replace its epithelial components, eventually resulting in permanent follicle loss (Eichmuller et al., 1998Eichmuller S. van der Veen C. Moll I. Hermes B. Hofmann U. Muller-Rover S. et al.Clusters of perifollicular macrophages in normal murine skin: physiological degeneration of selected hair follicles by programmed organ deletion.J Histochem Cytochem. 1998; 46: 361-370Crossref PubMed Scopus (73) Google Scholar; Harries et al., 2008aHarries M.J. Meyer K.C. Paus R. Hair loss as a result of cutaneous autoimmunity: frontiers in the immunopathogenesis of primary cicatricial alopecia.Autoimmun Rev. 2008Google Scholar; Hermes and Paus, 1998Hermes B. Paus R. Scar forming alopecia. Comments on classification, differential diagnosis and pathobiology.Hautarzt. 1998; 49: 462-472Crossref PubMed Scopus (27) Google Scholar). This hypothesis is supported by the following observations: (i) the location of the inflammatory infiltrate in PCA is typically centered on the bulge region (Harries et al., 2009Harries M.J. Trueb R. Tosti A. Messenger A. Whiting D.A. Sinclair R. et al.How not to get scar(r)ed: pointers to the correct diagnosis in patients with suspected primary cicatricial alopecia.Br J Dermatol. 2009; 160: 482-501Crossref PubMed Scopus (69) Google Scholar); (ii) the hair follicle epithelial progenitor cell marker keratin 15 is downregulated in LPP (Pozdnyakova and Mahalingam, 2008Pozdnyakova O. Mahalingam M. Involvement of the bulge region in primary scarring alopecia.J Cutan Pathol. 2008; 35: 922-925Crossref PubMed Scopus (44) Google Scholar), suggesting that eHFSCs located in the bulge are somehow destroyed by as yet obscure inflammatory processes; (iii) markers of bulge cell proliferation are downregulated in LPP (Mobini et al., 2005Mobini N. Tam S. Kamino H. Possible role of the bulge region in the pathogenesis of inflammatory scarring alopecia: lichen planopilaris as the prototype.J Cutan Pathol. 2005; 32: 675-679Crossref PubMed Scopus (84) Google Scholar), further supporting the concept that damage to eHFSCs in the bulge is important for at least LPP pathogenesis; and (iv) transgenic mice in which eHFSC cells undergo targeted deletion (exploiting the keratin 15 promoter) show complete hair follicle disappearance in the affected skin (Ito et al., 2005Ito M. Liu Y. Yang Z. Nguyen J. Liang F. Morris R.J. et al.Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis.Nat Med. 2005; 11: 1351-1354Crossref PubMed Scopus (931) Google Scholar). Intriguingly, however, prominent associated features usually seen in PCA, such as scarring, skin inflammation, epidermal atrophy, and follicular plugging (Harries et al., 2009Harries M.J. Trueb R. Tosti A. Messenger A. Whiting D.A. Sinclair R. et al.How not to get scar(r)ed: pointers to the correct diagnosis in patients with suspected primary cicatricial alopecia.Br J Dermatol. 2009; 160: 482-501Crossref PubMed Scopus (69) Google Scholar), are absent in these mice (Ito et al., 2005Ito M. Liu Y. Yang Z. Nguyen J. Liang F. Morris R.J. et al.Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis.Nat Med. 2005; 11: 1351-1354Crossref PubMed Scopus (931) Google Scholar). This suggests that eHFSC destruction is not the only critical feature of PCA pathogenesis (Harries et al., 2008aHarries M.J. Meyer K.C. Paus R. Hair loss as a result of cutaneous autoimmunity: frontiers in the immunopathogenesis of primary cicatricial alopecia.Autoimmun Rev. 2008Google Scholar). In fact, a key role of immunological events in PCA pathogenesis has long been evident from the many immunopathological in situ phenomena described in these disorders (Harries et al., 2009Harries M.J. Trueb R. Tosti A. Messenger A. Whiting D.A. Sinclair R. et al.How not to get scar(r)ed: pointers to the correct diagnosis in patients with suspected primary cicatricial alopecia.Br J Dermatol. 2009; 160: 482-501Crossref PubMed Scopus (69) Google Scholar; Olsen et al., 2003Olsen E. Stenn K. Bergfeld W. Cotsarelis G. Price V. Shapiro J. et al.Update on cicatricial alopecia.J Investig Dermatol Symp Proc. 2003; 8: 1-9Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar) and from the observed response of some PCA entities to treatment with immunosupressants (Harries et al., 2008bHarries M.J. Sinclair R. MacDonald-Hull S. Whiting D. Griffiths C.E. Paus R. Primary cicatricial alopecias—options for treatment.Br J Dermatol. 2008; 159: 1-22Crossref PubMed Scopus (80) Google Scholar). Moreover, proinflammatory cytokines are upregulated in LPP(Moretti et al., 2004Moretti S. Amato L. Massi D. Bianchi B. Gallerani I. Fabbri P. Evaluation of inflammatory infiltrate and fibrogenic cytokines in pseudopelade of Brocq suggests the involvement of T-helper 2 and 3 cytokines.Br J Dermatol. 2004; 151: 84-90Crossref PubMed Scopus (16) Google Scholar) and chronic cutaneous lupus erythematosus (Toro et al., 2000Toro J.R. Finlay D. Dou X. Zheng S.C. LeBoit P.E. Connolly M.K. Detection of type 1 cytokines in discoid lupus erythematosus.Arch Dermatol. 2000; 136: 1497-1501Crossref PubMed Scopus (44) Google Scholar), and appear to propagate recruitment of inflammatory cells, such as cytotoxic T lymphocytes, into lesional tissue. Direct cytotoxic cell damage (Wenzel et al., 2005Wenzel J. Uerlich M. Worrenkamper E. Freutel S. Bieber T. Tuting T. Scarring skin lesions of discoid lupus erythematosus are characterized by high numbers of skin-homing cytotoxic lymphocytes associated with strong expression of the type I interferon-induced protein MxA.Br J Dermatol. 2005; 153: 1011-1015Crossref PubMed Scopus (94) Google Scholar) and disordered apoptosis (Baima and Sticherling, 2001Baima B. Sticherling M. Apoptosis in different cutaneous manifestations of lupus erythematosus.Br J Dermatol. 2001; 144: 958-966Crossref PubMed Scopus (87) Google Scholar) are prominent in chronic cutaneous lupus erythematosus and suggest a central role in effecting tissue destruction in this disorder. Further, dysfunction of normal hair follicle immune protection systems—such as immune privilege collapse in the hair follicle bulge, which nurtures an immunosuppressive environment that may normally protect eHFSC from autoimmune destruction (Meyer et al., 2008Meyer K.C. Klopper J.E. Dinh H.V. Harries M.J. Reithmayer K. Meyer W. et al.Evidence that the bulge region is a site of relative immune privilege in human hair follicles.Br J Dermatol. 2008; 159: 1077-1085PubMed Google Scholar), including loss of the important "no danger" signal, CD200 (Rosenblum et al., 2006Rosenblum M.D. Yancey K.B. Olasz E.B. Truitt R.L. CD200, a "no danger" signal for hair follicles.J Dermatol Sci. 2006; 41: 165-174Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar)—is now thought to contribute to the immunopathology in PCA (Harries et al., 2008aHarries M.J. Meyer K.C. Paus R. Hair loss as a result of cutaneous autoimmunity: frontiers in the immunopathogenesis of primary cicatricial alopecia.Autoimmun Rev. 2008Google Scholar), complementing the existing evidence for irreversible eHFSC damage in the pathogenesis of PCA (Figure 1).A novel role for PPARγ in lichen planopilaris From this background, Karnik et al., 2009Karnik P. Tekeste Z. McCormick T.S. Gilliam A.C. Price V.H. et al.Hair follicle stem cell-specific PPARγ deletion causes scarring alopecia.J Invest Dermatol. 2009; 129: 1243-1257Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar) greatly expand our understanding of PCA pathogenesis. These authors present a clear and systematic argument in support of the claim that downregulation of PPARγ is a central mechanism in LPP pathogenesis. The authors propose that deficiency of this ubiquitous transcription factor not only explains the early sebaceous gland atrophy seen in this condition, but also accounts for the immune dysfunction and (presumed) stem cell destruction seen in these disorders. This work promises to link the current theories of PCA pathogenesis (discussed above) into a coherent explanation for all the recognized phenotypic features seen in PCA. PPARγ is a nuclear hormone receptor that is recognized as playing a central role in lipid homeostasis (Schmuth et al., 2008Schmuth M. Jiang Y.J. Dubrac S. Elias P.M. Feingold K.R. Thematic review series: skin lipids. Peroxisome proliferator-activated receptors and liver X receptors in epidermal biology.J Lipid Res. 2008; 49: 9-509Crossref Scopus (152) Google Scholar) and, in particular, in the differentiation and maturation of sebocytes (Michalik and Wahli, 2007Michalik L. Wahli W. Peroxisome proliferator-activated receptors (PPARs) in skin health, repair and disease.Biochim Biophys Acta. 2007; 1771: 991-998Crossref PubMed Scopus (130) Google Scholar). However, the rapidly growing literature on PPARγ clearly highlights a much more diverse role for this nuclear hormone receptor, which simultaneously orchestrates the regulation of numerous distinct metabolic and inflammatory processes in different cell types (Sertznig et al., 2008Sertznig P. Seifert M. Tilgen W. Reichrath J. Peroxisome proliferator-activated receptors (PPARs) and the human skin: importance of PPARs in skin physiology and dermatologic diseases.Am J Clin Dermatol. 2008; 9: 15-31Crossref PubMed Scopus (88) Google Scholar) in the control of tissue function. PPARγ is a ligand-dependent transcription factor that activates genes containing "PPAR response elements" in their promoter sequence when the appropriate (natural or exogenous) ligand becomes bound. The anti-inflammatory effects of PPARγ are numerous, with cytokine production, adhesion molecule expression, and immune cell function under the influence of its expression. Proinflammatory cytokines (e.g., tumor necrosis factor-α and IFN-γ) can downregulate PPARγ expression, whereas ligands of PPARγ (e.g., thiazolidinediones) can inhibit proinflammatory cytokine secretion in a dose-dependent manner (Szeles et al., 2007Szeles L. Torocsik D. Nagy L. PPARgamma in immunity and inflammation: cell types and diseases.Biochim Biophys Acta. 2007; 1771: 1014-1030Crossref PubMed Scopus (124) Google Scholar). To name just a few examples, PPARγ dysfunction may underlie a large spectrum of disease states, including atherosclerosis, scleroderma, and cancer cachexia, and PPARγ downregulation has been reported in psoriasis and atopic dermatitis (Plager et al., 2007Plager D.A. Leontovich A.A. Henke S.A. Davis M.D. McEvoy M.T. Sciallis 2nd, G.F. et al.Early cutaneous gene transcription changes in adult atopic dermatitis and potential clinical implications.Exp Dermatol. 2007; 16: 28-36Crossref PubMed Scopus (48) Google Scholar; Schmuth et al., 2008Schmuth M. Jiang Y.J. Dubrac S. Elias P.M. Feingold K.R. Thematic review series: skin lipids. Peroxisome proliferator-activated receptors and liver X receptors in epidermal biology.J Lipid Res. 2008; 49: 9-509Crossref Scopus (152) Google Scholar). Of particular interest to PCA pathogenesis is the fact that stearoyl-CoA desaturase 1 in mouse liver is regulated by PPARγ (see the discussion below of the asebia mouse) (Miller and Ntambi, 1996Miller C.W. Ntambi J.M. Peroxisome proliferators induce mouse liver stearoyl-CoA desaturase 1 gene expression.Proc Natl Acad Sci USA. 1996; 93: 9443-9448Crossref PubMed Scopus (212) Google Scholar) and that PPARγ dysfunction may promote fibrosis in scleroderma (Ghosh et al., 2004Ghosh A.K. Bhattacharyya S. Lakos G. Chen S.J. Mori Y. Varga J. Disruption of transforming growth factor beta signaling and profibrotic responses in normal skin fibroblasts by peroxisome proliferator-activated receptor gamma.Arthritis Rheum. 2004; 50: 1305-1318Crossref PubMed Scopus (172) Google Scholar). Disordered sebaceous gland function has been proposed as a pathomechanism in PCA—based primarily on observations in the asebia mutant mouse (Scd1ab), which exhibits a scarring alopecia phenotype (Stenn, 2001Stenn K.S. Insights from the asebia mouse: a molecular sebaceous gland defect leading to cicatricial alopecia.J Cutan Pathol. 2001; 28: 445-447Crossref PubMed Scopus (43) Google Scholar; Zheng et al., 1999Zheng Y. Eilertsen K.J. Ge L. Zhang L. Sundberg J.P. Prouty S.M. et al.Scd1 is expressed in sebaceous glands and is disrupted in the asebia mouse.Nat Genet. 1999; 23: 268-270Crossref PubMed Scopus (186) Google Scholar)—on the basis that it causes deficiency in the enzyme stearoyl-CoA desaturase 1. This results in sebaceous gland atrophy, defective gland secretion, and a massive overpopulation of the skin with mast cells. In these mice, the inner root sheath fails to desquamate, impeding hair shaft egress. Eventually, retrograde growth of the hair shaft occurs, causing the shaft to penetrate the bulb and incite a foreign-body reaction, with subsequent permanent hair follicle destruction. Although it remains to be seen whether this mechanism is important in major forms of human PCA, and whether it is the primary enzyme defect or a primary mast cell deregulation that is the key factor in this model, the current study by Karnik et al., 2009Karnik P. Tekeste Z. McCormick T.S. Gilliam A.C. Price V.H. et al.Hair follicle stem cell-specific PPARγ deletion causes scarring alopecia.J Invest Dermatol. 2009; 129: 1243-1257Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar is an impetus to reinvestigate the role of lipid metabolism and peroxisome biogenesis disturbances in PCA pathogenesis. Specifically, Karnik et al., using microarray and quantitative PCR techniques, show significant downregulation of PPARγ gene expression in paired lesional and uninvolved samples from patients with LPP. They also report absent peroxisome expression in lesional samples of LPP and demonstrate that, in cultured epidermal keratinocytes and outer root sheath cells, PPARγ agonists upregulate peroxisome expression. Finally, they describe a LPP-like phenotype in mutant mice subjected to a keratin 15 promoter–targeted deletion of PPARγ in the eHFSC-rich bulge region. This important new evidence supports the concept that defects in lipid metabolism and peroxisome biogenesis may well be implicated in LPP pathogenesis (see Figure 1). However, some methodological shortcomings of the study necessitate prudence when considering its conclusions. First, by extracting RNA from whole-tissue samples, the authors effectively present the average gene expression from a massive number of quite diverse cells, which may have masked subtle (yet possibly biologically more important) differences in gene expression among cell types or distinct tissue compartments as a result of massive background mRNA expression ("noise") in the sample. Laser-capture microdissection of defined hair follicle and sebaceous gland compartments from affected and nonlesional LPP hair follicles, compared with healthy controls, followed using subsequent microarray and quantitative PCR analyses, should be able to address this problem. Second, there is an overreliance on gene expression data without confirmation of the findings at the protein level, which would have been particularly interesting in the determination of whether protein changes are localized to specific cells or tissue compartments. This can now be accomplished in follow-up work stimulated by the study. Third, the authors conclude that the observed downregulation of PPARγ in LPP deregulates lipid metabolism in the pilosebaceous unit, leading to the accumulation of proinflammatory lipids. However, this conclusion is extrapolated from gene expression data alone, obtained from whole-tissue samples, without clear demonstration at the protein level of a buildup of proinflammatory lipids in the follicle and sebaceous gland. In fact, an alternative interpretation from this study could be that downregulation of PPARγ results in immune dysfunction (e.g., with the accumulation of proinflammatory, hair growth–inhibitory cytokines), which then causes eHFSC damage. Fourth, the authors conclude that xenobiotic metabolism, particularly via the ligand-dependent transcription factor aryl-hydrocarbon, may trigger LPP—a conclusion based on extrapolation from microarray findings showing upregulation of the P450 cytochrome CYP1A1. Unfortunately, there was no comparison with values from normal samples, and confounding factors, such as topical medication, perceived stress, and UV exposure (all of which may have substantially altered gene expression), remain to be controlled for. Fifth, although the skin and hair phenotype of the mutant mice can be interpreted as sufficient evidence to support a key role for PPARγ in the pathogenesis of LPP-like hair pathology in mice, not all features of human LPP (e.g., epidermal atrophy) seem to be reproduced in keratin 15–targeted PPARγ knockout mice. It remains unclear to what extent the considerable growth stunting of the mutant mice and their marked scratching behavior may have influenced the clinical findings. Sixth, if insufficient PPARγ stimulation plays a key role in human LPP, why are there no case reports of LPP patients whose alopecia has responded favorably to concomitant therapy with widely prescribed PPARγ agonists such as rosiglitazone, pioglitazone, and various nonsteroidal anti-inflammatory drugs? (Harries et al., 2008bHarries M.J. Sinclair R. MacDonald-Hull S. Whiting D. Griffiths C.E. Paus R. Primary cicatricial alopecias—options for treatment.Br J Dermatol. 2008; 159: 1-22Crossref PubMed Scopus (80) Google Scholar). Has this merely been overlooked (e.g., because LPP patients on thiazolidinedione medication make up a very small population) or is the identified PPARγ signaling defect less important for human than for mouse hair follicle biology? These concerns are dwarfed by the seminal contribution that the study by Karnik et al. makes as an infusion of new life into a long-ailing field of investigative dermatology by highlighting the potential importance of defects in lipid metabolism and peroxisome biogenesis in PCA pathogenesis—a convincing and thought-provoking new paradigm in PCA research. This work should encourage other investigators to run the required systematic immunohistological follow-up studies, ideally supplemented by laser-capture microdissection techniques, and to explore in functional assays (e.g., with organ-cultured human scalp hair follicles or intact scalp skin) how stimulation and antagonism of PPARγ receptors alter human pilosebaceous unit biology. Karnik et al., 2009Karnik P. Tekeste Z. McCormick T.S. Gilliam A.C. Price V.H. et al.Hair follicle stem cell-specific PPARγ deletion causes scarring alopecia.J Invest Dermatol. 2009; 129: 1243-1257Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar also encourage genetic analyses of PPARγ polymorphisms/single-nucleotide polymorphisms to identify susceptibility markers in affected individuals and introduce the question of whether examination of rare peroxisome disorders, such as chondrodysplasia punctata, which—intriguingly—displays a cicatricial alopecia phenotype (Steinberg et al., 2008Steinberg S. Jones R. Tiffany C. Moser A. Investigational methods for peroxisomal disorders.Curr Protoc Hum Genet. 2008; 17 (Chapter, Unit 17.6)PubMed Google Scholar), may shed additional light on the molecular pathogenesis of PCA. Finally, it is relevant to investigate systematically whether therapy with commonly employed PPARγ agonists (such as the thiazolidinediones, nonsteroidal anti-inflammatory drugs, and angiotensin II receptor antagonists) can alter the clinical course of PCA, namely, that of LPP. Obviously, the disappointing history of PPARγ agonists in psoriasis management (Ellis et al., 2007Ellis C.N. Barker J.N. Haig A.E. Parker C.A. Daly S. Jayawardene D.A. Placebo response in two long-term randomized psoriasis studies that were negative for rosiglitazone.Am J Clin Dermatol. 2007; 8: 93-102Crossref PubMed Scopus (31) Google Scholar) tempers our optimism that PPARγ stimulation will usher in a new era of efficiency in the very difficult and unsatisfactory management of LPP. Therefore, we are well advised to continue in the systematic exploration of other immunoregulatory defects (such as those summarized in Figure 1) that may conspire to cause irreversible eHFSC damage. These cautionary notes notwithstanding, Karnik and colleagues show us an exciting and important new avenue in PCA pathogenesis research. By building on the vast accumulated knowledge on the role of PPARγ function and dysfunction in other diseases and medical specialties (Bensinger and Tontonoz, 2008Bensinger S.J. Tontonoz P. Integration of metabolism and inflammation by lipid-activated nuclear receptors.Nature. 2008; 454: 470-477Crossref PubMed Scopus (601) Google Scholar; Landreth et al., 2008Landreth G. Jiang Q. Mandrekar S. Heneka M. PPARgamma agonists as therapeutics for the treatment of Alzheimer's disease.Neurotherapeutics. 2008; 5: 481-489Crossref PubMed Scopus (215) Google Scholar), we are likely to make significant progress in understanding at least one pathway through which eHFSCs may suffer irreversible damage and in developing strategies for preventing this damage. The authors state no conflict of interest. The writing of this commentary was made possible in part by the Geoffrey-Dowling Fellowship from the British Association of Dermatologists to MJH, a grant from the University of Lübeck Research Focus Programme on Autoimmunity to RP, and research grants from the Cicatricial Alopecia Research Foundation and British Skin Foundation to MJH and RP.
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