The Role of Tumor Necrosis Factor α in Down-Regulation of Osteoblast Phex Gene Expression in Experimental Murine Colitis

Uno, Jennifer K.; Kolek, Olga I.; Hines, Eric R.; Xu, Hua; Timmermann, Barbara N.; Kiela, Pawel R.; Ghishan, Fayez K.

doi:10.1053/j.gastro.2006.05.020

Cited by 48 publications

(41 citation statements)

References 54 publications

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“…Immortalized osteoblasts from Phexdeficient Hyp mice fail to mineralize under permissive conditions in vitro (109). We demonstrated that Phex expression is significantly depressed in various models of colitis (TNBS, adoptive T cell transfer, and IL-10 Ϫ/Ϫ mice) (64,104). This suppression can be reversed with anti-TNF antibody, and the effect of TNF on osteoblast mineralization correlates with decreased Phex protein and mRNA in vitro (104).…”

Section: Bone Formation Vs Resorption In Animal Models Of Ibdmentioning

confidence: 81%

Advances in the understanding of mineral and bone metabolism in inflammatory bowel diseases

Ghishan

Kiela

2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Ghishan FK, Kiela PR. Advances in the understanding of mineral and bone metabolism in inflammatory bowel diseases. Am J Physiol Gastrointest Liver Physiol 300: G191-G201, 2011. First published November 18, 2010 doi:10.1152/ajpgi.00496.2010.-Chronic inflammatory disorders such as inflammatory bowel diseases (IBDs) affect bone metabolism and are frequently associated with the presence of osteopenia, osteoporosis, and increased risk of fractures. Although several mechanisms may contribute to skeletal abnormalities in IBD patients, inflammation and inflammatory mediators such as TNF, IL-1␤, and IL-6 may be the most critical. It is not clear whether the changes in bone metabolism leading to decreased mineral density are the result of decreased bone formation, increased bone resorption, or both, with varying results reported in experimental models of IBD and in pediatric and adult IBD patients. New data, including our own, challenge the conventional views, and contributes to the unraveling of an increasingly complex network of interactions leading to the inflammationassociated bone loss. Since nutritional interventions (dietary calcium and vitamin D supplementation) are of limited efficacy in IBD patients, understanding the pathophysiology of osteopenia and osteoporosis in Crohn's disease and ulcerative colitis is critical for the correct choice of available treatments or the development of new targeted therapies. In this review, we discuss current concepts explaining the effects of inflammation, inflammatory mediators and their signaling effectors on calcium and phosphate homeostasis, osteoblast and osteoclast function, and the potential limitations of vitamin D used as an immunomodulator and anabolic hormone in IBD.bone mineral density; Crohn's disease; osteopenia; osteoporosis; ulcerative colitis INFLAMMATORY BOWEL DISEASES (IBDs) represent a group of chronic inflammatory disorders of the intestinal tract that to this date remains idiopathic. More recent basic and clinical research indicates that the chronic inflammatory reaction of the intestinal mucosa is directed against the gut microbiota in individuals with genetic and/or environmental susceptibilities. Disease onset occurs typically during young adulthood (25-35 yr), although ϳ20 -25% of cases are diagnosed during childhood (93). On a clinical basis, two major subtypes of IBD are defined as Crohn's disease (CD), which potentially affects any part of the gastrointestinal tract from the mouth to the anus, and ulcerative colitis (UC), an inflammatory condition limited to the colonic mucosa. However, IBD does not affect just a single organ and should be considered a systemic disease with several extraintestinal manifestations, which occur in a large proportion of IBD patients (60). Osteopenia and osteoporosis are two of the more common extraintestinal symptoms with a general consensus that IBD patients are at a significantly higher risk of developing metabolic bone disease and low bone mineral density (BMD) than the healthy subjects. The relative risk of fractur...

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Section: Bone Formation Vs Resorption In Animal Models Of Ibdmentioning

confidence: 81%

Advances in the understanding of mineral and bone metabolism in inflammatory bowel diseases

Ghishan

Kiela

2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Eleventhly, curcumin has been shown to inhibit colitis by inducing the production of tolerogenic dendritic cells that promote differentiation of T-cells into Treg, which include CD4 + CD25 + Foxp3 + Treg and IL-10-producing Tr1 cells, and by producing TGF-b (Cong et al, 2009). Twelfthly, curcumin can reverse TNF-a-mediated reduction in Phex protein in mice, which is responsible for the inhibition of osteoblast mineralization linked to the abnormal bone metabolism associated with IBD (Uno et al, 2006). For this, the authors examined calvaria of 6-to 7-week-old mice given TNBS with or without neutralizing TNF-a antibody, dietary curcumin or systemically with recombinant TNF-a.…”

Section: Inflammatory Bowel Diseasementioning

confidence: 99%

“…• Reversed TNF-a-mediated reduction in Phex protein responsible for the inhibition of osteoblast mineralization linked abnormal bone metabolism in IBD (Uno et al, 2006). • Prevented the development of DSS-induced experimental colitis in BALB/c mice through inhibition of MPO and NF-kB (Deguchi et al, 2007).…”

Section: Psoriasismentioning

confidence: 99%

Curcumin: an orally bioavailable blocker of TNF and other pro‐inflammatory biomarkers

Aggarwal

Gupta

Sung

2013

British J Pharmacology

337

239

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TNFs are major mediators of inflammation and inflammation-related diseases, hence, the United States Food and Drug Administration (FDA) has approved the use of blockers of the cytokine, TNF-a, for the treatment of osteoarthritis, inflammatory bowel disease, psoriasis and ankylosis. These drugs include the chimeric TNF antibody (infliximab), humanized TNF-a antibody (Humira) and soluble TNF receptor-II (Enbrel) and are associated with a total cumulative market value of more than $20 billion a year. As well as being expensive ($15 000-20 000 per person per year), these drugs have to be injected and have enough adverse effects to be given a black label warning by the FDA. In the current report, we describe an alternative, curcumin (diferuloylmethane), a component of turmeric (Curcuma longa) that is very inexpensive, orally bioavailable and highly safe in humans, yet can block TNF-a action and production in in vitro models, in animal models and in humans. In addition, we provide evidence for curcumin's activities against all of the diseases for which TNF blockers are currently being used. Mechanisms by which curcumin inhibits the production and the cell signalling pathways activated by this cytokine are also discussed. With health-care costs and safety being major issues today, this golden spice may help provide the solution. LINKED ARTICLESThis article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx

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“…Since metabolic bone diseases like osteopenia and osteoporosis are associated with IBD, it is necessary to understand the molecular mechanisms of aberrant phosphate homeostasis in patients with IBD. Although TNF-␣ has been found to affect bone density by inducing osteoclasts to erode the bone and by inhibiting osteoblasts to lay new bone matrix (35), how the state of inflammation affects the intestinal phosphate absorption is unknown. Because of the fact that phosphate absorption is segment specific (ileum in mouse and jejuna in rat), we chose both of the animals as our in vivo model in our present studies.…”

mentioning

confidence: 99%

Tumor necrosis factor-alpha impairs intestinal phosphate absorption in colitis

Chen¹,

Xu²,

Dong³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Phosphate homeostasis is critical for many physiological functions. Up to 85% of phosphate is stored in bone and teeth. The remaining 15% is distributed in cells. Phosphate absorption across the brush-border membrane (BBM) of enterocytes occurs mainly via a sodium-dependent pathway, which is mediated by type IIb sodium-phosphate cotransporters (NaPi-IIb). Patients of inflammatory bowel diseases (IBDs) suffer not only from diarrhea and nutrient malabsorption but also from bone loss. About 31–59% of patients with IBD develop bone disorders. Since the intestine is a primary location for dietary phosphate absorption, it is logical to postulate that there is an inverse relationship between gastrointestinal disorders and phosphate transport, which, in turn, contributes to bone disorders observed in patients with IBD. Phosphate absorption and NaPi-IIb expression was studied with BBM vesicles isolated from trinitrobenzene sulphonic acid (TNBS) animals as well as in Caco-2 cells. The mechanism of TNF-α downregulation of NaPi-IIb expression was investigated by luciferase assay, gel mobility shift assay (GMSA), and coimmunoprecipitation. Intestinal phosphate absorption mediated by NaPi-IIb was reduced both in TNBS colitis and in TNF-α-treated cells. Transient transfection indicated that TNF-α inhibits NaPi-IIb expression by reducing NaPi-IIb basal promoter activity. GMSAs identified NF1 protein as an important factor in TNF-α-mediated NaPi-IIb downregulation. Signaling transduction study and coimmunoprecipitation suggested that TNF-α interacts with EGF receptor to activate ERK1/2 pathway. Intestinal phosphate absorption mediated by NaPi-IIb protein is reduced in colitis. This inhibition is mediated by the proinflammatory cytokine TNF-α through a novel molecular mechanism involving TNF-α/EGF receptor interaction.

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The Role of Tumor Necrosis Factor α in Down-Regulation of Osteoblast Phex Gene Expression in Experimental Murine Colitis

Cited by 48 publications

References 54 publications

Advances in the understanding of mineral and bone metabolism in inflammatory bowel diseases

Advances in the understanding of mineral and bone metabolism in inflammatory bowel diseases

Curcumin: an orally bioavailable blocker of TNF and other pro‐inflammatory biomarkers

Tumor necrosis factor-alpha impairs intestinal phosphate absorption in colitis

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