Melanocortin receptor type 2 (MC2R, ACTH receptor) expression in patients with alopecia areata.

Human skin expresses elements of the hypothalamo-pituitary-adrenal (HPA) axis that function as a local stress response system. Because adrenocorticotropic hormone (ACTH) is an intermediate in the HPA axis from corticotropin-releasing hormone (CRH) signal to cortisol secretion, MC2R that binds only ACTH may be important in the stress response of skin. We investigated the local expression of MC2R by immunohistochemistry to identify the role of ACTH/MC2R in stress-associated alopecia areata (AA). MC2R appeared to be highly compartmentalized in scalp skin including the epidermal cells of hair follicles and epidermis, sebaceous and eccrine glands, as well as dermal fibroblasts. The expression of MC2R was lower in AA lesions than in normal scalp tissue in almost all scalp skin cells, especially in epithelial cells. These findings demonstrate that MC2R expression is aberrant in AA and suggest a deficit in ACTH/MC2R activity may play an important role in the pathophysiology of AA.

Smac/DIABLO regulates the apoptosis of hypertrophic scar fibroblasts.

In abnormal skin wound healing, hypertrophic scars (HS) are characterized by excessive fibroblast hypercellularity and an overproduction of collagen, leading to atypical extracellular matrix (ECM) remodeling. Although the exact mechanisms of HS remain unclear, decreased HS fibroblast (HSFB) apoptosis and increased proliferation are evident in the development of HS. In this study, the contribution of the second mitochondria-derived activator of caspases/direct inhibitor of apoptosis protein (IAP)-binding protein with a low isoelectric point (pI) (Smac/DIABLO), an apoptosis-promoting protein released from the mitochondria, was investigated in human normal skin and HSFB cultures. The expression of Smac/DIABLO is usually decreased in many malignant tumors compared with normal tissues. Immunohistochemical analysis of skin tissues and the western blot analyses of fibroblasts revealed that the expression of Smac/DIABLO was lower in HS tissues compared with normal skin tissues. Of note, adenovirus-mediated Smac/DIABLO overexpression in the cultured HSFBs significantly reduced cell proliferation, as detected by the cell counting kit-8, and increased caspase-3 and -9 activity, as detected by spectrofluorimetry. In addition, it increased apoptosis, as detected by fluorescence-activated cell sorting (FACS). Furthermore, we found that the silencing of Smac with siRNA in the HSFBs induced a noticeable decrease in caspase-3 and -9 activity, leading to a significant reduction in apoptosis. In addition, the mRNA expression of type I and III pro-collagen detected in the HSFBs was significantly increased following the silencing of Smac with siRNA and was inhibited following Smac/DIABLO overexpression, as shown by real-time RT-PCR. In conclusion, Smac/DIABLO decreases the proliferation and increases the apoptosis of HSFBs. To our knowledge, the data from our study suggest for the first time that Smac/DIABLO is a novel therapeutic target for HS.

The -2T/C polymorphism in the adrenocorticotropin receptor gene affects stress perception of patients with alopecia areata.

BACKGROUND: Altered hypothalamic-pituitary-adrenal (HPA) axis response involved in the pathogenesis of stress-associated alopecia areata (AA) has been reported. A novel polymorphism -2T>C of the adrenocorticotropin receptor (ACTHR) can result in an insufficient HPA response to stress; therefore, the functional polymorphism may underlie a role in stress-associated AA. OBJECTIVE: To investigate the relationship between psychosocial factors and the risk of developing AA and to detect the association between the -2T>C polymorphism of ACTHR and AA. METHODS: Stressful situations were evaluated using Holmes and Rahe's social readjustment rating scale. The ACTHR -2T>C polymorphism was examined in 263 patients with AA and 241 controls. RESULTS: Significant elevation of psychological stress experienced by some patients with AA compared with controls (Z = 6.628, P < 0.01). The frequency of the ACTHR C allele showed a significant difference between patients with AA and controls (P = 0.004). Allele C is the risk allele with a dominant model as the -2C allele occurred more often in patients with AA (P = 0.001). There were significant differences between patients with AA with a severe stress attack versus patients with AA with no obvious stress (P < 0.001), whereas the genotype frequencies were not correlated with the type, duration of disease, and age at onset. Notably, the C allele carrier was significantly associated with stress risk in both AA and controls (P = 0.002, OR = 1.576, 95% CI: 1.148-2.162; P = 0.042, OR = 1.529, 95% CI: 1.022-2.288). CONCLUSIONS: These findings suggest AA in some patients may be associated with stress. The ACTHR gene -2T>C variant may be one important factor that influences stress perception of patients with AA.

An implication for post-transcriptional control: reciprocal changes of melanocortin receptor type 2 mRNA and protein expression in alopecia areata.

Alopecia areata (AA) is a hair follicle-specific autoimmune disease that is inherited genetically but triggered environmentally. Stress response is believed to play a role in the pathogenesis of AA. The hypothalamic-pituitary-adrenal axis (HPA axis), known as the stress axis, plays a cardinal role in the stress response. Growing evidence demonstrates that stress responses are under the control of both the central and peripheral nervous systems. Skin and hair follicles display peripheral HPA axis-like signaling systems. Some studies have revealed that a modified HPA axis, which is characterized by enhanced CRH/CRHR and insufficient glucocorticoid, is involved in the pathology of AA, suggesting that the paradoxical expression differs from that of normal control and should be further examined. Because adrenocorticotropic hormone (ACTH) is an intermediary in the HPA axis, MC2R, which specifically binds ACTH, may be important in the stress response of skin. Therefore, we investigated the gene and protein expression of MC2R in AA lesions and tried to elucidate the connection between HPA axis regulation, MC2R and AA. Reciprocal changes in MC2R mRNA and proteins in human AA were observed in our study; while mRNA levels were higher in lesions from AA patients compared with scalp tissues from normal controls, protein levels of MC2R were lower. The paradoxical expression of MC2R gene and protein levels coincided with evidence that over-responsive HPA activity coexists with a deficient HPA response in AA. We hypothesized that the HPA axis response in human AA may be the following: stressors first activate excess CRH/CRHR to produce increased ACTH, which up-regulates the expression of MC2R mRNA, but the stress response cannot create sufficient cortisol when the binding of ACTH/MC2R is deficient due to decreased MC2R protein. This hypothesis rationally clarifies the changed HPA axis in human AA and highlights the importance of MC2R in the pathogenesis of AA. The inconsistent expression of protein and mRNA implicates post-transcriptional control of human MC2R gene expression as found in murine MC2R gene.