CD4+CD45RBHi T cell transfer induced colitis in mice is accompanied by osteopenia which is treatable with recombinant human osteoprotegerin

Byrne, Fergus R.; Morony, Sean; Warmington, Kelly; Geng, Zhaopo; Brown, Heather; Flores, Silvia Alicia; Fiorino, Marie F.; Yin, Shi-an; Hill, David J.; Porkess, Veronica; Duryea, Diane; Pretorius, Jim; Adamu, Stephen A.; Manuokian, R; Danilenko, Dimitry M.; Sarosi, Ildiko; Lacey, David L.; Kostenuik, Paul J.; Senaldi, Giorgio

doi:10.1136/gut.2003.035113

Cited by 58 publications

(42 citation statements)

References 49 publications

(44 reference statements)

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“…In the CD4 + CD45RB Hi T-cell transfer mouse model of inflammatory bowel disease (IBD), the effects of OPG-Fc administration were similar to those in RA: While dramatically improving bone density, OPG-Fc did not modify inflammatory parameters nor reduce infiltration of the gastrointestinal tract by inflammatory cells (colitis) [60]. In contrast, in IL-2-deficient mice-that spontaneously develop an autoimmune disease characterized by hyperactivation of CD4 + T cells with multi-organ inflammation and massive T-cell infiltration of the gastrointestinal tractadministration of OPG-Fc not only led to a significant increase in bone density but also improved gastrointestinal tissue architecture [61].…”

Section: Inflammatory Bowel Diseasesmentioning

confidence: 88%

“…Infectious disease BCG bacterial infection [70] Mouse Influenza viral infection [97] Mouse Autoimmune disease Immune-mediated arthritis [56] Rat Inflammatory bowel disease [60] Mouse LN lymph nodes, dvp development, L B lymphocytes B, L T lymphocytes T; Ig immunoglobulin, DC dendritic cells, ND not determined their cell surfaces, which protects these cells from apoptosis, increases their phagocytic properties, and activates antigen presentation [33]. However, in studies on RANKL −/− mice, both the number and distribution of monocyte-macrophages were normal [18].…”

Section: Effects On Monocyte-macrophagesmentioning

confidence: 99%

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Do RANKL inhibitors (denosumab) affect inflammation and immunity?

2010

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Receptor activator of nuclear factor kappa B ligand (RANKL) and its natural antagonist, osteoprotegerin (OPG), are, respectively, an indispensable factor and a potent inhibitor for osteoclast differentiation, activity, and survival. The development of a human monoclonal antibody to RANKL, denosumab, constitutes a novel approach to prevent fragility fractures in osteoporosis, skeletal complications of malignancy, and potentially bone erosions in rheumatoid arthritis (RA). In addition to being expressed by osteoblasts, RANKL is abundantly produced by activated T cells, and synoviocytes in RA, whereas its receptor, RANK, is also expressed by monocytes/macrophages and dendritic cells. However, in preclinical and clinical studies of RA-including patients with some degree of immunosuppression-RANKL inhibitors did not significantly alter inflammatory processes. RANKL, RANK, and OPG deficiency in murine models highlights the important role of this pathway in the development and maturation of the immune system in rodents, including functions of T and/or B cells, whereas OPG overexpression in mice and rats seems innocuous with regard to immunity. In contrast, loss-of-function mutations in humans have more limited effects on immune cells. In clinical studies, the overall rate of infections, cancer, and death was similar with denosumab and placebo. Nevertheless, the risk of severe infections and cancer in some specific tissues remains to be carefully scrutinized.

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Section: Inflammatory Bowel Diseasesmentioning

confidence: 88%

Section: Effects On Monocyte-macrophagesmentioning

confidence: 99%

Do RANKL inhibitors (denosumab) affect inflammation and immunity?

2010

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“…Surprisingly, OPG-Fc treatment resulted in a loss of detectable osteoclasts as well as osteoblasts. Although the authors concluded that "osteopenia was induced by inflammatory cell infiltration and not by malabsorption of calcium," the presented data show that OPG-Fc did not alter TNF-positive mononuclear infiltrate in the bone while offering only measurement of serum Ca 2ϩ and P i concentration, which are not reliable markers of moderate changes in mineral (re)absorption (21).…”

Section: Bone Formation Vs Resorption In Animal Models Of Ibdmentioning

confidence: 65%

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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“…However, the in vivo responses to immune challenges in genetically intact animals were normal when RANKL was inhibited (14 -16). In numerous animal models of immune-mediated disease, RANKL inhibition has been shown to suppress bone resorption without measurable effects on inflammation (5,(17)(18)(19)(20)(21)(22)(23)(24). These results suggest that RANKL might play a redundant role in the integrated function of the postnatal immune system, a role that is evident primarily when the more important CD40-CD40L costimulatory pathway is absent.…”

Section: R Eceptor Activator Of Nf-〉 Ligand (Rankl)mentioning

confidence: 96%

Continuous RANKL Inhibition in Osteoprotegerin Transgenic Mice and Rats Suppresses Bone Resorption without Impairing Lymphorganogenesis or Functional Immune Responses

Stolina¹,

Dwyer²,

Ominsky³

et al. 2007

The Journal of Immunology

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Receptor activator of NF-κB ligand (RANKL) is an essential mediator of osteoclast formation, function, and survival. The effects of RANKL are inhibited by a soluble decoy receptor called osteoprotegerin (OPG). Total ablation of RANKL in knockout mice leads to high bone mass, lymph node agenesis, and altered lymphocyte differentiation. In contrast, RANKL inhibition via OPG suppresses bone resorption but not inflammation in animal models of inflammatory bone loss. This suggests that the immune phenotype of RANKL knockout mice is related to total RANKL ablation. We hypothesized that prenatal RANKL inhibition via OPG overexpression would suppress bone resorption without influencing lymph node formation or subsequent immune responses. Transgenic rats were created, wherein soluble OPG was overexpressed by 100-fold vs wild type (WT) controls, by gestational day 11 (i.e., before lymph node formation). The structure of lymph nodes, spleen, and thymus of OPG-transgenic (OPG-Tg) animals were comparable to those of age-matched WT rats at gestational day 19 and in adulthood. The OPG-Tg neonates had elevated bone mass, confirming the prenatal inhibition of RANKL. Adult OPG-Tg rats and OPG-Tg mice exhibited no significant functional alterations relative to WT controls when subjected to immune challenges to test for altered innate and humoral responses (e.g., contact hypersensitivity to oxazolone, IgM response to Pneumovax, IgG response to keyhole limpet hemocyanin, or cytokine response to LPS). In summary, prenatal RANKL inhibition did not impair lymph node development, nor did continuous life-long RANKL inhibition cause obvious changes in innate or humoral immune responses in mice or rats.

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CD4+CD45RBHi T cell transfer induced colitis in mice is accompanied by osteopenia which is treatable with recombinant human osteoprotegerin

Cited by 58 publications

References 49 publications

Do RANKL inhibitors (denosumab) affect inflammation and immunity?

Do RANKL inhibitors (denosumab) affect inflammation and immunity?

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

Continuous RANKL Inhibition in Osteoprotegerin Transgenic Mice and Rats Suppresses Bone Resorption without Impairing Lymphorganogenesis or Functional Immune Responses

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