Strain dependent differences in glucocorticoid-induced bone loss between C57BL/6J and CD-1 mice

Ersek, Adel; Santo, Ana I. Espirito; Vattakuzhi, Youridies; George, Saumya; Clark, Andrew R.; Horwood, Nicole J.

doi:10.1038/srep36513

Cited by 31 publications

(26 citation statements)

References 41 publications

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“…Our studies demonstrate that GC treatment has a significant effect on both trabecular and cortical bone parameters: trabecular bone volume and in some groups cortical thickness decreased and marrow area as well as endocortical perimeter and in some cases periosteal perimeter increased. Previous studies also report that GC‐Tx decreases cortical thickness and increases marrow area . Reports have also reported increased endocortical perimeter .…”

Section: Discussionmentioning

confidence: 76%

“…Previous studies also report that GC-Tx decreases cortical thickness and increases marrow area. (140,141) Reports have also reported increased endocortical perimeter. (141) However, reports on GC-Tx effects on periosteal bone perimeter or formation have been variable, (141,142) in part because of differences in models, the bone analyzed, and animal age.…”

Section: Discussionmentioning

confidence: 97%

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Involvement of the Gut Microbiota and Barrier Function in Glucocorticoid-Induced Osteoporosis

Schepper

Collins

Rios‐Arce

et al. 2019

Journal of Bone and Mineral Research

133

119

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Glucocorticoids (GCs) are potent immune‐modulating drugs with significant side effects, including glucocorticoid‐induced osteoporosis (GIO). GCs directly induce osteoblast and osteocyte apoptosis but also alter intestinal microbiota composition. Although the gut microbiota is known to contribute to the regulation of bone density, its role in GIO has never been examined. To test this, male C57/Bl6J mice were treated for 8 weeks with GC (prednisolone, GC‐Tx) in the presence or absence of broad‐spectrum antibiotic treatment (ABX) to deplete the microbiota. Long‐term ABX prevented GC‐Tx‐induced trabecular bone loss, showing the requirement of gut microbiota for GIO. Treatment of GC‐Tx mice with a probiotic (Lactobacillus reuteri [LR]) prevented trabecular bone loss. Microbiota analyses indicated that GC‐Tx changed the abundance of Verrucomicobiales and Bacteriodales phyla and random forest analyses indicated significant differences in abundance of Porphyromonadaceae and Clostridiales operational taxonomic units (OTUs) between groups. Furthermore, transplantation of GC‐Tx mouse fecal material into recipient naïve, untreated WT mice caused bone loss, supporting a functional role for microbiota in GIO. We also report that GC caused intestinal barrier breaks, as evidenced by increased serum endotoxin level (2.4‐fold), that were prevented by LR and ABX treatments. Enhancement of barrier function with a mucus supplement prevented both GC‐Tx–induced barrier leakage and trabecular GIO. In bone, treatment with ABX, LR or a mucus supplement reduced GC‐Tx–induced osteoblast and osteocyte apoptosis. GC‐Tx suppression of Wnt10b in bone was restored by the LR and high‐molecular‐weight polymer (MDY) treatments as well as microbiota depletion. Finally, we identified that bone‐specific Wnt10b overexpression prevented GIO. Taken together, our data highlight the previously unappreciated involvement of the gut microbiota and intestinal barrier function in trabecular GIO pathogenesis (including Wnt10b suppression and osteoblast and osteocyte apoptosis) and identify the gut as a novel therapeutic target for preventing GIO. © 2019 American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 97%

Involvement of the Gut Microbiota and Barrier Function in Glucocorticoid-Induced Osteoporosis

Schepper

Collins

Rios‐Arce

et al. 2019

Journal of Bone and Mineral Research

133

119

View full text Add to dashboard Cite

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“…Studies in which 5‐month‐old female C57Bl/6 mice were treated with prednisolone for 28 days, found that femoral cortical thickness and vertebral cortical and trabecular thickness were decreased relative to vehicle‐treated mice . A recent study found that when compared to CD‐1 mice, C57BL/6 mice are resistant to GIO . In addition, older mice are more prone to GIO relative to young mice .…”

Section: Discussionmentioning

confidence: 48%

The CRH‐Transgenic Cushingoid Mouse Is a Model of Glucocorticoid‐Induced Osteoporosis

et al. 2017

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Glucocorticoids (GCs) have unparalleled anti‐inflammatory and immunosuppressive properties, which accounts for their widespread prescription and use. Unfortunately, a limitation to GC therapy is a wide range of negative side effects including Cushing's syndrome, a disease characterized by metabolic abnormalities including muscle wasting and osteoporosis. GC‐induced osteoporosis occurs in 30% to 50% of patients on GC therapy and thus, represents an important area of study. Herein, we characterize the molecular and physiologic effects of GC‐induced osteoporosis using the Cushing's mouse model, the corticotropin releasing hormone (CRH) transgenic mouse (CRH‐Tg). The humeri, femurs, and tibias from wild‐type (WT) and CRH‐Tg male mice, aged 13 to 14 weeks old were subjected to multiple bone tests including, micro–computed tomography (μCT), static and dynamic histomorphometry, strength testing, and gene expression analyses. The CRH‐Tg mice had a 38% decrease in cortical bone area, a 35% decrease in cortical thickness, a 16% decrease in trabecular thickness, a sixfold increase in bone adiposity, a 27% reduction in osteoid width, a 75% increase in bone‐resorbing osteoclast number/bone surface, a 34% decrease in bone formation rate, and a 40% decrease in bone strength compared to WT mice. At the gene expression level, CRH‐Tg bone showed significantly increased osteoclast markers and decreased osteoblast markers, whereas CRH‐Tg muscle had increased muscle atrophy gene markers compared to WT mice. Overall, the CRH‐Tg mouse model aged to 14 weeks recapitulated many features of osteoporosis in Cushing's syndrome and thus, represents a useful model to study GC‐induced osteoporosis and interventions that target the effects of GCs on the skeleton. © 2017 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

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“…Finally, data from rodent models of ANS should be interpreted with reference to the strain of animal used, as different laboratory rodents appear to possess pronounced differences in steroid responsiveness. For example, Ersek et al (32) reported that, when treated with prednisolone, adult CD-1 mice had significant reductions in femur strength and elasticity; in contrast C57BL/6J mice exhibited no changes in femur strength or elasticity after receiving the same treatment, suggesting that C57BL/6J osteoclasts were less sensitive to glucocorticoid treatment and were tolerant of higher steroid doses. In contrast, C57BL/6J mice were more sensitive to inhibition of hippocam-pal cell proliferation than MRL/MpJ mice when chronically treated with corticosterone exposure (38).…”

Section: Rodent Modelsmentioning

confidence: 99%

Efficacy and safety of antenatal steroids

Kemp

Jobe

Usuda

et al. 2018

American Journal of Physiology-Regulatory, Integrative and Comp

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Antenatal steroids (ANS) are among the most important and widely utilized interventions to improve outcomes for preterm infants. A significant body of evidence demonstrates improved outcomes in preterm infants (24-34 wk) delivered between 1 and 7 days after the administration of a single course of ANS. Moreover, ANS have the advantage of being widely available, low cost, and easily administered via maternal intramuscular injection. The use of ANS to mature the fetal lung is, however, not without contention. Their use in pregnancy is not FDA approved, and treatment doses and regimens remain largely unoptimized. Their mode of use varies considerably between countries, and there are lingering concerns regarding the safety of exposing the fetus to high doses of exogenous steroids. A significant proportion of women deliver outside the 1- to 7-day therapeutic window after ANS treatment, and this delay may be associated with an increased risk of adverse outcomes for both mother and baby. Today, animal-based studies are one means by which key questions of dosing and safety relating to ANS may be resolved, allowing for further refinement(s) of this important therapy. Complementary approaches using nonhuman primates, sheep, and rodents have provided invaluable advances to our understanding of how exogenous steroid exposure impacts fetal development. Focusing on these three major model groups, this review highlights the role of three key animal models (sheep, nonhuman primates, rodents) in the development of antenatal steroid therapy, and provides an up-to-date synthesis of current efforts to refine this therapy in an era of personalised medicine.

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Strain dependent differences in glucocorticoid-induced bone loss between C57BL/6J and CD-1 mice

Cited by 31 publications

References 41 publications

Involvement of the Gut Microbiota and Barrier Function in Glucocorticoid-Induced Osteoporosis

Involvement of the Gut Microbiota and Barrier Function in Glucocorticoid-Induced Osteoporosis

The CRH‐Transgenic Cushingoid Mouse Is a Model of Glucocorticoid‐Induced Osteoporosis

Efficacy and safety of antenatal steroids

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