The glucocorticoid receptor (GR) was one of the first nuclear hormone receptors cloned and represents one of the most effective drug targets available today for the treatment of severe inflammation. The physiologic consequences of endogenous or exogenous glucocorticoid excess are well established and include hyperglycemia, insulin resistance, fatty liver, obesity, and muscle wasting. However, at the molecular and tissue-specific level, there are still many unknown protein mediators of glucocorticoid response and thus, much remains to be uncovered that will help determine whether activation of the GR can be tailored to improve therapeutic efficacy while minimizing unwanted side effects. This review summarizes recent discoveries of tissue-selective modulators of glucocorticoid signaling that are important in mediating the unwanted side effects of therapeutic glucocorticoid use, emphasizing the downstream molecular effects of GR activation in the liver, adipose tissue, muscle, and pancreas.

The glucocorticoid receptor (GR) represents the crucial molecular mediator of key endocrine, glucocorticoid hormone–dependent regulatory circuits, including control of glucose, protein, and lipid homeostasis. Consequently, aberrant glucocorticoid signaling is linked to severe metabolic disorders, including insulin resistance, obesity, and hyperglycemia, all of which also appear upon chronic glucocorticoid therapy for the treatment of inflammatory conditions. Of note, long‐term glucocorticoid exposure under these therapeutic conditions typically induces glucocorticoid resistance, requiring higher doses and consequently triggering more severe metabolic phenotypes. However, the molecular basis of acquired glucocorticoid resistance remains unknown. In a screen of differential microRNA expression during glucocorticoid‐dependent adipogenic differentiation of human multipotent adipose stem cells, we identified microRNA 29a (miR‐29a) as one of the most down‐regulated transcripts. Over‐expression of miR‐29a impaired adipogenesis. We found that miR‐29a represses GR in human adipogenesis by directly targeting its mRNA, and downstream analyses revealed that GR mediates most of miR‐29a's anti‐adipogenic effects. Conversely, miR‐29a expression depends on GR activation, creating a novel miR‐29‐driven feedback loop. miR‐29a and GR expression were inversely correlated both in murine adipose tissue and in adipose tissue samples obtained from human patients. In the latter, miR‐29a levels were additionally strongly negatively correlated with body mass index and adipocyte size. Importantly, inhibition of miR‐29 in mice partially rescued the down‐regulation of GR during dexamethasone treatment. We discovered that, in addition to modulating GR function under physiologic conditions, pharmacologic glucocorticoid application in inflammatory disease also induced miR‐29a expression, correlating with reduced GR levels. This effect was abolished in mice with impaired GR function. In summary, we uncovered a novel GR‐miR‐29a negative feedback loop conserved between mice and humans, in health and disease. For the first time, we elucidate a microRNA‐related mechanism that might contribute to GR dysregulation and resistance in peripheral tissues.—Glantschnig, C, Koenen, M., Gil‐Lozano, M., Karbiener, M., Pickrahn, I., Williams‐Dautovich, J., Patel, R., Cummins, C. L., Giroud, M., Hartleben, G., Vogl, E., Blüher, M., Tuckermann, J., Uhlenhaut, H., Herzig, S., Scheideier, M. A. miR‐29a–driven negative feedback loop regulates peripheral glucocorticoid receptor signaling. FASEB J. 33, 5924–5941 (2019). http://www.fasebj.org

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.