Bone Abstracts

Glucocorticoids (GCs) are widely used to treat acute and chronic inflammatory diseases such as acute lung injury (ALI) and rheumatoid arthritis (RA) and lead to multiple side effects including GC induced osteoporosis (GIO). Molecularly GCs act by binding to the GC receptor (GR), a ligand induced transcription factor. We discovered that pharmacologically GC exposure reprograms binding of GR monomers towards GR dimers (Genome Research 2015 25:836). Furthermore we challenged the dogma that transrepression by GR monomer suffices for anti-inflammatory activities of GCs, whereas GR dimers would cause side effects such as osteoporosis. We revealed in transgenic mice that transrepression of genes by the GR is not sufficient to suppress inflammation in mouse models of arthritis (PNAS 2011 108:19317) and acute lung injury (Nat Comm 2015 6:7796). Surprisingly, synergistic activity of the GR in concert with pro-inflammatory signaling is required for the induction of anti-inflammatory acting genes.

In contrast GC induced osteoporosis (GIO), the most secondary osteoporosis and a major side effect of steroid therapy, depends on GR mediated transrepression of genes mainly in osteoblasts (Cell Metabolism 2010 11:517).

By setting up an siRNA screen in pre-osteoblasts we functionally characterized novel GR target genes involved in osteoblast differentiation, which could serve as novel drug targets to avoid GIO.

Our work defines new criteria for novel GR modifying compounds and provides new GR target genes that can be addressed to optimize anti-inflammatory therapy by avoiding deleterious effects on bone.