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

Abstract

Glucocorticoids (GCs) are potent drugs to treat rheumatoid arthritis but exert adverse skeletal effects. Compound A (CpdA) is a selective GC receptor modulator with an improved risk/benefit profile in mouse models of inflammation and bone loss. Here we tested whether CpdA also exerts bone-sparing effects under proinflammatory circumstances using the collagen-induced arthritis model, a murine model of rheumatoid arthritis. CpdA decreased disease activity, paw swelling, and the paw temperature by 43%, 12%, and 7%, respectively, but was less potent than dexamethasone (DEX), which reduced these parameters by 72%, 22%, and 10%, respectively. Moreover, T cells isolated from CpdA-and DEX-treated animals were less active based on proliferation rates after challenge with type II collagen and produced smaller amounts of interferon-␥ and TNF as compared with T cells from PBS-treated mice. Histological assessment of the joints confirmed the weaker potency of CpdA as compared with DEX in preventing infiltration of inflammatory cells, induction of osteoclastogenesis, and destruction of articular cartilage. Due to the lack of GC-susceptible arthritis models, we were not able to fully address the bone-sparing potential of CpdA in inflammatory conditions. Nevertheless, the bone formation marker procollagen type 1 N-terminal peptide, a surrogate marker for GC-mediated suppression of bone formation, was significantly decreased by DEX in arthritic mice but not by CpdA. Our data indicate that CpdA moderately suppresses inflammation, whereas the concurrent effects on bone remain unknown. In light of its narrow therapeutic range, CpdA may be more useful as a molecular tool for dissecting GC actions rather than a therapeutic agent. (Endocrinology 154: 3719 -3728, 2013)

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“…These findings indicate that CpdA has a bone sparing effect compared to classical GCs (Rauch et al, 2011;Thiele et al, 2012;Rauner et al, 2013). Of special interest, the ability of CpdA to preserve osteoblast differentiation (Rauch et al, 2011) is most probably linked to CpdA's maintenance of AP-1 activity (De Bosscher et al, 2014), a crucial regulatory factor for IL-11, in turn indispensable for proper bone metabolism (Rauch et al, 2010).…”

“…indicates positive regulation, indicates negative regulation. assumption that an anti-inflammatory therapy with less side effects remains a feasible goal (De Bosscher et al, 2005, 2010a, 2014Zhang et al, 2009b;Reber et al, 2012;Thiele et al, 2012;Beck et al, 2013;Rauner et al, 2013;Saksida et al, 2014). However, CpdA's lability (Wust et al, 2009), in combination with a narrow therapeutic range, causes this SEGRM to be inappropriate for therapy, yet excellent as a tool compound for research purposes.…”

“…Some SEGRMs were tested in human tissues, but also in mice and rat models. With regards to the latter, the anti-inflammatory effects of the test SEGRMs were assessed using inflammatory disease models in vivo, such as allergic conjunctivitis (Baiula et al, 2014), (rheumatoid) arthritis Dewint et al, 2008;López et al, 2008;Thiele et al, 2012;Rauner et al, 2013;Carson et al, 2014), neuro-inflammation (Zhang et al, 2009a;van Loo et al, 2010), asthma (Reber et al, 2012) and colitis (Reuter et al, 2012a,b). Yet, it needs to be said that, although it has been proven that all SEGRMs discussed here (except PF-802) can bind to GR (Coghlan et al, 2003;Schacke et al, 2004Schacke et al, , 2009De Bosscher et al, 2005;Chivers et al, 2006;Miner et al, 2007;Zhang et al, 2009b;van Lierop et al, 2012;Brandish et al, 2014;Carson et al, 2014), only CpdA and ZK 216346 are shown to elicit a partial or full nuclear translocation of GR (De Bosscher et al, 2005;Dewint et al, 2008;Yemelyanov et al, 2008;Robertson et al, 2010;Reuter et al, 2012b;Presman et al, 2014;Drebert et al, 2015) (also see 2.1 Structure of Glucocorticoid receptors).…”

“…Although the SEGRM CpdA suppresses inflammation, in vivo studies indicate that stability issues, an alkylating potential, and hence a narrow therapeutic range (causing high doses to be toxic) has as result that for the same dose its anti-inflammatory effect is less efficient compared to the classic GC dexamethasone, and that therefore its clinical potential is severely limited (Rauner et al, 2013). Not all SEGRMs are unstable, however, a study where Mapracorat was topically administered to guinea pigs with induced allergic conjunctivitis, showed that Mapracorat caused more eosinophil apoptosis than dexamethasone.…”

“…Studies on mice models with arthritis comparing CpdA to prednisolone or dexamethasone showed that CpdA, on the one hand, was less potent in suppressing inflammation compared to the GCs, yet, on the other hand, was able to maintain bone mineral density (Thiele et al, 2012;Rauner et al, 2013) and did not inhibit osteoblast differentiation (Rauch et al, 2011), in contrast to prednisolone. These findings indicate that CpdA has a bone sparing effect compared to classical GCs (Rauch et al, 2011;Thiele et al, 2012;Rauner et al, 2013).…”