RESUMEN
BACKGROUND: In patients with inflammatory bowel disease (IBD), accelerated bone loss and osteopenia have been found. Potential etiologies of these bone abnormalities have included malnutrition, poor calcium intake or absorption, and the use of corticosteroids. Recent studies have suggested that circulating pro-inflammatory cytokines, which are produced in inflamed bowel, can have a profound effect on bone metabolism, particularly bone resorption. Our aim was to characterize the effects of serum from subjects with IBD on bone metabolism in an in vitro bone culture system. METHODS: Organ cultures of fetal rat parietal bones were treated with sera from 9 subjects with Crohn's disease, 7 with ulcerative colitis, and 10 controls with functional bowel disease (age range of all subjects 7-16 years). Patients were also classified by disease activity, serum albumin level, erythrocyte sedimentation rate (ESR), and serum interleukin (IL) 6 levels. The effects of sera on bone formation and resorption were quantified. RESULTS: Compared with control serum, serum from patients with Crohn's disease significantly decreased bone dry weight (p < 0.01) and calcium content (p < 0.001) during 96 h of culture, while serum from ulcerative colitis patients had no effect. While no difference in collagen synthesis was noted between any of the three experimental groups, noncollagen protein synthesis was lower in the ulcerative colitis group than in the control group or those with Crohn's disease (p < 0.05). DNA content was similar in all groups. There was no significant effect of serum from any experimental group on bone resorption. There was no demonstrable relationship between clinical disease activity, ESR, or serum IL-6 levels and measures of bone metabolism. Histologic evaluation of cultured bone showed marked differences between control subjects and Crohn's disease patients, with the latter being characterized by disorganization of mineral and osteoid and morphologically abnormal osteoblasts. CONCLUSIONS: Serum from children with IBD has a significantly different effect than control serum on an in vitro model of bone metabolism. Our data suggest that circulating factors may affect osteoblasts and bone formation, leading to bone loss. Further work will be required to further characterize the nature of these factors and develop treatment strategies to minimize their effects.
Asunto(s)
Huesos/metabolismo , Enfermedades Inflamatorias del Intestino/metabolismo , Adolescente , Animales , Sedimentación Sanguínea , Resorción Ósea , Huesos/embriología , Niño , Colitis Ulcerosa/sangre , Colitis Ulcerosa/metabolismo , Colágeno/metabolismo , Colagenasas/metabolismo , Enfermedad de Crohn/sangre , Enfermedad de Crohn/metabolismo , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/sangre , Interleucina-6/sangre , Masculino , Técnicas de Cultivo de Órganos , Prolina/metabolismo , Ratas , Albúmina Sérica/metabolismoRESUMEN
Previous work has suggested that the interleukin-1 (IL-1) receptor antagonist, IL-1ra, may regulate mucosal inflammation in inflammatory bowel disease. The present study assessed the relationship of mucosal IL-1ra levels to histologic severity of inflammation and the related proinflammatory cytokines IL-1 beta and IL-6 in children with inflammatory bowel disease. Colonic biopsy specimens from 29 patients with ulcerative colitis, 27 with Crohn's disease, and 24 noninflammatory control subjects were assayed for IL-1ra, IL-1 beta, and IL-6 by enzyme-linked immunosorbent assay. Histologic activity was graded as none, mild, moderate, or severe. Mucosal IL-1 beta levels, but not IL-1ra levels, were significantly elevated in moderate/severely inflamed biopsies from patients with either ulcerative colitis (p < 0.01) or Crohn's disease (p < 0.001) compared with those with none/mild inflammation. The mucosal molar ratio of IL-1ra/IL-1 beta was significantly lower for moderate/severe inflammation compared with none/mild inflammation for patients with ulcerative colitis (p < 0.05) and Crohn's disease (p < 0.01). The mucosal IL-1ra/IL-1 beta ratio was similar in controls to none/mild inflamed biopsies from subjects with either ulcerative colitis or Crohn's disease. Our observations suggest that increasing mucosal inflammation in inflammatory bowel disease in children is associated with a decrease in the "normal" effective IL-1ra/IL-1 beta ratio in which IL-1ra predominates. The importance of this abnormality to the pathogenesis of inflammatory bowel disease awaits further study.
Asunto(s)
Colitis Ulcerosa/patología , Enfermedad de Crohn/patología , Mucosa Intestinal/patología , Sialoglicoproteínas/fisiología , Adolescente , Adulto , Biopsia , Niño , Colitis Ulcerosa/metabolismo , Enfermedad de Crohn/metabolismo , Ensayo de Inmunoadsorción Enzimática , Humanos , Proteína Antagonista del Receptor de Interleucina 1 , Interleucina-1/análisis , Interleucina-6/análisis , Mucosa Intestinal/metabolismo , Sialoglicoproteínas/análisisRESUMEN
The cytokines IL-1 beta and IL-6 appear to be important in the pathogenesis of inflammatory bowel disease (IBD). Recently, a naturally occurring interleukin-1 receptor antagonist, designated IL-1ra, which inhibits IL-1 beta activity in vitro and in vivo has been described. The purpose of the present study was to assess the circulating levels and relative relationships of IL-1ra, IL-1 beta, and IL-6 in children with IBD of varying severity. Serum/plasma samples were obtained from 32 children with ulcerative colitis, 45 with Crohn's disease, and 24 control patients. Cytokine assays were performed by enzyme-linked immunoassay. IL-1ra levels were significantly elevated in children with ulcerative colitis or Crohn's disease of moderate/severe activity compared to patients with inactive/mild IBD or control subjects (P < 0.001). IL-1 beta was only detectable in the circulation of two subjects with severe colitis (one ulcerative colitis, one Crohn's disease), and both had extremely elevated IL-1ra levels. IL-1ra levels were significantly related to IL-6 levels for patients with IBD (P < 0.00001). Our results suggest that circulating IL-1ra appears in increasing concentrations in children with mounting degrees of disease severity as determined by clinical scoring methods as well as by the level of IL-6. Future work will need to address the clinical and prognostic value of measuring circulating IL-1ra in individuals with inflammatory bowel disease.
Asunto(s)
Colitis Ulcerosa/sangre , Enfermedad de Crohn/sangre , Interleucina-1/sangre , Receptores de Interleucina-1/antagonistas & inhibidores , Adolescente , Adulto , Niño , Colitis Ulcerosa/etiología , Enfermedad de Crohn/etiología , Femenino , Humanos , Interleucina-6/sangre , MasculinoRESUMEN
BACKGROUND: Intestinal and peripheral blood mononuclear cell interleukin 6 (IL-6) production in inflammatory bowel disease might present an increased quantity of IL-6 into the systemic circulation. The aim of the present study was to examine the relationship of circulatory IL-6 to the clinical and laboratory expression of inflammatory bowel disease in children. METHODS: Sera were obtained from 26 children with ulcerative colitis, 49 with Crohn's disease, and 29 control patients. Serum functional IL-6 was measured by a bioassay and antigenic IL-6 by enzyme linked immunosorbent assay. RESULTS: Functional and antigenic serum IL-6 levels were higher in Crohn's disease than in ulcerative colitis or controls (P < 0.0001) and higher in ulcerative colitis than controls (P < 0.04). In Crohn's disease affecting the colon, functional and antigenic serum IL-6 levels were greater than in disease limited to the small bowel (P < 0.002). Increasing disease severity was reflected by increasing antigenic but not functional IL-6 levels in both Crohn's disease (P < 0.001) and ulcerative colitis (P < 0.02). Serum antigenic IL-6 levels were related to acute phase reactants in both diseases (P < 0.001) whereas functional levels were not. CONCLUSIONS: Our results underscore the importance of using both functional and antigenic methodologies in examining the relationship of circulating cytokines to the clinical manifestations of inflammatory bowel disease.
Asunto(s)
Antígenos/inmunología , Enfermedades Inflamatorias del Intestino/sangre , Enfermedades Inflamatorias del Intestino/inmunología , Interleucina-6/sangre , Interleucina-6/inmunología , Proteínas de Fase Aguda/análisis , Adolescente , Adulto , Bioensayo , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/patología , Masculino , Pronóstico , Índice de Severidad de la EnfermedadRESUMEN
The serum concentrations of the carboxy-terminal propeptide of type I procollagen and the amino-terminal propeptide of type III procollagen as biochemical markers of growth activity were compared in 46 children and adolescents with inflammatory bowel disease. Significant correlations were noted between growth velocity and type I procollagen (r = 0.65; P less than 0.001) and type III procollagen concentrations (r = 0.64; P less than 0.001). Although the serum concentration of type I procollagen was generally about 15 times greater than that of type III, the respective serum concentrations were highly correlated (r = 0.66; P less than 0.001) at all growth velocities. The use of daily corticosteroid therapy was associated with significantly lower concentrations of both propeptides (P less than 0.01) than was alternate-day or no corticosteroid therapy, respectively. Children with growth arrest (0.0 cm/mo) had type I and type III procollagen concentrations similar to those found in adults. These observations indicate that the serum concentrations of both collagen propeptides reflect growth activity in children with inflammatory bowel disease and suggest that routine measurement of collagen propeptides may have clinical value in monitoring normal and abnormal growth. The data suggest that the measurement of one propeptide does not offer an advantage over the other.
Asunto(s)
Biomarcadores/sangre , Trastornos del Crecimiento/sangre , Enfermedades Inflamatorias del Intestino/sangre , Fragmentos de Péptidos/sangre , Procolágeno/sangre , Adolescente , Análisis de Varianza , Niño , Preescolar , Femenino , Trastornos del Crecimiento/diagnóstico , Trastornos del Crecimiento/etiología , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/fisiopatología , MasculinoRESUMEN
Chronic undernutrition and high-dose daily corticosteroid therapy are well-accepted causes of growth failure in children with inflammatory bowel disease. Occasionally, children are seen with minimal gastrointestinal symptoms but in whom severe anorexia and profound growth impairment are evident. Recent observations that elevated serum levels of tumor necrosis factor-alpha (TNF) in cachexia associated with a number of disease states have suggested a similar possible role in inflammatory bowel disease. Accordingly, we determined TNF levels in 45 children and adolescents with inflammatory bowel disease (18 ulcerative colitis, 27 Crohn's disease) at varying times during their clinical course and compared them to values obtained from a group of 25 children with functional bowel disease. No differences were noted in serum TNF levels between the children with inflammatory bowel disease and the control population. Values were generally within the range of the lower limit of detection of the assay. In the children with inflammatory bowel disease, there was no significant correlation between TNF levels and disease activity or growth parameters. Our observations suggest that elevated TNF levels are not associated with inflammatory bowel disease in children.