Hair Follicle Stem Cell-Specific PPARγ Deletion Causes Scarring Alopecia
Hair Follicle Stem Cell-Specific PPARγ Deletion Causes Scarring Alopecia
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DOI：
10.1038/jid.2008.369
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发表时间：
2009-05-01
影响因子：
6.5
通讯作者：
Mirmirani, Paradi
中科院分区：
文献类型：
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作者：
Karnik, Pratima;Tekeste, Zenar;Mirmirani, Paradi
原发性瘢痕性或瘢痕性脱发（CA）是一组发病机制未知的炎症性头发疾病，其特征是毛囊的永久性破坏。目前的治疗方案在控制疾病进展方面是无效的，主要是因为CA的分子基础尚不清楚。与正常头皮活检相比，对淋巴细胞性扁平毛癣（LPP）的微阵列分析发现，脂质代谢和过氧化物酶体生物发生所需基因的表达减少。免疫组织化学分析显示过氧化物酶体的进行性丢失，促炎脂质积累，炎症细胞浸润，随后毛囊皮脂腺单位破坏。调控这些过程的转录因子过氧化物酶体增殖物激活受体(PPAR) γ的表达在LPP中显著降低。PPAR γ特异性激动剂可有效诱导人角质形成细胞的过氧化物酶体和脂质代谢基因表达。最后，小鼠滤泡干细胞中PPAR γ的靶向缺失导致皮肤和头发表型模拟瘢痕性脱发。这些研究表明，PPAR γ对健康的毛囊皮脂腺单位至关重要，正是这种功能的丧失引发了LPP的发病机制。我们认为PPAR靶向治疗可能是治疗这些疾病的一种新策略。
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 PPAR gamma are effective in inducing peroxisomal and lipid metabolic gene expression in human keratinocytes. Finally, targeted deletion of PPAR gamma in follicular stem cells in mice causes a skin and hair phenotype that emulates scarring alopecia. These studies suggest that PPAR gamma is crucial for healthy pilosebaceous units and it is the loss of this function that triggers the pathogenesis of LPP. We propose that PPAR gamma-targeted therapy may represent a new strategy in the treatment of these disorders.