An anti‐inflammatory selective glucocorticoid receptor modulator preserves osteoblast differentiation

Abstract

Glucocorticoids (GCs) are in widespread use to treat inflammatory bone diseases, such as rheumatoid arthritis (RA). Their anti-inflammatory efficacy, however, is accompanied by deleterious effects on bone, leading to GC-induced osteoporosis (GIO). These effects include up-regulation of the receptor activator of NF-κB ligand/osteoprotegerin (RANKL/OPG) ratio to promote bone-resorbing osteoclasts and include inhibition of bone-forming osteoblasts. We previously identified suppression of osteoblast differentiation by the monomer glucocorticoid receptor (GR) via the inhibition of Il11 expression as a crucial mechanism for GIO. Here we show that the GR-modulating substance compound A (CpdA), which does not induce GR dimerization, still suppresses proinflammatory cytokines in fibroblast-like synovial cells from patients with RA and in osteoblasts. In contrast to the full GR agonist dexamethasone, it does not unfavorably alter the RANKL/OPG ratio and does not affect Il11 expression and subsequent STAT3 phosphorylation in these cells. Notably, while dexamethasone inhibits osteoblast differentiation, CpdA does not affect osteoblast differentiation in vitro and in vivo. We describe here for the first time that selective GR modulators can act against inflammation, while not impairing osteoblast differentiation.

Effect of the Plant Derivative Compound A on the Production of Corticosteroid-Resistant Chemokines in Airway Smooth Muscle Cells

“…These marked differences in CpdA inhibitory profile point to two important conclusions: (1) it suggests that different mechanisms regulate the expression of GC-insensitive chemokines, and (2) it suggests that CpdA inhibits the expression of these GC-resistant chemokines by acting on various pathways. Our observation is in agreement with previous reports showing that CpdA suppressed the expression of various proinflammatory mediators, including TNF-a (18), IL-6 (16, 21, 34), CXCL8 (21,35), CCL2, CCL5, and CCL11 (22), with varying inhibition potencies and magnitudes. In contrast to some of these studies where dexamethasone was equally effective as CpdA in repressing inflammatory gene expression, our study is the first to report a therapeutic action of CpdA in steroid-resistant conditions.…”

“…Importantly, these beneficial effects of CpdA were not associated with the typical side effects of GC, which affect the hypothalamic-pituitary-adrenal (HPA) axis (19), levels of insulin (18,19) or glucose (17), or osteoblast differentiation (21) linked to transactivation of GCinducible genes. Recently, CpdA was found to be as effective as dexamethasone in preventing allergen responses in a murine model of asthma (22).…”

Effects of the Selective Glucocorticoid Receptor Modulator Compound A on Bone Metabolism and Inflammation in Male Mice With Collagen-Induced Arthritis

“…In initial studies on bone cells, CpdA, in contrast to conventional GCs, did not increase the receptor activator of NF-B ligand to osteoprotegerin ratio or stimulate osteoclastogenesis in vitro (9). Furthermore, no suppressive effects of osteoblast function were found (9,25). Finally, CpdA maintained bone mineral density (BMD) in a mouse model of GC-induced bone loss, whereas prednisolone decreased BMD by 24% (21).…”

Paradoxical resistance to high-fat diet-induced obesity and altered macrophage polarization in mineralocorticoid receptor-overexpressing mice

“…One major challenge would be to dissociate the putative beneficial effects of such drugs from their immunomodulatory properties. Interestingly, a recent work has identified the so-called compound A as a GR-modulating substrate that preserves antiinflammatory properties but has, for instance, no side effects on bone formation (59). We anticipate that such selective MR modulators could be a relevant strategy in metabolic diseases through an appropriate pharmacological targeting of the proinflammatory properties of MR.…”