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

Abstract

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.

Corticotropin releasing factor-overexpressing mouse is a model of chronic stress-induced muscle atrophy

“…For the experiment, five-week-old male and female CRF-OE mice and their sex-and age-matched WT littermates, as control groups, were housed in standard cages in a room at 22 ± 2.0˚C and 50 ± 5% relative humidity and maintained under 12 h:12 h light-dark conditions with a commercial diet (AIN 93 M, Purina Mills, St. Louis MO, USA) and distilled water ad libitum. It was previously reported that CRF-OE mice showed various pathological changes from 6 to 21 weeks of age (eg, osteoporosis, insulin resistance, hypercortisolism and obesity) [30][31][32][33]; We chose to use CRF-OE mice at 7 and 19 weeks of age to investigate muscle atrophy.…”

“…These mice also display elevated plasma corticosterone levels associated with chronic activation of the HPA axis alongside anxiogenic behaviors [27], brain atrophy [28], and exaggerated voiding and defecation in response to novel environmental stressors [29]. Furthermore, CRF-OE mice recapitulated many features of osteoporosis with increased expression of muscle atrophy gene markers [30]. In the present study, we aimed to assess muscle atrophy in the CRF-OE mouse model, and elucidate its molecular mechanism.…”

Phenotyping of Klf14 mouse white adipose tissue enabled by whole slide segmentation with deep neural networks

“…Common mouse models to study obesity are numerous genetics models such as the ob/ob, db/db, POMC, MC4 knockout, ectopic agouti and AgRP, FABP4-Wnt10b, LXRβ−/−, Sfrp5−/− and Timp−/− models, surgical/chemical models and diet induced obesity 2,29 . Other models to study WAT phenotypes are R6/2 and CAG140 for Huntington’s disease 30 and CRH for Cushing’s syndrome 31 . In this paper, as an exemplar we focus on the C57BL/6NTac Klf14 knockout model ( Klf14 tm1(KOMP)Vlcg ) previously developed by Small et al 13 .…”