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Abstract Number: 1442

Suppression of Acute Arthritis By N-Methyl-3,4-Dichloropropionaniline (N-MeDCPA), a Reversible Orai Calcium Channel Inhibitor

John Barnett1, Lisa Robinson2, Jonathan Soboloff3, Rosana Schafer4, Ida Holaskova5, Meenal Elliott1, Michelle Witt2, Raphael Hirsch6 and Harry Blair7, 1Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV, 2Pathology, West Virginia University, Morgantown, WV, 3Dept of Medical Genetics and Molecular Biochemistry, Temple University, Philadelphia, PA, 4Dept Micro, Immun & Cell Biol, West Virginia University, Morgantown, WV, 5West Virginia University, Morgantown, WV, 6Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, 7pathology, University of Pittsburgh, Pittsburgh, PA

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Arthritis, drug treatment, Inflammation, osteoclastogenesis and osteoclasts

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Session Information

Date: Monday, November 14, 2016

Session Title: Rheumatoid Arthritis – Animal Models - Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:  Bone maintenance is a balance between the removal of old bone by osteoclasts (OCL) and the production of new bone by osteoblasts. In the arthritides, bone erosion by OCL occurs at normally protected sites in the joints where bone replacement does not occur. N-MeDCPA allows the regulated reduction of OCL activity, that is, control damage to joints without complete elimination of OCL activity. Thus, the balance of bone maintenance in joints can be restored. OCL maturation is suppressed when calcium-release activated calcium (CRAC) currents are blocked by targeting Orai1, the pore-forming unit of CRAC. We provide evidence that N-MeDCPA is a Orai1 antagonist that suppresses OCL maturation, without significantly affecting osteoblastogenesis or immune function.

Methods:  The Orai1-blocking activity of N-MeDCPA was measured in Jurkat T cells using Fura-2. In vivo data was collected after the induction of CIA in DBA/1 mice. Animals were dosed with 0 or 21 mg/kg body weight per day N-MeDCPA via a subcutaneous 21-day continuous time-release pellet inserted at day 20 – dose equivalent to 350 mg qid as a human anti-inflammatory drug. A booster injection of collagen II was administered at day 21 and the Arthritis Index (AI) and paw swelling were measured for 20 d thereafter. Bone erosion was assessed using micro-computer tomography (m-CT). Serum anti-(mouse) collagen IgG was measured by ELISA and serum cytokine levels were measured using MSD V–PLEX panels.

Results:  Orai1 activity was blocked by N-MeDCPA in a concentration-related manner. CIA measurements, by blinded observers, showed that N-MeDCPA suppressed the AI (severity) over 3 weeks. Bone and cartilage damage in sections of animal feet was reduced; overall swelling of joints was reduced by a similar amount. Effects on bone density by µ CT showed clear separation in N-MeDCPA-treated CIA animals from CIA without treatment, while differences between controls without CIA and CIA treated with N-MeDCPA differed by small amounts and in most cases were not statistically different. Response was not related to anti-collagen titers. 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 TNF-α, IL-1, or IL-6 in the serum of the animals were similar in treated and untreated animals.

Conclusion:  N-MeDCPA, a novel inhibitor of Orai1 channels, suppresses bone erosion associated with acute arthritis in mice and potentially represents a new treatment modality for acute arthritis.


Disclosure: J. Barnett, None; L. Robinson, None; J. Soboloff, None; R. Schafer, None; I. Holaskova, None; M. Elliott, None; M. Witt, None; R. Hirsch, None; H. Blair, None.

To cite this abstract in AMA style:

Barnett J, Robinson L, Soboloff J, Schafer R, Holaskova I, Elliott M, Witt M, Hirsch R, Blair H. Suppression of Acute Arthritis By N-Methyl-3,4-Dichloropropionaniline (N-MeDCPA), a Reversible Orai Calcium Channel Inhibitor [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/suppression-of-acute-arthritis-by-n-methyl-34-dichloropropionaniline-n-medcpa-a-reversible-orai-calcium-channel-inhibitor/. Accessed June 30, 2022.
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