Calcium-Permeable Channels Cooperation for Rheumatoid Arthritis: Therapeutic Opportunities

Abstract

Rheumatoid arthritis is a common autoimmune disease that results from the deposition of antibodies–autoantigens in the joints, leading to long-lasting inflammation. The main features of RA include cartilage damage, synovial invasion and flare-ups of intra-articular inflammation, and these pathological processes significantly reduce patients’ quality of life. To date, there is still no drug target that can act in rheumatoid arthritis. Therefore, the search for novel drug targets has become urgent. Due to their unique physicochemical properties, calcium ions play an important role in all cellular activities and the body has evolved a rigorous calcium signaling system. Calcium-permeable channels, as the main operators of calcium signaling, are widely distributed in cell membranes, endoplasmic reticulum membranes and mitochondrial membranes, and mediate the efflux and entry of Ca2+. Over the last century, more and more calcium-permeable channels have been identified in human cells, and the role of this large family of calcium-permeable channels in rheumatoid arthritis has gradually become clear. In this review, we briefly introduce the major calcium-permeable channels involved in the pathogenesis of RA (e.g., acid-sensitive ion channel (ASIC), transient receptor potential (TRP) channel and P2X receptor) and explain the specific roles and mechanisms of these calcium-permeable channels in the pathogenesis of RA, providing more comprehensive ideas and targets for the treatment of RA.

(2R,4aS,6aS,12bR,14aS,14bR)-N-(2-(2-(2-(2-Azidoethoxy)ethoxy)ethoxy)ethyl)-10-hydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydropicene-2-carboxamide

“…In particular, following the protocol reported in the literature [29], 11-azido-3,6,9-trioxaundecan-1-amine 3 was prepared by the reaction of 2-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)isoindoline-1,3-dione 2 in ethanol with hydrazine monohydrate by Gabriel synthesis. The structure of 3 was determined by 1 H-, 13 C-NMR, and DEPT-135 spectra (Supplementary Materials, Figures S1-S3). 1) that are important for its biological activity.…”

“…Heteronuclear single quantum coherence spectroscopy (HSQC), correlation spectroscopy ( 1 H-1 H-COSY), and distortionless enhancement by polarization transfer (DEPT-135, DEPT-90, and DEPT-45) were also used to assign 13 C signals of compound 4, as shown in Table S1 (see Supplementary Materials for 2D spectra, Figures S6-S10). The 13 C-NMR spectrum of 4 exhibited 37 carbon signals were classified by DEPT experiments as six methyl groups, fifteen methylene, four methines, and twelve quaternary carbons.…”

“…All chemicals were purchased from Bide Pharmatech., Ltd. (Shanghai, China) and J & K scientific (Hong Kong, China). 1 H-NMR and 13 C-NMR spectra were collected in CDCl 3 and DMSO at 25 • C on a Bruker Ascend ® -600 NMR spectrometer (600 MHz for 1 H and 150 MHz for 13 C). All chemical shifts were reported in the standard δ notation of parts per million using the peak of residual proton signals of CDCl 3 as an internal reference (CDCl 3 , δ C 77.2 ppm, δ H 7.26 ppm).…”

“…The pathogenesis of RA is complex and not fully understood, since a variety of cell populations (e.g., macrophages, lymphocytes, and fibroblasts) and molecules as are involved in these mechanisms [12]. Among these, Ca 2+ has a pivotal function, since it plays a role in autoimmunity and the consequent progress of the disease [13]. One of the effectors dependent on the presence of Ca 2+ is the sarcoplasmic/endoplasmic reticulum (SR/ER) Ca 2+ -ATPase (SERCA).…”

Biomimetic Hyaluronic Acid-Based Brush Polymers Modulate Chondrocyte Homeostasis via ROS/Ca2+/TRPV4

“…Members of the vanilloid subfamily of transient receptor potential vanilloid channels have received attention in OA studies . Among them, transient receptor potential vanilloid 4 (TRPV4) plays a crucial role in initiating [Ca 2+ ] i signaling in chondrocytes and is involved in the regulation of ECM biosynthesis . It has been found that the use of a TRPV4 agonist (GSK101) leads to an increase in type II collagen (Col-II) and glycosaminoglycans (GAG) in cartilage .…”