Interleukin 10-deficient mice develop osteopenia, decreased bone formation, and mechanical fragility of long bones

Dresner–Pollak, Rivka; Gelb, Nir; Rachmilewitz, Daniel; Karmeli, Fanny; Weinreb, Miron

doi:10.1053/j.gastro.2004.06.013

Cited by 147 publications

(130 citation statements)

References 53 publications

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“…Besides Ca 2ϩ malabsorption, inflammatory cytokines, which are released during IBD, can directly stimulate osteoclast activity and decrease osteoblast function. Dresner-Pollak et al (12), using an IL-10 knockout IBD mouse model, measured enhanced serum TNF-␣, IL-1␤, and IL-6 levels and showed an increased incidence of osteopenia (8,12). It is evident that the occurrence of reduced BMD has multifactorial causes and cannot be explained by just one mechanism.…”

Section: Discussionmentioning

confidence: 99%

Prednisolone-induced Ca²⁺malabsorption is caused by diminished expression of the epithelial Ca²⁺channel TRPV6

Huybers¹,

Naber²,

Bindels³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

103

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Huybers S, Naber TH, Bindels RJ, Hoenderop JG. Prednisolone-induced Ca 2ϩ malabsorption is caused by diminished expression of the epithelial Ca 2ϩ channel TRPV6. Am J Physiol Gastrointest Liver Physiol 292: G92-G97, 2007. First published August 10, 2006; doi:10.1152/ajpgi.00317.2006.-Glucocorticoids, such as prednisolone, are often used in clinic because of their anti-inflammatory and immunosuppressive properties. However, glucocorticoids reduce bone mineral density (BMD) as a side effect. Malabsorption of Ca 2ϩ in the intestine is supposed to play an important role in the etiology of low BMD. To elucidate the mechanism of glucocorticoid-induced Ca 2ϩ malabsorption, the present study investigated the effect of prednisolone on the expression and activity of proteins responsible for active intestinal Ca 2ϩ absorption including the epithelial Ca 2ϩ channel TRPV6, calbindin-D9K, and the plasma membrane ATPase PMCA1b. Therefore, C57BL/6 mice received 10 mg/kg body wt prednisolone daily by oral gavage for 7 days and were compared with control mice receiving vehicle only. An in vivo 45 Ca 2ϩ absorption assay indicated that intestinal Ca 2ϩ absorption was diminished after prednisolone treatment. We showed decreased duodenal TRPV6 and calbindin-D9K mRNA and protein abundance in prednisolone-treated compared with control mice, whereas PMCA1b mRNA levels were not altered. Importantly, detailed expression studies demonstrated that in mice these Ca 2ϩ transport proteins are predominantly localized in the first 2 cm of the duodenum. Furthermore, serum Ca 2ϩ and 1,25-dihydroxyvitamin D 3 [1,25(OH)2D3] concentrations remained unchanged by prednisolone treatment. In conclusion, these data suggest that prednisolone reduces the intestinal Ca 2ϩ absorption capacity through diminished duodenal expression of the active Ca 2ϩ transporters TRPV6 and calbindin-D 9K independent of systemic 1,25(OH)2D3.1,25-dihydroxyvitamin D3; duodenum; epithelial calcium channel 2; calcium transporter 1 REDUCED BONE MINERAL DENSITY (BMD) is particularly present in the elderly and women, which implies that age and gender are important risk factors for developing low BMD. However, in clinical practice low BMD is frequently observed in several patient groups, including inflammatory bowel disease (IBD) patients. Estimates of osteopenia in IBD range from 31 to 59% and osteoporosis from 5 to 41%. Various studies exploring the cause of low BMD in IBD found a significant correlation between glucocorticoid treatment and decreased BMD (3,5,17,28,29). Glucocorticoids, such as prednisolone, are wellknown drugs for their potent anti-inflammatory and immunosuppressive properties. As a consequence, glucocorticoids are widely used in clinic as drugs to treat inflammatory conditions such as IBD. To date, glucocorticoids are generally accepted to reduce BMD, despite the fact that in a number of studies an effect on bone mass could not be observed (5, 11) or could be observed only in male glucocorticoid users (31).This effect of glucocorticoids on BMD is caused by the c...

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Section: Discussionmentioning

confidence: 99%

Prednisolone-induced Ca²⁺malabsorption is caused by diminished expression of the epithelial Ca²⁺channel TRPV6

Huybers¹,

Naber²,

Bindels³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

103

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“…Primary OBL cultures from bone marrow (BM) stromal cells (medullary cavities of humeri, femora, and tibiae) or calvariae were established from 2-month-old or 3-to 4-dayold mice (n ϭ 4 or 5), respectively, as described previously (55,56), and maintained for 21 to 28 days. Runx3 expression in calvaria-derived OBL cultures was analyzed by Western blotting (see Fig.…”

Section: Methodsmentioning

confidence: 99%

Loss of Osteoblast Runx3 Produces Severe Congenital Osteopenia

Bauer

Sharir

Kimura

et al. 2015

Molecular and Cellular Biology

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bCongenital osteopenia is a bone demineralization condition that is associated with elevated fracture risk in human infants. Here we show that Runx3, like Runx2, is expressed in precommitted embryonic osteoblasts and that Runx3-deficient mice develop severe congenital osteopenia. Runx3-deficient osteoblast-specific (Runx3 fl/fl /Col1␣1-cre), but not chondrocyte-specific (Runx3 fl/fl /Col1␣2-cre), mice are osteopenic. This demonstrates that an osteoblastic cell-autonomous function of Runx3 is required for proper osteogenesis. Bone histomorphometry revealed that decreased osteoblast numbers and reduced mineral deposition capacity in Runx3-deficient mice cause this bone formation deficiency. Neonatal bone and cultured primary osteoblast analyses revealed a Runx3-deficiency-associated decrease in the number of active osteoblasts resulting from diminished proliferation and not from enhanced osteoblast apoptosis. These findings are supported by Runx3-null culture transcriptome analyses showing significant decreases in the levels of osteoblastic markers and increases in the levels of Notch signaling components. Thus, while Runx2 is mandatory for the osteoblastic lineage commitment, Runx3 is nonredundantly required for the proliferation of these precommitted cells, to generate adequate numbers of active osteoblasts. Human RUNX3 resides on chromosome 1p36, a region that is associated with osteoporosis. Therefore, RUNX3 might also be involved in human bone mineralization.

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“…Using IL-10 Ϫ/Ϫ mice as a model of Crohn's-like colitis, Drezner-Pollak et al (32) showed that the effect of intestinal inflammation on the development of osteopenia and osteoporosis was primarily mediated by deficient bone formation. This was evidenced by decreased cancellous double-labeled surface, mineralizing surface, serum osteocalcin level, and mineralized nodule number in bone marrow stromal cell cultures.…”

Section: Bone Formation Vs Resorption In Animal Models Of Ibdmentioning

confidence: 99%

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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Interleukin 10-deficient mice develop osteopenia, decreased bone formation, and mechanical fragility of long bones

Cited by 147 publications

References 53 publications

Prednisolone-induced Ca²⁺malabsorption is caused by diminished expression of the epithelial Ca²⁺channel TRPV6

Prednisolone-induced Ca²⁺malabsorption is caused by diminished expression of the epithelial Ca²⁺channel TRPV6

Loss of Osteoblast Runx3 Produces Severe Congenital Osteopenia

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

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Interleukin 10-deficient mice develop osteopenia, decreased bone formation, and mechanical fragility of long bones

Cited by 147 publications

References 53 publications

Prednisolone-induced Ca2+malabsorption is caused by diminished expression of the epithelial Ca2+channel TRPV6

Prednisolone-induced Ca2+malabsorption is caused by diminished expression of the epithelial Ca2+channel TRPV6

Loss of Osteoblast Runx3 Produces Severe Congenital Osteopenia

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

Contact Info

Product

Resources

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Prednisolone-induced Ca²⁺malabsorption is caused by diminished expression of the epithelial Ca²⁺channel TRPV6

Prednisolone-induced Ca²⁺malabsorption is caused by diminished expression of the epithelial Ca²⁺channel TRPV6