Suppression of arthritis-induced bone erosion by a CRAC channel antagonist

Abstract

ObjectiveWe have shown in vitro and in vivo that osteoclast maturation requires calcium-release activated calcium (CRAC) channels. In inflammatory arthritis, osteoclasts mediate severe and debilitating bone erosion. In the current study, we assess the value of CRAC channels as a therapeutic target to suppress bone erosion in acute inflammatory arthritis.MethodsCollagen-induced arthritis (CIA) was induced in mice. The CRAC channel inhibitor 3,4-dichloropropionaniline (DCPA) and a placebo was administered 1 day prior to collagen II booster to induce arthritis. Effects on swelling, inflammatory cell invasion in joints, serum cytokines and bone erosion were measured.ResultsAssays, by blinded observers, of arthritis severity showed that DCPA, 21 mg/kg/day, suppressed arthritis development over 3 weeks. Bone and cartilage damage in sections of animal feet was reduced approximately 50%; overall swelling of joints was reduced by a similar amount. Effects on bone density by µCT showed clear separation in DCPA-treated CIA animals from CIA without treatment, while differences between controls without CIA and CIA treated with DCPA differed by small amounts and in most cases were not statistically different. Response was not related to anticollagen titres. There were no adverse effects in the treated group on animal weight or activity, consistent with low toxicity. The effect was maximal 12–17 days after collagen booster, during the rapid appearance of arthritis in untreated CIA. At 20 days after treatment (day 40), differences in arthritis score were reduced and tumour necrosis factor α, interleukin (IL)-1, or IL-6 in the serum of the animals were similar in treated and untreated animals.ConclusionsDCPA, a novel inhibitor of CRAC channels, suppresses bone erosion associated with acute arthritis in mice and might represent a new treatment modality for acute arthrits.

Ca2+-Dependent Regulation of NFATc1 via KCa3.1 in Inflammatory Osteoclastogenesis

“…The important role of Ca 2+ influx for osteoclast formation has previously been demonstrated (12, 13) and a number of therapeutic approaches have been attempted with regulation of Ca 2+ in mind (32, 48). The inhibition of CRAC channels with 3,4-dichloropropionaniline (DCPA) has been shown to reduce bone erosion and inflammation in an inflammatory arthritis mouse model (48). However, the ubiquitous expression of CRAC channels on several immune cells including T cells challenge the therapeutic use of CRAC inhibitors because of the risk of broad immunosuppression (49).…”

ORAI Calcium Channels

“…Several studies from many groups have implicated STIM1 and ORAI1 in a large number of physiological functions, including immune, secretory, vascular, neuronal, and muscle cells (86). STIM1 and ORAI1 play crucial roles in lymphocyte activation and clonal expansion, neutrophil chemotaxis, skeletal muscle development and resistance to fatigue, osteoblast differentiation, sperm and enamel development, and sweat, lacrimal, and mammary gland secretion, among others (8,12,14,17,18,23,86). Mutations in STIM1 and ORAI1 or disruption of their expression patterns underlies a large collection of diseases, including immunodeficiency, autoimmunity, muscular dystrophy, hypertension, vascular remodeling, cardiac hypertrophy, sterility, and several types of cancer, to cite a few (47,90,97,99,100,115,124).…”

ADAM15 in Apoptosis Resistance of Synovial Fibroblasts: Converting Fas/CD95 Death Signals Into the Activation of Prosurvival Pathways by Calmodulin Recruitment

“…The death‐promoting effect of both compounds is critically dependent on synergistic Fas ligation, which is provided under pathophysiologic conditions in RA by high FasL concentrations in the synovial fluid of inflamed joints . While TFP, applied in our study for its CaM‐blocking effects, is a Food and Drug Administration–approved antipsychotic drug with preferred therapeutic use for schizophrenia, CRAC antagonists have recently already been tested for their antiarthritis potential in murine collagen‐induced arthritis resulting in ameliorated disease development, relief from pain, and a 50% reduction of structural joint damage . In this context, the newly discovered role of CaM and CRAC/Orai channels as pharmacologic targets to break Fas‐mediated apoptosis resistance in RASFs might encourage further studies aiming at new treatment options in RA.…”