Division of mitochondria in cultured human fibroblasts.

Ovate mitochondria in cultured human fibroblasts divide by pinching. In the process, as observed by transmission electron microscopy, a deep incisure of the surface membranes separates the organelle into two lobes connected by a slender isthmus. A single element of smooth endoplasmic reticulum (SER) invariably accompanies each incisure, extending deep into the cleft. When the ingrowing membranes meet and fuse with the antipodal membranes, fission occurs. Elongated mitochondria that give no indication of division often are cloaked by a single, continuous cistern of SER.

Sterol intermediates of cholesterol biosynthesis inhibit hair growth and trigger an innate immune response in cicatricial alopecia.

Primary cicatricial alopecia (PCA) is a group of inflammatory hair disorders that cause scarring and permanent hair loss. Previous studies have implicated PPARγ, a transcription factor that integrates lipogenic and inflammatory signals, in the pathogenesis of PCA. However, it is unknown what triggers the inflammatory response in these disorders, whether the inflammation is a primary or secondary event in disease pathogenesis, and whether the inflammatory reaction reflects an autoimmune process. In this paper, we show that the cholesterol biosynthetic pathway is impaired in the skin and hair follicles of PCA patients. Treatment of hair follicle cells with BM15766, a cholesterol biosynthesis inhibitor, or 7-dehydrocholesterol (7-DHC), a sterol precursor, stimulates the expression of pro-inflammatory chemokine genes. Painting of mouse skin with 7-DHC or BM15766 inhibits hair growth, causes follicular plugging and induces the infiltration of inflammatory cells into the interfollicular dermis. Our results demonstrate that cholesterologenic changes within hair follicle cells trigger an innate immune response that is associated with the induction of toll-like receptor (TLR) and interferon (IFN) gene expression, and the recruitment of macrophages that surround the hair follicles and initiate their destruction. These findings reveal a previously unsuspected role for cholesterol precursors in PCA pathogenesis and identify a novel link between sterols and inflammation that may prove transformative in the diagnosis and treatment of these disorders.

Lipids to the top of hair biology.

Little attention has been given to the impact of lipid metabolism on hair follicle biology and pathology. Three recent papers (one in the current issue) describe a major effect of altered lipid metabolism on hair growth. A direct link was made to at least one form of cicatricial alopecia, but the role lipids play in other follicular pathologies, such as the acneiform conditions, are inadequately explored and must be tested.

Lichen planopilaris treated with a peroxisome proliferator-activated receptor gamma agonist.

Primary cicatricial alopecias (PCAs), rare disorders that lead to permanent hair loss, have been poorly understood and are difficult to treat. Lichen planopilaris (LPP)is a prototypical PCA; patients often present with sudden onset of hair loss and clinically significant symptoms of itching, burning, and pain of the scalp. Examination reveals patchy alopecia or a more diffuse thinning of the scalp with characteristic perifollicular erythema and perifollicular scale at the margins of the areas of alopecia.Treatment typically includes use of antiinflammatory medications; although symptoms may improve,hair loss is often progressive.

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.

Suppression of malignant growth of human breast cancer cells by ectopic expression of integrin-linked kinase.

Allelic loss at the short arm of chromosome 11 is one of the most common and potent events in the progression and metastasis of breast cancer. Here, we present evidence that the Integrin-Linked Kinase (ILK) gene maps to the commonly deleted chromosome 11p15.5 and suppresses malignant growth of human breast cancer cells both in vitro and in vivo. ILK is expressed in normal breast tissue but is downregulated in metastatic breast cancer cell lines and in advanced breast cancers. Transfection of wild-type ILK into the MDA-MB-435 mammary carcinoma cells potently suppressed their growth and invasiveness in vitro and reduced the cells' ability to induce tumors and metastasize in athymic nude mice. Conversely, expression of the ankyrin repeat or catalytic domain mutants of ILK failed to suppress the growth of these cells. Growth suppression by ILK is not due to apoptosis but is mediated by its ability to block cell-cycle progression in the G1 phase and by modulating the levels of integrins. These findings directly demonstrate that ILK deficiency facilitates neoplastic growth and invasion and suggest a novel role for the ILK gene in the suppression of tumor metastasis.