The Role of Tryptophan Metabolites in Musculoskeletal Stem Cell Aging.

Although aging is considered a normal process, there are cellular and molecular changes that occur with aging that may be detrimental to health. Osteoporosis is one of the most common age-related degenerative diseases, and its progression correlates with aging and decreased capacity for stem cell differentiation and proliferation in both men and women. Tryptophan metabolism through the kynurenine pathway appears to be a key factor in promoting bone-aging phenotypes, promoting bone breakdown and interfering with stem cell function and osteogenesis; however, little data is available on the impact of tryptophan metabolites downstream of kynurenine. Here we review available data on the impact of these tryptophan breakdown products on the body in general and, when available, the existing evidence of their impact on bone. A number of tryptophan metabolites (e.g., 3-hydroxykynurenine (3HKYN), kynurenic acid (KYNA) and anthranilic acid (AA)) have a detrimental effect on bone, decreasing bone mineral density (BMD) and increasing fracture risk. Other metabolites (e.g., 3-hydroxyAA, xanthurenic acid (XA), picolinic acid (PIA), quinolinic acid (QA), and NAD+) promote an increase in bone mineral density and are associated with lower fracture risk. Furthermore, the effects of other tryptophan breakdown products (e.g., serotonin) are complex, with either anabolic or catabolic actions on bone depending on their source. The mechanisms involved in the cellular actions of these tryptophan metabolites on bone are not yet fully known and will require further research as they are potential therapeutic targets. The current review is meant as a brief overview of existing English language literature on tryptophan and its metabolites and their effects on stem cells and musculoskeletal systems. The search terms used for a Medline database search were: kynurenine, mesenchymal stem cells, bone loss, tryptophan metabolism, aging, and oxidative stress.

Rare clinical form in two patients affected by a new variant of endemic pemphigus in northern Colombia.

BACKGROUND: Recently, the authors described a new variant of endemic pemphigus foliaceus in rural areas surrounding El Bagre, Colombia, but without association with malignant tumors. METHODS: The authors' 10-year fieldwork provided the opportunity to observe various manifestations of El Bagre endemic pemphigus foliaceus, including the presence of bilateral plaques in pretibial areas. RESULTS: Based on personal experience and literature reviews, the authors have correlated the auto-antibody profile with the appearance of pretibial plaques. CONCLUSION: Since pretibial plaques occur in patients with both fogo selvagem and El Bagre variants of endemic pemphigus foliaceus, as well as in other forms of pemphigoid, these diseases must be considered in the differential diagnosis of patients with clinical, immunologic, and/or epidemiologic risk factors.

A unique form of endemic pemphigus in northern Colombia.

BACKGROUND: Endemic forms of pemphigus are a unique group of autoimmune diseases that represent opportunities to study interactions of the environment and genetics with the immune system. The restriction to relatively well-defined regions of South and Central America and perhaps Africa characterizes these diseases. OBJECTIVES: The aims of this study were to confirm the endemic nature of a new type of autoimmune disease occurring in a mining town in northeastern Colombia in the El Bagre area, to characterize it, and to compare it with other forms of endemic pemphigus. METHODS: A 10-year prospective, controlled epidemiologic, humanitarian, and immunologic fieldwork case-control survey was performed in El Bagre, Colombia. RESULTS: Our work revealed that this disease is endemic in rural areas surrounding El Bagre. The disease appeared in 4.7% of middle-aged and older men and postmenopausal women from these rural areas. This disease differs from previously described forms of endemic pemphigus. It shares some heterogeneous immunoreactivity with paraneoplastic pemphigus but is not associated with malignant tumors. The disease resembles Senear-Usher syndrome (pemphigus and lupus) but occurs endemically either with a localized stable clinical course or in a systemic form. This systemic form may affect organs other than skin and is characterized by episodic relapses and poor prognosis in comparison with the localized form. CONCLUSION: We have confirmed endemic pemphigus foliaceus in El Bagre as an autoimmune disease that shares features with Senear-Usher syndrome but occurs in an endemic fashion. Heterogeneous antigenic reactivity is observed as in paraneoplastic pemphigus but with no evidence of association with neoplasia. In addition, constant exogenous antigenic stimulation and a genetic predisposition may be required in the pathogenesis of this disease.

Analyses of autoantigens in a new form of endemic pemphigus foliaceus in Colombia.

BACKGROUND: We previously described a new focus of endemic pemphigus foliaceus in rural areas of El Bagre, Colombia, with clinical and direct immunofluorescence characteristics of pemphigus erythematosus. OBJECTIVE: The aim of this study was to characterize autoantigen profiles for 34 serum samples obtained from patients with this condition. METHODS: Immunofluorescence, various immunoblot analyses with different antigen sources and detection methods, and immunoprecipitation were performed. RESULTS: Immunofluorescence with the use of human skin sections showed IgG autoantibodies against keratinocyte cell surfaces in all 34 serum samples. Some samples also showed weak reactivity with the basement membrane zone. The results of immunoblot and immunoprecipitation analysis indicated that all sera had antibodies reactive with desmoglein 1, the pemphigus foliaceus antigen. In addition, in various immunoblot assays, many sera reacted with several other proteins with molecular weights of 250 kd, 210 kd, and 190 kd, which appear to correspond to desmoplakin I, envoplakin, and periplakin, respectively. CONCLUSION: This endemic pemphigus disease in El Bagre showed immunologic features similar to pemphigus foliaceus or erythematosus. In addition, paraneoplastic pemphigus-like reactivity with various epidermal antigens was detected.

Detection of mercury and other undetermined materials in skin biopsies of endemic pemphigus foliaceus.

A novel variant of endemic pemphigus foliaceus (EPF) was described among individuals in an area surrounding El Bagre, Colombia, South America. The population in this rural mining community is exposed to high environmental levels of mercury, used for gold extraction, as well as other minerals, metalloids, and trace elements (e.g., quartz, rutile, granite, magnetite, and almenite) and ultraviolet radiation. Fifty control subjects and fifty EPF patients in the endemic area were examined for the presence of mercury in skin biopsies and hair, using autometallographic and mass spectroscopic analyses, respectively. Simultaneously, serum levels of IgE were measured, and cutaneous tests for hypersensitivity reactions were performed. Using autometallography, mercuric sulfides/selenides were detected in 14 of 51 skin biopsies distributed similarly in the control and patient groups. However, significantly higher serum IgE levels and mercury concentrations in hair, urine, and nails were found in patients compared with controls. Microscopic analysis revealed mercuric sulfides/selenides concentrated within and around the sweat gland epithelium, as well as in dendritic cells. Five skin biopsies from EPF patients and five from controls that tested positive for the presence of mercuric sulfides/selenides by autometallography were randomly selected for electron microscopic analysis. This analysis revealed a mixed electron-dense and electron-light material closely associated with desmosomes in patients. However, there were intracellular vesicles containing an amalgam of electron-dense and electron-light materials only in the EPF patients. Thus, EPF-affected individuals are exposed to high levels of environmental mercuric sulfides/selenides and other elements. This is the first study reporting mercuric sulfides/selenides in skin biopsies from people living in a focus of EPF, and these compounds may play a role in the pathogenesis of autoimmunity.