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Gastrointestinal tract conditions are frequently associated with low bone mineral density and increased risk of fractures due to osteoporosis, the latter concerning particularly inflammatory bowel disease (IBD) patients. One of the candidate genes involved in osteoporosis is the transforming growth factor beta-1 (TGFB1) whose polymorphisms may be responsible for the development of this disease. The aim of this study was to analyse the frequency of TGFB1 polymorphic variants and determine the association between the c.29T>C TGFB1 polymorphism, and bone mineral density and fractures in IBD patients. The study subjects included 198 IBD patients [100 suffering from Crohn's disease (CD) and 98 from ulcerative colitis (UC)] and 41 healthy volunteers as a control group. Densitometric bone measurements were obtained using dual energy X-ray absorptiometry. The TGFB1 genotyping was conducted using restriction fragments length polymorphism. We conducted an analysis of genotype distribution's concordance with Hardy-Weinberg equilibrium. We found statistically significant differences in lumbar spine (L2-L4) and femoral neck BMD and T-scores between CD, UC and control subgroups. The distribution of TGFB1 polymorphic variants among CD and UC patients was concordant with Hardy-Weinberg equilibrium. There were no statistically significant differences in densitometric parameters (lumbar spine and femoral neck BMD, T-score, and Z-score) between carriers of different TGFB1 polymorphisms among IBD (CD and UC) patients nor among controls. We have found no statistically significant differences in the prevalence of low-energy fractures between groups of different TGFB1 polymorphic variant carriers. The allele dose effect, recessive effect and dominant effect analysis did not show an association between low-energy fractures and the TGFB1 polymorphisms among CD and UC patients. We have not observed an association between the c.29T>C TGFB1 polymorphic variant and the bone mineral density within the cancellous and cortical bones (L2-L4 and femoral neck, respectively), or the occurrence of fractures among the IBD patients and their family members.

Osteoporosis is more frequent in inflammatory bowel disease (IBD) patients. A reduction in bone mineral mass in these individuals is caused not only by inflammatory processes in the bowel, because osteoporosis occurs already in very young IBD patients and in newly diagnosed individuals who have not yet undergone any pharmacological treatment. One of individual determinants of the bone turnover parameters is osteoprotegerin (OPG) encoded by the TNFRSF11B gene. The c.-223C > T polymorphism in this gene has been extensively studied in post-menopausal osteoporosis patients. However, no such studies exist for osteoporosis related to IBD. The aim of our study was to determine whether the c.-223C > T (rs2073617) polymorphism in the 5'UTR region of the gene encoding osteoprotegerin is a functional polymorphism which may change the gene expression and resulting OPG levels, and so be associated with osteopenia and osteoporosis, and impaired bone metabolism in Crohn's disease and ulcerative colitis patients. Our study included 198 IBD patients and 41 healthy controls. Lumbar spine and femoral neck bone mineral density, T-score, Z-score as well as OPG, RANKL, vitamin D, calcium and interleukin 4 and 10 concentrations were determined for all study subjects. Genotyping of the TNFRSF11B polymorphic site was performed by restriction fragment length polymorphism technique. Statistical analyses were conducted using Statistica software. Odds ratios, 95 % confidence intervals, and P values were calculated using the HWE calculator. Our results did not allow determining an unequivocal association between the polymorphic variants of the TNFRSF11B 5'UTR region and a susceptibility to osteoporosis in IBD patients. We have shown, however, that the c.-223T allele was twice as more frequent in Crohn's disease (CD) patients than among controls (OR = 1.99, P value = 0.009). Interestingly, average osteoprotegerin levels in CD patients did not significantly differ from those in controls, whereas in ulcerative colitis patients, OPG levels were significantly lower. We have concluded that low OPG levels may be associated with osteoporosis in ulcerative colitis, but it is not correlated with the c.-223C > T polymorphism in the TNFRSF11B gene. In CD patients, in turn, we observed increased RANKL levels. Our observations confirm different pathogeneses of Crohn's disease and ulcerative colitis as well as different molecular backgrounds of osteoporosis associated with these two diseases., Competing Interests: Iwona Krela-Kaźmierczak, Marta Kaczmarek-Ryś, Aleksandra Szymczak, Michał Michalak, Marzena Skrzypczak-Zielińska, Natalia Drwęska-Matelska, Michalina Marcinkowska, Piotr Eder, Lilianna Łykowska-Szuber, Ewa Wysocka, Krzysztof Linke and Ryszard Słomski have declare that they have no conflict of interest. Ethical Approval The study was approved by the Bioethical Committee of the University of Medical Sciences in Poznań, Poland, under Resolution No. 92/09. Informed consent was obtained from every participant. Human and Animal Rights and Informed Consent All followed procedures were in accordance with the ethical standards of the responsible committee on human experimentation (Bioethical Committee of the University of Medical Sciences in Poznań, Poland, Resolution No. 92/09). Informed consent was obtained from all individual participants included in the study.

The mechanisms of action of antitumor necrosis factor α (anti-TNF-α) antibodies in the therapy of inflammatory bowel disease (IBD) are not completely understood. Binding of antibodies to transmembrane TNF-α seems to be crucial for the induction of several cellular responses, including complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and reverse signaling. However, these processes alone do not fully explain the diversity of responses to anti-TNF-α therapy seen in different patients. Thus, the present review aimed to discuss the current role of anti-TNF-α antibodies in treatment algorithms for IBD as well as the current knowledge on the mechanisms of action of these antibodies, particularly the less well known aspects of anti-TNF-α blockade. We also discussed a complex role of particular macrophage subpopulations, T regulatory cells, and intestinal endothelial cells, as well as presented new data on the clinical relevance of anti-inflammatory responses attributed to the Fc region of anti-TNF-α antibodies.

M ethotrexate (MTX) as an immunomodulatory drug has numerous applications in autoimmune diseases. Autoimmune patomechanism is one of the factors responsible for development of inflammatory bowel diseases (IBD). MTX is an alternative therapy in the treatment of IBD. Over the past several years clinical trials has confirmed the efficacy of MTX in the treatment of Crohn's disease (CD). Data concerning use of MTX in ulcerative colitis (UC) are not as numerous as in the CD. Currently, MTX is recommended for the induction treatment and maintenance therapy in CD patients, especially in steroid-dependent patients, disease refractory to corticosteroids, no improvement after treatment with azathioprine and 6-mercaptopurine, or in case of intolerance to these drugs. Preferred route of administration in the treatment of CD is parenteral supply. Contraception is indicated during MTX treatment since it's teratogenic.

The etiology of inflammatory bowel disease (IBD) is still not fully understood. Angiogenesis is one of the crucial phenomena sustaining chronic inflammation in the gastrointestinal tract. It has been also shown that the most potent anti-inflammatory drugs--anti-tumor necrosis factor alpha antibodies down-regulate intestinal angiogenesis, what is believed to contribute to their therapeutic efficacy. There are many proteins engaged in gastrointestinal angiogenesis, including pro-inflammatory cytokines, vascular growth factors, and adhesion molecules. Several of them are considered to be promising molecular targets for new drugs--monoclonal antibodies or fusion proteins. Here, we review new data highlighting the key role of proteins that regulate immune-mediated angiogenesis in IBD, like vascular endothelial growth factor, hypoxia inducible factor, angiopoietins, or basic fibroblast growth factor. We present the molecular mechanisms regulating the pathological proangiogenic activity in inflammatory conditions in IBD. We also discuss how new anti-cytokine regimens affect the function of angiogenesis-related proteins.