Calcium signaling dysregulation in rheumatoid arthritis: a comparative perspective with osteoarthritis

Review Calcium signaling dysregulation in rheumatoid arthritis: a comparative perspective with osteoarthritis Thuy Duong Nguyen a,b,1 , Hugo Abreu a,b,1 , Nicoletta Tommasi a,b , Luigi Azzarone d , Rita Maria Concetta Di Martino c , Beatrice Riva d , Davide Raineri a,b,* , Tracey Pirali c,d , Annalisa Chiocchetti a,b , Giuseppe Cappellano a,b a Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, University of Eastern Piedmont, 28100 Novara, Italy b Center for Translational Research on Autoimmune and Allergic Diseases, University of Eastern Piedmont, 28100 Novara, Italy c Department of Pharmaceutical Sciences, University of Eastern Piedmont, 28100 Novara, Italy d ChemiCare srl, University of Eastern Piedmont, 28100 Novara, Italy ARTICLE INFO Keywords: Rheumatoid arthritis osteoarthritis calcium signaling Store-operated Ca 2+ entry channels ABSTRACT Rheumatoid arthritis and osteoarthritis are among the most prevalent chronic diseases worldwide, imposing a significant burden on both patients and healthcare systems. Despite their distinct etiology and progression, emerging evidence suggests that calcium signaling plays a pivotal role in the pathogenesis of both diseases by influencing a variety of cellular processes within joint tissues. Calcium is essential for regulating key cellular functions, including gene expression, muscle contraction, cell cycle progression, proliferation, apoptosis, excitation-contraction coupling, synaptic transmission, and embryonic development. Particularly, in the context of arthritic diseases, an imbalance in calcium homeostasis has significant consequences, since the osteogenic and chondrogenic processes, as well as extracellular matrix formation, are highly influenced by calcium levels. Given these insights, a deeper understanding of the mechanisms governing calcium uptake, release, and metabolism could enhance our comprehension of disease pathogenesis and facilitate the development of novel therapeutic strategies. This review provides an overview of calcium signaling mechanisms, particularly in the most affected cells and tissues in rheumatoid arthritis and osteoarthritis, and summarizes the emerging therapies targeting calcium metabolism that may improve current treatment options. 1. Introduction Rheumatoid arthritis (RA) and osteoarthritis (OA) are among the most prevalent chronic arthritic diseases worldwide, affecting tens to hundreds of millions of individuals and causing disability and significant socio-economic burdens on both patients and society [1,2]. OA is the most common and debilitating form, with an estimated 500 million patients globally, predominantly among middle-aged and older individuals [3,4]. OA is primarily characterized by the degeneration of articular cartilage, often accompanied by subchondral bone alterations and osteophyte (bone spurs) formation [5,6]. Although its pathogenesis remains incompletely understood, OA is driven by a combination of mechanical stress and complex biochemical processes, leading to structural deterioration and dysfunction of the entire joint [4]. The global burden of OA is expected to rise significantly in the coming decades, driven by aging populations and the increasing prevalence of obesity. By 2050, it is estimated that OA will affect around 1 billion people worldwide, with millions experiencing severe disability due to disease progression [7]. In contrast, RA is a systemic autoimmune disorder with an unclear etiology, characterized by aggressive autoimmune responses against joint tissue and chronic inflammation of the synovial membrane [8,9]. This persistent inflammation can result in progressive and irreversible whole-joint damage, including sustained synovitis and progressive cartilage/bone degradation [9]. Furthermore, RA may involve extraarticular complications, such as cardiovascular disease, pulmonary issues, and neurological and renal impairment [10]. RA affects slightly less than 1% of the global population, with a * Corresponding author at: Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, University of Eastern Piedmont, 28100 Novara, Italy. E-mail address: [email protected] (D. Raineri). 1 These authors contributed equally to this work. Contents lists available at ScienceDirect Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev https://doi.org/10.1016/j.autrev.2025.103923 Received 29 May 2025; Received in revised form 26 August 2025; Accepted 26 August 2025 Autoimmunity Reviews 24 (2025) 103923 Available online 28 August 2025 1568-9972/© 2025 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ ). notably higher prevalence among women [9]. While it predominantly occurs in individuals between the ages of 35 and 60, it can develop at any age [11]. The global incidence of RA continues to rise, reflected by current projections estimating that approximately 31.7 million people will be living with this condition by 2050 [12]. The multifactorial etiopathogenesis of RA includes a complex interplay of genetic predisposition and environmental factors, such as diet [13]. Although RA and OA arise from fundamentally different pathogenic mechanisms, RA being an autoimmune disorder driven by aberrant immune responses and OA being primarily a degenerative disease associated with mechanical wear and cartilage breakdown, both conditions exhibit dysregulation of Calcium (Ca 2+ ) signaling pathways. This convergence highlights Ca 2+ ’s pivotal role in joint pathology, despite the diseases’ distinct etiologies. Ca 2+ represents a crucial intracellular messenger that regulates a wide array of cellular processes, including cell proliferation, activation, migration, apoptosis, and differentiation [14]. In the context of joint tissues, such as chondrocytes, synoviocytes, and immune cells (resident and/or infiltrating), precise control of Ca 2+ signaling is essential for maintaining normal cellular function and joint integrity [15]. In RA, the dysregulation of Ca 2+ signaling is often linked to immune cell hyperactivation, increased inflammatory cytokine production, and synovial hyperplasia, all of which contribute to joint destruction [16]. In contrast, in OA, aberrant Ca 2+ signaling in chondrocytes and other jointresident cells may promote cartilage matrix degradation and altered mechanotransduction, exacerbating structural deterioration over time [17–19]. Therefore, the disruption of Ca 2+ homeostasis and signaling cascades in both RA and OA highlights a shared molecular pattern, independent of their distinct causes. Recognizing this commonality opens new avenues for understanding the molecular features of joint diseases and for developing novel Ca 2+ -targeted therapies. Overall, this review aims to provide a comparative analysis of Ca 2+ - mediated signaling in RA and OA, offering a broader perspective on how Ca 2+ ’s regulatory network can influence diverse disease processes. By identifying both overlapping mechanisms and disease-specific features, we hope to illuminate new therapeutic targets and foster a more integrated view of arthritis, bridging the gap between immune-mediated and mechanical forms of joint degeneration. 2. Calcium signaling 2.1. Role of Ca 2+ in cellular functions Ca 2+ is a multifunctional ion involved in many cellular functions, ranging from fertilization to cell death. It is significantly more abundant in organelles and extracellular matrix (ECM), approximately 10 5 times higher than in the cytoplasm, where it acts as a second messenger in many cellular signaling pathways [20]. Different cell types utilize a variety of components in the Ca 2+ ‘toolkit’, including specific and nonspecific channels that regulate both extracellular Ca 2+ entry and intracellular Ca 2+ release, key to many intracellular Ca 2+ dependent pathways [14,21,22]. Ca 2+ entry from external sources is regulated by several channels located on the plasma membrane, such as Voltage-Operated Ca 2+ Channels (VOCCs) and Receptor-Operated Ca 2+ Channels (ROCCs). VOCCs, activated by membrane depolarization, are mainly found in excitable cells like neurons and muscle cells [14]. In contrast, ROCCs, present in secretory cells and nerve terminals, are triggered by ligand binding to membrane receptors, including Nicotinic Acetylcholine Receptor, N-Methyl-D-Aspartate receptor, and the Adenosine Triphosphate (ATP)-gated ion channels (P2X receptors) [14,20]. Moreover, Transient Receptor Potential (TRP) channels are activated by various stimuli, including temperature, mechanical stress, and pH changes [20]. Additionally, Calcium Release-Activated Calcium (CRACs) channels, characterized by multimers of Ca 2+ release-activated Ca 2+ modulator subunits (Orai), are highly selective for Ca 2+ and activated in response to intracellular Ca 2+ store depletion. A reduction in Ca 2+ level within the endoplasmic reticulum (ER) is detected by Stromal Interaction Molecule 1 (STIM1), which undergoes a conformational change and physically interacts with Orai channels at the plasma membrane. This interaction triggers the opening of CRAC channels, allowing extracellular Ca 2+ to enter the cell and replenish ER stores, a mechanism known as Store-Operated Ca 2+ Entry (SOCE) [23]. Furthermore, Ca 2+ influx can be triggered by intracellular messengers like long-chain fatty acids, small oxygen/nitrogen radicals, and even Ca 2+ itself [14]. Besides Ca 2+ influx, Ca 2+ is released from intracellular stores via specific Ca 2+ channels on the ER/sarcoplasmic reticulum (SR). Inositol 1,4,5-Trisphosphate Receptors (InsP3Rs) mediate this release, which is essential for the generation of complex Ca 2+ signaling in mammalian cells. Upon activation of plasma membrane receptors by external stimuli, such as hormones or growth factors, InsP3, a specific ligand of InsP3Rs, is produced by the phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP₂) [14]. The activation of InsP3Rs is regulated by both InsP3 and cytosolic Ca 2+ concentrations [14]. Similarly, Ryanodine Receptors (RyRs), which exhibit greater molecular mass and conductance compared to InsP3Rs, can be directly activated by Ca 2+ itself, without the necessity of InsP3 [14]. Leukotriene B4, derived from arachidonic acid, may modulate Ca 2+ release by inhibiting InsP3Rs and potentiating RyRs activity during fertilization [14]. Furthermore, Sphingolipid Ca 2+ -Release Mediating Proteins of the ER (SCaMPERs) represent small Ca 2+ release channels activated by sphingolipids, such as sphingosylphosphoryl choline and sphingosine-1phosphate, found in tissues including the heart and liver. These channels are structurally distinct and smaller than InsP3Rs and RyRs [21]. Ca 2+ can also be released gradually via a sodium-dependent exchanger on mitochondria, acting as a temporary internal store to support prolonged cytosolic Ca 2+ signals [21]. Mitochondrial Ca 2+ plays a critical role in regulating cellular energy metabolism, redox balance, and intracellular signaling. Its uptake is primarily mediated by the Mitochondrial Calcium Uniporter (MCU), a highly selective channel in the inner mitochondrial membrane that facilitates Ca 2+ entry into the matrix, thereby activating Tri-Carboxylic Acid cycle enzymes and promoting ATP synthesis [24]. Under physiological conditions, mitochondrial Ca 2+ homeostasis promotes cell viability and metabolic function. However, excessive or prolonged Ca 2+ influx through the MCU leads to mitochondrial dysfunction, characterized by membrane depolarization, increased production of Reactive Oxygen Species (ROS), and activation of cell death pathways [25]. Furthermore, Nicotinic Acid Adenine Dinucleotide Phosphate activates two-pore channels on lysosomes to release Ca 2+ , bypassing RyRs [14]. In addition, some specific members of TRP channels, such as polycystin-2, can be directly activated by Ca 2+ itself to release intracellular Ca 2+ [14]. 2.2. Key cellular processes regulated by Ca 2+ Cells use a diverse array of components from the Ca 2+ signaling ‘toolkit’ to fine-tune their Ca 2+ signaling pathways, enabling the regulation of several physiological functions, such as gene expression, muscle contraction, cell cycle progression, proliferation, apoptosis, excitation-contraction coupling, synaptic activity, and embryonic development [21,22,26]. Intracellular Ca 2+ acts as a key trigger for various genetic programs by activating Ca 2+ -dependent transcription factors, either directly or indirectly [21,27,28]. A well-known example of these transcription factors is the Cyclic AMP-Response Element-Binding Protein (CREB), which is activated by elevated Ca 2+ through several kinases such as (i) cAMP-dependent Protein Kinase A (PKA), (ii) Ca 2+ /calmodulin-regulated protein Kinase IV (CaMK IV), (iii) Mitogenand Stress-activated Protein Kinase (MSK), MAP Kinase Kinase (MKK) 6, (iv) Protein Kinase B (PKB/Akt), and (v) Ribosomal S6 Kinase, among others [29]. When intracellular Ca 2+ levels rise, these kinases activate CREB, which then promotes the transcription T.D. Nguyen et al. Autoimmunity Reviews 24 (2025) 103923 2 of target genes via co-activators like CREB-binding protein or p300 [29]. Similarly, the Nuclear Factor of Activated T cells (NFAT), another Ca 2+ - responsive transcription factor, regulates gene expression in immune cells [28,29]. Ca 2+ also plays a crucial role in muscle contraction and relaxation. In skeletal muscle, VOCCs interact with RyRs on the SR, while STIM activates SOCE, triggering local Ca 2+ release and initiating muscle contraction [14]. In smooth muscle, different Ca 2+ signaling mechanisms, including InsP3Rs, SOCE, RyRs, two-pore channels, and VOCCs, regulate contraction and relaxation [14]. Ca 2+ signals can either promote contraction via Ca 2+ /calmodulin-dependent enzymes or induce relaxation through localized Ca 2+ sparks that activate hyperpolarizing ion channels [30]. Furthermore, Ca 2+ regulates cell cycle by interacting with key proteins including (i) Ca 2+ -sensors calmodulin (CAM), (ii) Calcineurin (CaN), (iii) Ca 2+ /CAMK, and (iv) Cyclin-Dependent protein Kinases (CDK)/cyclin complexes, which influence DNA synthesis, microtubule stability, and cytokinesis [31]. Ca 2+ signaling also plays a crucial role in energy production by facilitating Ca 2+ transfer between the ER and mitochondria, sustaining mitochondrial ATP synthesis, metabolic homeostasis, and thus promoting cell proliferation [31]. However, perturbation of Ca 2+ homeostasis can trigger programmed cell death, particularly through the regulation of mitochondrial permeability. Elevated mitochondrial Ca 2+ levels lead to the release of pro-apoptotic factors like cytochrome c and apoptotic protease-activating factor-1, leading to apoptosome formation and caspase activation [14]. Conversely, anti-apoptotic proteins, like B cell lymphoma type 2 (Bcl-2), inhibit apoptosis by lowering ER Ca 2+ levels and reducing the overload of mitochondrial Ca 2+ [14]. Additionally, the p53 tumor suppressor enhances apoptosis by activating the Sarco-endoplasmic Reticulum Ca 2+ -ATPase (SERCA) pumps and promoting ER Ca 2+ release [31]. Other tumor suppressors, including Breast Cancer-associated protein 1 and Phosphatase-TEN sin homolog, also regulate Ca 2+ -mediated apoptosis through InsP3 receptor modulation [31]. 2.3. Ca 2+ signaling pathways in joint homeostasis The knee joint is a complex structure comprising bones, cartilage, ligaments, tendons, and synovial fluid, all cooperating to maintain joint health and function. Among these components, cartilage is essential for reducing friction and absorbing mechanical stress. Chondrocytes, the only cellular component of cartilage, rely on tightly regulated Ca 2+ signaling pathways to control (i) chondrogenesis, (ii) differentiation, (iii) survival, and (iv) balance between anabolic and catabolic responses [32,33]. Several mechanotransduction factors, including compression, shear, fluid flow, hydrostatic pressure, histamine, parathyroid hormone, and Transforming Growth Factor-Beta (TGF-b), influence intracellular Ca 2+ levels through ion channels and signaling molecules, like TRP vanilloid 4 (TRPV4), TRPV1, PIEZO channels, G-Protein Coupled Receptors (GPCRs), PLC, and Ca 2+ /CAMK [33–36]. Furthermore, Ca 2+ signaling regulates extracellular matrix composition in cartilage via Ttype Voltage-Dependent Calcium Channels (T-VDCC) and InsP3Rs [37]. Bone remodeling, crucial for skeletal integrity, involves osteoclastmediated bone resorption and osteoblast-driven bone formation [38]. Both cell types regulate extracellular Ca 2+ levels, which influence their respective functions [38]. Osteoblasts’ proliferation is governed by Ca 2+ -Sensing Receptors (CaSRs) and signaling pathways like Extracellular signal-Regulated Kinase 1/2 (ERK1/2), Akt, Glycogen Synthase Kinase 3Beta (GSK3β), and PLC-dependent activation of SOCE [38]. The differentiation of osteoblasts is driven by the Ca 2+ /CaN/NFAT pathway that activates CaN, facilitating NFAT translocation to the nucleus and promotion of osteogenic gene expression by the association with other transcription factors (e.g., Osterix) [39]. Specific mechanical stimuli also regulate osteoblast differentiation through PIEZO1 and TRPV4 channels [40]. PIEZO channels regulate the intranuclear translocation of Yes-Associated Protein 1 (YAP1), promoting osteogenic transcription factors such as Runt-Related Transcription Factor 2 (RUNX2) and Bone Morphogenetic Protein 2 (BMP-2), while TRPV4 channels promote matrix organization and mineralization via CAMKII [40]. Like osteoblasts, Ca 2+ signaling is also essential to regulate many cellular activities in osteoclasts. In these cells, extracellular Ca 2+ inhibits resorptive activity while promoting cytoskeletal rearrangement through PLC-mediated pathways [38]. Furthermore, the activation of Ca 2+ - sensing receptors in osteoclast precursors promotes chemotaxis and bone resorption through the PI3K/Akt signaling pathway [38]. Furthermore, Receptor Activator of Nuclear Factor-κB Ligand (RANKL) induces Ca 2+ oscillations and activates Ca 2+ /CaN/NFAT pathway, driving osteoclast differentiation [36,41,42]. In the immune system, Ca 2+ signaling is crucial for processes such as lymphocyte activation, macrophage inflammatory responses, dendritic cell maturation and migration, neutrophil phagocytosis, and ROS production [43]. SOCE-mediated Ca 2+ influx via STIM1 and ORAI1 is essential for lymphocyte activation and functionality [44,45], while TRP channels modulate inflammatory responses [44,46,47]. Moreover, the key players of SOCE (STIM and Orai) and TRPs are also involved in Ca 2+ homeostasis maintenance, more specifically in regulating the activation and the functionality of natural killer cells, dendritic cells, neutrophils, and macrophages [44,48]. Due to the involvement of Ca 2+ signaling in different cellular processes, its dysregulation can impair joint structural and functional integrity, contributing to arthritic disorders like OA and RA. 3. Altered Ca 2þ signaling in OA 3.1. Pathophysiology of OA OA is one of the most prevalent age-related disabling joint disorders, characterized by the progressive degeneration of articular cartilage, synovitis, alterations of subchondral and periarticular bone, and involvement of supporting connective tissues, such as menisci, ligaments, and tendons [49–52]. Subjects with OA usually suffer from great pain during daily movement, which restricts them from physical activities and increases the risk of comorbidities such as obesity, diabetes, and cardiovascular disease [51]. The most affected joints are the knee, hand, and hip, although ankles, feet, and spine can also be damaged [50]. OA is a multifactorial disease driven by mechanical, biological, and genetic factors, with key risk contributors including obesity, metabolic syndrome, female sex, aging, genetic predisposition, joint injury, malalignment, and high-impact physical activity [4,53]. OA-related joint pathology triggers pro-inflammatory cytokines and degradative enzymes (e.g., IL-1β, TNFα , IL-6, MMPs), accelerating cartilage and bone damage in a self-perpetuating cycle [49,54]. Abnormal mechanical loading is a significant cause of OA onset and worsening [55]. Chondrocytes sense mechanical stress via mechanically activated ion channels, translating it into intracellular biochemical signals, which it is missing ion OA [51]. In summary, Ca 2+ homeostasis in chondrocytes is essential for the regulation of enzymatic activity, ECM production, and response to mechanical stimuli [33]. Aging is another primary risk factor for the development of OA, attributed to age-related changes in biological and molecular communication within the body, leading to natural degeneration with a reduction in cartilage efficiency [4]. The average age at which OA is diagnosed has declined over time, possibly because of enhanced comprehension of the illness, advancements in diagnostic instruments, or lifestyle changes. During aging, mitochondrial dysfunction, ROS accumulation, and proteolytic enzyme overproduction contribute to chondrocyte senescence and apoptosis, ECM disruption, an imbalance of catabolic and anabolic signals, and amplified cartilage damage [56]. Additionally, aging also influences the joint microenvironment by altering the structure of collagen fibers, affecting the collagen network’s stability and integrity [52]. Current treatments aim to manage symptoms and slow disease T.D. Nguyen et al. Autoimmunity Reviews 24 (2025) 103923 3 progression through pharmacological therapies, physiotherapy, and surgical interventions such as joint replacement [53]. However, given the intricate interplay of multifaceted risk factors, together with the significant impact on quality of life and the global healthcare system, it is essential to develop targeted preventive strategies for OA (Fig. 1). 3.2. Mechanisms of Ca 2+ dysregulation in OA 3.2.1. Dysfunctional mechanotransduction The dysregulation of Ca 2+ signaling has been reported in OA pathogenesis, which directly affects the survival and functionality of chondrocytes as well as cartilage integrity. Mechanotransduction allows cells, particularly chondrocytes, to sense and respond to mechanical loads by converting them into biochemical signals in the joint. This process regulates critical aspects including chondrocyte metabolism, ECM maintenance, and responses to dynamic stimuli [57]. Intracellular Ca 2+ oscillation is one of the earliest molecular responses that chondrocytes exhibit when exposed to mechanical stimuli. Proper regulation of Ca 2+ is essential for chondrocyte homeostasis and the preservation of the ECM integrity [58]. Recently, emerging research has focused on the role of mechanical stress in OA, such as the pattern, force, and duration of joint stress [54]. Many studies demonstrated that dysregulated mechanosensitive ion channels, such as TRP and Piezo channels, inducing abnormal intracellular Ca 2+ levels, play important roles in OA development, leading to chondrocyte apoptosis, irregular cellular responses, and cartilage degradation [58,59]. TRP channels, including TRPV4, TRPV2, TRPM7, and TRPC1, are involved in regulating cellular mechanical and biochemical responses, but their atypical activities can trigger cellular damage and ECM alterations [59]. Particularly, TRPV4 senses physiologic dynamic compression loading in chondrocytes, and regulates cell volume and anabolic response to mechanical stress [51,60]. However, excessive mechanical stress can activate TRPV4, thus triggering Ca 2+ influx-mediated chondrocyte apoptosis [51,61]. Moreover, the deletion of Trpv4 in mice disrupted osmotically induced Ca 2+ signaling in chondrocytes, leading to increased bone density and severe osteoarthritic joint degradation [62]. Conversely, in another Trpv4 gene-targeted mouse model, the inhibition of TRPV4 reduced the age-related OA severity but did not prevent the OA onset [54,63]. Therefore, the proper functionality of TRPV4 is essential to maintain the joint structure. Another member of the TRP family, TRPV2, is a Ca 2+ -permeable channel that regulates intracellular Ca 2+ levels in response to mechanical stimuli. In an OA mouse model, Trpv2 knockout reduced mechanical stress–induced Ca 2+ influx and subsequent Prg4 expression via the Ca 2+ /CAMK-cyclic AMP signaling pathway, while promoting hypertrophic differentiation in chondrocytes [64]. Other mechanosensitive cation channels regulating Ca 2+ influx are expressed in chondrocytes, namely PIEZO1 and PIEZO2 channels, which regulate the response to supraphysiologic strain (injurious level) and trigger cell death [60]. Upregulation of PIEZO1 expression has been reported in the cartilage of OA patients and in the anterior cruciate ligament of transection-induced OA rats [65]. Excessive mechanical strain triggers apoptosis and imbalance in the metabolism of anabolic and catabolic matrix via the activation of the PIEZO1 in chondrocytes Fig. 1. Immunological and calcium signaling differences between RA and OA. The schematic illustration shows a side-by-side comparison of calcium signaling and immune mechanisms in OA (left panel) and RA (right panel). In OA, low-grade local inflammation and mechanical stress contribute to progressive cartilage degeneration. Dysfunctional chondrocytes respond to excessive mechanical loading through aberrant activation of mechanosensitive ion channels (e.g., PIEZO1), leading to disrupted intracellular Ca 2+ homeostasis, mitochondrial dysfunction and oxidative stress. Although immune cell infiltration is limited, inflammatory cytokines such as IL-1β and TNFα exacerbate Ca 2+ dysregulation and joint damage. In contrast, RA is a systemic autoimmune disease characterized by aggressive synovial inflammation, driven by the infiltration and activation of CD4 + T cells, plasma cells and macrophages. The chronic inflammatory environment leads to elevated production of cytokines (e.g., TNFα , IL-1β, IL-6, IL-17), EVs and autoantibodies (RF, ACPA). Calcium signaling is hyperactivated in immune and FLS, primarily via TRPV1, enhancing T cell responsiveness, FLS invasiveness, and cytokine production through NFAT activation. Created with BioRender.com. ACPA = anti-citrullinated peptide autoantibody; RF =rheumatoid factor; RA =rheumatoid arthritis; OA =osteoarthritis; PIEZO1 =Piezo-type mechanosensitive ion channel component 1; ROS =reactive oxygen species; NFAT =Nuclearfactor of activated T-cells; FLS =fibroblast like-synoviocytes; IL1β =interleukin 1 beta; IL-6 = interleukin 6; IL-17 =interleukin 17; TNFα =tumor necrosis factor alfa; TRPV4 =transient receptor potential cation channel subfamily V member 4 T.D. Nguyen et al. Autoimmunity Reviews 24 (2025) 103923 4 [65]. Moreover, Steinecker-Frohnwieser et al. reported that activation of PIEZO1 by Yoda1, a selective PIEZO1 agonist, leads to the increase of both intracellular Ca 2+ levels and expression of MMPs, BMP-2, collagen type I α 1 (COL1A1) and various interleukins, such as IL-6 and IL-8 in OA chondrocytes [66]. In this study, the interference between PIEZO1 and TRPV4 was also investigated by Yoda1/GSK1016790A (TRPV4 agonist) application. PIEZO activation inhibits the effects of subsequent TRPV4 activation to a greater extent than vice versa in chondrocytes, suggesting their direct or indirect physical interactions [59,66]. Furthermore, PIEZO2 has been implicated in mechanical pain in OA. Knock-out of nociceptor-specific PIEZO2 in mice inhibits nerve growth factormediated knee swelling and osteoarthritis mechanical sensitization [67]. Many studies reported that the non-selective PIEZO inhibitor, GsMTx4, could protect chondrocytes, reducing apoptosis and increasing cartilage matrix production via the activation of PIEZO/Calcineurin/ NFAT1 pathway as well as alleviate pain in mice [51,65,67] (Figure 2). 3.2.2. Influence of inflammatory mediators on Ca 2+ influx OA was considered a non-inflammatory disease, but recent evidence showed that early-stage OA exhibits low-grade inflammation that persists throughout all OA phases [3,68]. Several studies demonstrated a correlation between the inflammatory mediators and abnormal Ca 2+ signaling pathway, which imbalances Ca 2+ homeostasis and worsens OA progression. Apart from response to mechanical loads, TRP and PIEZO channels are also involved in the chondrocyte’s sensing of inflammatory signals [69]. Particularly, activation of IL-1 α upregulates PIEZO1 expression and function in primary porcine chondrocytes and human OA cartilage, increasing the intracellular Ca 2+ levels and the mechanical sensitivity of chondrocytes to injurious loads [17]. Moreover, stimulation of pro-inflammatory cytokines such as IL-1β and TNFα increases the expression of many TRP channels such as TRPA1, TRPV1, and TRPV3 in human OA chondrocytes [54,70]. TRPV1 under exposure to inflammatory mediators also plays an important role in chronic arthritis pain [71]. In addition, IL-1β-induced TRPA1 activation triggers chondrocyte apoptosis through intracellular Ca 2+ overload and mitochondrial dysfunction [54,72]. Mitochondrial Ca 2+ overload contributes to chondrocyte dysfunction through activation of calpain and CaMKII pathways, leading to mitochondrial depolarization, swelling, and apoptosis [73]. It also promotes ROS production, which induces cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) [74]. Elevated mitochondrial Ca 2+ levels are observed in both OAassociated macrophages and mesenchymal stem cells, correlating with pro-inflammatory and dysfunctional phenotypes [75,76]. Additionally, Ca 2+ overload impairs cartilage matrix synthesis and promotes pathological mineralization via disrupted respiratory chain activity and nitric oxide signaling [77]. Concerning TRP channels, particularly TRPV1 and TRPV4, their activation is strictly correlated to both the release and the effects of pro-inflammatory molecules. More in detail, TRPV1 activation induces the secretion of inflammatory cytokines and hormones, leading to chronic inflammation and joint pain [54]. In contrast, TRPV4 activation contributes to anti-inflammatory chondroprotective effects by the (i) inhibition of IL-1β signaling, (ii) regulation of ciliary tubulin, (iii) activation of CaMKK/AMP-activated protein kinase (AMPK) and (iv) suppression of NF-κB activation [69,78,79]. 4. Altered calcium signaling in RA 4.1. Pathophysiology of RA RA is an autoimmune inflammatory disorder, primarily targeting synovial joints and also affecting various extra-articular organs such as the heart, lungs, kidneys, skin, and nervous system [20]. Localized synovial inflammation in RA involves leukocyte infiltration and elevated cytokines, driven by macrophages, plasma cells, dendritic cells, and others through adaptive and innate immunity, cytokine signaling, and mesenchymal responses [20]. During inflammation, dendritic cells and other APCs initiate immune responses by presenting self-antigens via TLRs to T cells, triggering Tand B-cell activation. Activated immune cells release cytokines (e.g., GM-CSF, IL17, TNFα , IL-6), while B cells produce autoantibodies such as Rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPAs). These autoantibodies form immune complexes with citrullinated Fig. 2. Principal mechanisms of Ca 2+ signaling alteration in OA. Mechanoinflammation in OA involves several signaling pathways that can be activated by both proinflammatory cytokines and mechanical stimuli. Activation of mechanoinflammatory signaling contributes to increased pro-inflammatory gene expression, alterations in cytoskeletal phenotype and energy homeostasis, and an increase in catabolic mediators. Dysregulation of mechanical and biochemical stimuli activates ion channels such as TRPV4 and Piezo channels, leading to Ca 2+ influx from the extracellular space, which contributes to cartilage destruction, inflammation, and pain in OA. Activation of Piezo1 and Piezo2 channels leads to Ca 2+ influx, which activates calcineurin and the transcription factor NFAT, thereby regulating chondrocyte metabolism and cell death. In contrast, TRPV4 activation has shown chondroprotective effects on articular cartilage by activating the CaMKK/AMPK pathway and suppressing the NF-κB pathway. Activation of ASIC1a, induced by extracellular acidification, also leads to Ca 2+ influx in articular chondrocytes, resulting in the upregulation of calpain and calcineurin, which ultimately triggers chondrocyte injury and cell death in arthritis. Furthermore, ASIC1a activation by acidification promotes chondrocyte proliferation via the ERK/MAPK signaling pathway. Created with BioRender.com. T.D. Nguyen et al. Autoimmunity Reviews 24 (2025) 103923 5 proteins, promoting joint damage and sustaining chronic inflammation in RA [9,20,80]. Recent studies have highlighted the potential pathogenic role of extracellular vesicles (EVs) in RA. EVs are small particles released by both eukaryotic and prokaryotic cells. These EVs may serve as biomarkers of diseases as well as carriers of autoantigens, facilitating the propagation of autoimmune responses [81]. In contrast, in OA, EVs are unlikely to trigger intense inflammatory storms, likely due to their relatively low immunogenicity. Alterations in the mechanical properties of EVs may restrict joint mobility, while the bioactive molecules they carry can influence the behavior and fate of FLS and chondrocytes [82]. Furthermore, the chronic inflammatory environment in the RA joint is linked to hyperplastic synovial membrane and cartilage erosion [20]. After the onset of localized inflammation, the synovium can thicken to approximately 10 cell layers, primarily including macrophage-like and fibroblast-like synovial cells (FLSs) [20]. Under the stimulation of many pro-inflammatory cytokines from infiltrating immune cells, FLSs are activated to be hyperproliferative and resistant to apoptosis [20]. Cartilage degradation is driven by ADAMTS, MMPs, collagenase, and inflammatory cytokines released by FLSs, immune cells, and chondrocytes under inflammatory conditions [9]. In addition, the bone surrounding joints is also damaged under the persistent inflammation caused by many cytokines, MMPs, and oxidative stress [9]. Bone erosion in RA is primarily driven by osteoclast activation via the RANK/RANKL/OPG axis [9,20]. Upon stimulation, osteoclasts attach to bone and secrete hydrochloric acid and cathepsin K to degrade matrix proteins like osteonectin and aggrecan. ACPA stimulation also contributes to osteoclast-mediated bone loss [83] (Fig. 1). 4.2. Mechanisms of Ca 2+ dysregulation in RA Ca 2+ signaling exhibits a crucial role in many cellular processes characterizing immune cells. Therefore, dysregulated Ca 2+ in different cell types, particularly leukocytes, FLSs, chondrocytes, and bone cells, has been widely shown to trigger chronic inflammation and significantly contribute to the progression of RA. The activation of immune cells, especially of T cells, is tightly regulated by Ca 2+ signaling, particularly through SOCE and its downstream pathways [84,85]. Several data reported in the literature show that RA is associated with dysregulated Ca 2+ signaling in T cells. Peripheral T cells from RA patients exhibit higher intracellular Ca 2+ levels and increased SOCE compared to healthy controls [46,86]. In addition, naïve CD4 + T cells from RA patients show increased intracellular Ca 2+ levels correlated with an overactivated SOCE and an overexpression of ORAI1, which stimulates cytokine release and TCR responsiveness, leading to disease progression [43]. Moreover, genetic studies have shown polymorphisms in the ORAI1 gene (e.g., SNP rs7135617) linked to a higher risk of RA [43]. Besides the above, TRPV1 is another Ca 2+ channel correlated with abnormal functionality of immune cells (i.e., dendritic cells, macrophages, and T cells), including the production of pro-inflammatory cytokines and pain transmission in RA [36]. In addition to SOCE mechanism and TRPV1, other Ca 2+ channels are involved in T-cell activation and functionality: (i) P2X receptors, which stimulate Ca 2+ influx based on ATP and act as a costimulatory signal to T-cell activation; and (ii) arachidonic acid-regulated Ca 2+ -selective (ARC) channels, primarily composed of ORAI1/ORAI3 subunits, with ORAI3 being particularly important in T-cell responses. Despite the smaller effects on Ca 2+ influx than those of CRACs, ARC channels are still sufficient to induce CaMKII and CD3ζ phosphorylation [45]. In naïve RA T cells, ORAI3 overexpression by IKAROS hypoexpression enhances ARC activity, leading to an increased Ca 2+ influx. This Ca 2+ overload triggers the phosphorylation of TCR signaling components and the expression of activation markers like CD69 and Nuclear Receptor 77 (NUR77), even in the absence of TCR stimulation. This mechanism activates the TCR signaling cascade and promotes T-cell responses to low-avidity self-antigens, contributing to chronic autoimmune inflammation in RA [45]. Additionally, it has been demonstrated that a mutation in SH2 domain of ZAP-70, an important TCR-associated signal transduction molecule, can alter TCR-dependent Ca 2+ signaling, allowing autoreactive T cells to evade negative selection in the thymus and contribute to autoimmune arthritis [87]. Furthermore, since the calcineurin-NFAT pathway is downstream to SOCE, TRPV1, and P2XR, it is also altered in RA pathogenic T cells, leading to an exacerbated production of proinflammatory cytokines, in particular IL-17 and TNFα [43]. During RA progression, in addition to T cells, Ca 2+ influx dysregulation and its downstream pathways also stimulate infiltration, activation, proliferation, and differentiation of several other leukocytes, triggering the chronic inflammatory environment in synovium joints [20,43]. As the most abundant leukocytes, neutrophils derived from the synovial fluid of RA patients exhibit abnormal Ca 2+ release patterns in response to stimulation compared to healthy controls. This altered signaling led to an increased production of pro-inflammatory cytokines [88] (Fig. 3). 4.2.1. Hyperactivation of synovial fibroblasts and invasive behavior The hyperactivation and aggressive behaviors of FLSs are closely associated with the dysregulation of Ca 2+ signaling in RA. A comprehensive PCR screening of in vitro treatments in RA-FLSs identified 23 Ca 2+ -modulated genes that may be involved in different key pathogenic processes, including apoptosis, cell proliferation, migration/invasion, and immune/inflammatory responses [89]. These multifunctional genes encode various products driving the pathogenic behavior of RA-FLSs, ranging from upstream cellular receptors like TLR6 and the leptin receptor, to signaling molecules and downstream transcription factors such as IK cytokine, a down-regulator of Human Leukocyte Antigen (HLA) class II, as well as BMP-1, NFAT c3 and signal transducer and activator of transcription 3 (STAT3) [89]. Aberrant activities of Ca 2+ transport are also linked to the aggressive behaviors of RA-FLS. In RA-FLSs, stimulation of TRPV1 by capsaicin upregulates gene and protein expression of IL-6 [90]. Furthermore, acidsensitive ion channel 1a (ASIC1a) overactivation induces elevated Ca 2+ influx, promoting cell proliferation through the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK/MAPK) and NFAT signaling, amplifying the expression of pro-inflammatory cytokines via the NFATc3/Chemokine (C-C motif) ligand 5 (CCL5) pathway, as well as contributing to the synovial invasion via the Ca 2+ /Ras-related C3 botulinum toxin substrate 1 (Rac1) pathway [20,91–93]. On the other hand, the inhibition of SERCA has been shown to reduce FLS proliferation, enhance apoptosis, and induce autophagy-dependent cytotoxicity in RA-FLSs [94,95]. Finally, regarding the impact of mitochondrial Ca 2+ in RA FLS, upregulated MCU expression enhances mitochondrial Ca 2+ uptake, promoting mitochondrial dysfunction and increased invasiveness, which can be mitigated by MCU inhibition [96]. Additionally, elevated mitochondrial Ca 2+ transfer through Mitochondria Associated Membranes (MAMs) facilitates inflammatory angiogenesis by upregulating the expression of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) via serum response factor signaling [97]. Mitochondrial dysfunction, characterized by excessive ROS production and mitochondrial DNA release further activates inflammatory pathways, including the NOD-Like Receptor Protein 3 (NLRP3) inflammasome, thereby amplifying synovial inflammation and immune responses, suggesting that mitochondrial Ca 2+ homeostasis and MCU-mediated signaling as critical contributors to RA progression [98]. 4.2.2. Cartilage damage and osteoclast-mediated bone resorption Cartilage damage in RA primarily derives from chondrocyte apoptosis and degradation of the ECM. Ca 2+ signaling is known as one of the most relevant mediators of apoptosis. In RA chondrocytes, disrupted intracellular Ca 2+ homeostasis may be associated with the activation of peptidylarginine deiminase (PAD) and enhanced intracellular citrullination, potentially contributing to disease severity [99]. Moreover, T.D. Nguyen et al. Autoimmunity Reviews 24 (2025) 103923 6 some Ca 2+ -permeable channels are dysregulated in chondrocytes from patients with RA. Several studies have specifically reported that elevated intracellular Ca 2+ levels resulting from ASIC1 activation can trigger downstream signaling pathways, including the MAPK/ERK cascade and the calpain-2/calcineurin pathway. These signaling events impair chondrocyte ECM metabolism and promote both apoptosis and pyroptosis [20,100–102]. Dysregulation of Ca 2+ levels has also been linked to bone resorption in RA, although the underlying mechanisms remain unclear. Notably, aberrant extracellular Ca 2+ levels have been shown to affect osteoclast differentiation via the CaSR/NF-κB/NFATc1 signaling cascade, contributing to RA pathogenesis [103]. Knockdown of CaSR in osteoclast precursors has been reported to increase osteoclasts’ number, potentially exacerbating bone destruction in RA [103]. Furthermore, Ca 2+ is essential for the activation of PADs, which mediate protein citrullination. Given the high Ca 2+ concentration in the bone microenvironment, PAD-induced citrullinated protein in osteoclasts may interact with ACPAs, promoting autoimmune responses and contributing to joint inflammation and damage in RA [83]. 5. Similarities and differences between OA and RA 5.1. Shared mechanisms in OA and RA Despite differing in etiology, OA and RA exhibit some shared mechanisms, such as cytokine-driven upregulation and sensitization of TRP channels (TRPV4, TRPA1, TRPV1) that lead to aberrant Ca 2+ influx in chondrocytes, synoviocytes, and resident immune cells [104]. This process increases ROS production and triggers calcium-dependent proinflammatory signaling pathways. As a result, it drives the release of MMPs, promotes apoptosis, contributes to the formation of synovial pannus, and heightens pain sensitivity, ultimately creating a vicious cycle of inflammation and degeneration [104]. TRP channels, particularly members of the TRPV, TRPA, and TRPM subfamilies, act as sensors for mechanical, chemical, and thermal stimuli and are increasingly recognized as key regulators of chondrocyte and synoviocyte mechanotransduction, inflammatory signaling, and nociception [104]. Their abnormal expression has been reported in chondrocytes and synovial cells, contributing to pain, inflammation, and cartilage breakdown [54]. TRPV4 becomes dysregulated under inflammatory and mechanical stress, leading to pathological Ca 2+ oscillations and promoting cartilage matrix degradation. Similarly, TRPA1 and TRPV1, typically expressed in sensory neurons and synovium, are dysregulated in OA and RA joints [105], where their heightened activity facilitates neurogenic inflammation and pain sensitization. These channels also interact with oxidative stress and lipid mediators present in the inflammatory milieu, amplifying calcium-dependent signaling cascades that exacerbate joint damage [54]. In chondrocytes, TRPV4 plays a vital role in mechanotransduction and maintaining Ca 2+ balance. Upon activation by normal mechanical stress, it helps support the expression of Sox9, aggrecan, and collagen-II through Ca 2+ /calmodulin signaling [106,107]. However, in OA models, both the expression and activity of TRPV4 become disrupted, leading to issues like cartilage degeneration, synovitis, and the formation of osteophytes. Interestingly, blocking TRPV4 has been shown to ameliorate the disease by decreasing the infiltration of M1 macrophages as well as ROS/NLRP3 signaling [108]. In RA synoviocytes, TRPV4 regulates intracellular Ca 2+ and its dysregulation is linked to aberrant synovial responses and joint pathology [109]. Furthermore, TRPV1 is also found in synovial fibroblasts in both OA and RA [90]. In both conditions, TRPV1 dysfunction affects Ca 2+ influx and NF-κB signaling, which in turn drives cytokine production and heightens pain sensitivity [110,111]. In chondrocytes and synoviocytes, the presence of IL-1β and TNFα increases TRPA1 and TRPV1/TRPV4 at both mRNA and protein levels, by promoting the opening of these channels and allowing for a surge of Ca 2+ influx, which ultimately leads to mitochondrial dysfunction, the generation of ROS, the induction of MMPs, and apoptosis [54,109]. Additionally, TNFα enhances the sensitivity of TRPV1 through p38 MAPK pathways and similarly affects TRPV4 [112]. These cytokines Fig. 3. Overview of the major altered Ca 2+ signaling pathways in RA. The SRC family protein tyrosine kinase LCK binds to CD4 and CD8 co-receptor cytosolic domains and is recruited to the T cell receptor (TCR) complex through the interaction with MHC class II or class I molecules. LCK phosphorylates immunoreceptor tyrosine-based activation motifs in the CD3 chains, facilitating docking and activation of the tyrosine kinase ZAP70. Activated ZAP70 phosphorylates the transmembrane adaptor protein LAT (linker for activation of T cells), which recruits multiple adaptor and effector proteins. Antigen specific TCR activation leads to the activation of phospholipase Cγ1 (PLCγ1), resulting in the production of inositol-1,4,5-trisphosphate (Ins(1,4,5)P₃) and the subsequent release of Ca 2+ from endoplasmic reticulum (ER) stores via InsP₃ receptor (InsP₃R) channels. The resulting depletion of ER luminal Ca 2+ is detected by stromal interaction molecule 1 (STIM1), which undergoes a conformational change, oligomerizes, and relocates to ER–plasma membrane junctions, where it activates the calcium release-activated calcium (CRAC) channel subunit ORAI1. This process initiates the store-operated Ca 2+ entry (SOCE) mechanism, triggering Ca 2+ –calmodulin-dependent signaling pathways, including the nuclear translocation of nuclear factor of activated T cells (NFAT). Additional plasma membrane channels involved in Ca 2+ signaling during T cell activation include non-selective transient receptor potential (TRP) channels (e.g., TRPV1) and purinergic ionotropic receptors (P2RXs). Ca 2+ homeostasis between cytosol and ER is also maintained by various transporters and pumps, including sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPases (SERCAs). Created with BioR ender.com. T.D. Nguyen et al. Autoimmunity Reviews 24 (2025) 103923 7 activate pathways that depend on Ca 2+ , like CaMKII, calcineurin–NFAT, and Ca 2+ /calmodulin signaling. This activation leads to an increase in MMPs, prostaglandins (like PGE2), inflammatory mediators, and ultimately results in the destruction of joint tissue [39,43]. Additionally, the activation of downstream signaling of TRPV1 boosts the secretion of IL1β, IL-6, and IL-8 in immune or synovial cells, which further intensifies inflammation and pain in both OA and RA [36,113]. The similarities point to the idea that focusing on the interaction between TRP channels and Ca 2+ , particularly blocking or modulating Ca 2+ -related channels such as SOCE, thus reducing cytokine-triggered Ca 2+ entry [20], could be a promising approach to lessen both the inflammatory and degenerative issues seen in OA and RA. 5.2. Distinct features between OA and RA OA and RA diverge sharply in initiating mechanisms and primary cellular targets, which may impact on their clinical course and therapeutic response. Mechanical stress acts as a primary driver in OA, while autoimmune triggers represent the initiating event in RA. OA is classically initiated by chronic mechanical overload and altered joint biomechanics [55]. Repetitive stress on articular cartilage and subchondral bone induces microdamage, leading to mechanotransduction changes in chondrocytes [52,55]. These cells respond with altered extracellular matrix synthesis and increased catabolic enzyme release, including MMPs and ADAMTS. OA-associated Ca 2+ dysregulation is initiated by defective mechanotransduction in chondrocytes, involving mechanosensitive channels such as TRPV4, TRPV2, TRPA1, and PIEZO1/2 [58,59,114]. Importantly, inflammation in OA is secondary, arising from the release of Damage-Associated Molecular Patterns (DAMPs) from stressed chondrocytes and extracellular matrix fragments, which activate synovium and innate immune responses [115]. In RA, the initiating insult is immune dysregulation [116]. Genetic susceptibility (e.g., HLA-DRB1 alleles) and environmental factors (e.g., smoking, mucosal infections) break tolerance to citrullinated and other post-translationally modified self-antigens [117]. The earliest pathological changes occur in synovial tissue, where autoreactive T and B cells infiltrate, driving pannus formation and chronic synovitis. In RA, dysregulated Ca 2+ signaling occurs in many different cell types, including immune cells, FLSs, chondrocytes, and osteoclasts [20,36,46,78,89]. Thus, many Ca 2+ signaling pathways are involved in RA progression, mainly TRP channels, ORAI1/3, ASIC1a-mediated influx, and mitochondrial Ca 2+ uptake [20,43,91,96]. Moreover, the crosslink between the dysregulation of Ca 2+ signaling and the release of pro-inflammatory cytokines (TNFα , IL-6, IL-1β) amplifies synovial fibroblast activation and osteoclast differentiation, resulting in marginal bone erosion and cartilage invasion. The involvement of genetic factors was also shown in RA, such as ORAI1 polymorphisms, IKAROS hypoexpression, and ZAP70 mutations, while evidence of human genetic alterations in OA was limited [45,87]. Lastly, OA and RA also differ in primary cell targets. In OA, the central effector cells are chondrocytes and subchondral bone osteoblasts. Synovial cells are involved but are typically activated downstream of cartilage damage [118]. Thus, therapeutic strategies focus on preserving chondrocyte viability, modulating mechanotransduction, and maintaining extracellular matrix integrity. On the other hand, in RA, the central players are immune cells, especially autoreactive T and B cells, and macrophages. Synovial fibroblasts undergo epigenetic changes, becoming invasive “imprinted” effectors that perpetuate inflammation and joint destruction. In this case, chondrocytes are affected in a later phase of the disease, primarily as bystanders exposed to cytokine-rich pannus tissue and direct enzymatic attack [119]. Consequently, RA-tailored therapies typically target the immune system [120], instead of joint-resident cells such as chondrocytes or osteoblasts. These shared mechanisms and distinct features are comprehensively summarized in Table 1. Table 1 Similarities and differences in calcium-related mechanisms between OA and RA. OA RA Shared outcomes Key Ca 2+ entry dysregulation Mainly mechanosensitive Ca 2+ channels: TRP channels (TRPV4/ TRPA1/ TRPV1) and PIEZO (PIEZO 1/2). [51,54,59,66,67,70,71] Various Ca 2+ channels: ORAI1/ORAI3 through SOCE, TRP channels (TRPV1/ TRPV4), ASIC1a, P2X receptors, ARC channels. [36,43,45,46,86,91,108] Dysregulated TRP channels, especially TRPV1 and TRPV4. [36,43,54,71,90] Key aberrant downstream Ca 2+ signaling Ca 2+ /CAMK, calcineurin/ NFAT1, ROS–COX-2–PGE2 pathways; NF-κB suppression and ECM degradation pathways (MMPs). [64,69,78,79] Ca 2+ /calcineurin–NFAT, MAPK/ERK, Rac1, NFATc3/CCL5, CaSR/NF-κB/NFATc1; TCR signaling cascade via ORAI/ARC. [20,43,45,87,92,93,102,103] Calcineurin–NFAT pathway [20,43,64] Mitochondrial Ca 2+ involvement Ca 2+ overload promotes ROS, mitochondrial depolarization, and ECM synthesis impairment. [73,75–77] Mitochondrial Ca 2+ uptake through MCU promotes mitochondrial dysfunction, ROS, and DNA release. MAM-mediated Ca 2+ transfer promotes angiogenesis via VEGFR2. [96–98] Mitochondrial Ca 2+ overload. [73,75,96–98] Cytokine–Ca 2+ crosstalk Inflammatory cytokines (IL-1β, TNFα ) upregulate TRP/PIEZO channels, increasing Ca 2+ influx. [54,69,70,72,79] Pro-inflammatory cytokines (TNFα , IL-6, IL17) are both triggers and consequences of Ca 2+ dysregulation. [43,90] Inflammation amplifies Ca 2+ dysregulation in both [20,43,54,69] Genetic associations Limited mention of human genetics. ORAI1 SNPs, IKAROS hypoexpression, ZAP70 mutations. [43,45,87] Main cell types Chondrocytes [54,57,59,75,76] Immune cells (T cells, neutrophils, macrophages), FLSs, chondrocytes, osteoclasts. [20,43,46,86,88,100–102] Chondrocyte dysfunction [54,59,100–102] Key pathogenic outcomes Chondrocyte apoptosis, ECM degradation, osteophyte formation, and chronic pain. [51,54,59,64,65,67,73,75,77] Autoimmune-induced chronic inflammation, synovial proliferation, leukocyte-driven cytokine release, cartilage destruction, bone erosion, and inflammatory pain. [20,36,43,45,83,87,89–92,96,98,100,103] Cell apoptosis, cartilage damage, chronic inflammation, pain, and joint destruction. [3,17,20,36,43,51,54,58,59,64,65,69,72,73,75–77,83,89–92,96,98,100,103] T.D. Nguyen et al. Autoimmunity Reviews 24 (2025) 103923 8 6. Ca 2þ -related pathological mechanisms in arthritic disorders OA and RA are both chronic joint disorders without a curative treatment. However, their underlying pathologies result in fundamentally different alterations in Ca 2+ signaling. In OA, they are primarily related to mechanical wear and tear, chondrocyte dysfunction, and mild synovial inflammation. In contrast, in RA, dysregulated Ca 2+ signaling is driven by aggressive autoimmune activation, pronounced synovitis, and severe cartilage and bone erosion. Given these different pathological mechanisms, the Ca 2+ -targeted therapeutic approach should be specifically tailored to the underlying disease context. While OA therapies primarily aim to promote chondroprotection and reduce mechanical stress [121,122], RA treatments focus on immunosuppression and systemic inflammation reduction [123]. 6.1. Emerging targets in OA The development of new therapeutic strategies for OA has led to the exploration of innovative approaches, including (i) TRPV4 modulators to protect articular cartilage and (ii) mitochondria-targeted antioxidants to counteract oxidative and metabolic dysfunction. In OA, altered mechanotransduction significantly contributes to cartilage degeneration and joint inflammation. In particular, TRPV4 is predominantly involved in mechanosensitive intracellular Ca 2+ signaling pathways in chondrocytes, regulating responses to mechanical stress and maintaining intracellular Ca 2+ homeostasis [54,106]. Numerous studies have demonstrated that TRPV4 modulation can influence cartilage integrity, highlighting its potential as a promising therapeutic target for OA. Quinazolin-4(3H)-one derivatives, known TRPV4 agonists, have been shown to promote cartilage matrix production and reduce tissue damage by inducing anabolic responses and enhancing chondrogenic differentiation in animal models [124]. Another extensively studied TRPV4 agonist, GSK1016790A, has demonstrated chondroprotective effects in several preclinical studies, including inhibition of inflammatory responses under mechanical loading, reversal of IL-1β-induced MMP-13 upregulation, enhancement of aggrecan expression, and reduction of proteoglycan loss [78,79]. These positive effects are mediated by TRPV4-induced suppression of the NF-κB phosphorylation through the CAMKK/AMPK signaling pathway [79]. However, other studies contradicted these evidences suggesting that TRPV4 may also offer therapeutic benefits. In particular, TRPV4 blockade has been shown to alleviate pain in the monoiodoacetate-induced OA rat model as well as to reverse (i) dynamin-related protein 1-induced mitochondrial dysfunction, (ii) chondrocyte pyroptosis, and (iii) cartilage degeneration in a mouse model of anterior cruciate ligament transection [125,126]. Moreover, a study investigated capsaicin, a specific TRPV1 agonist, which demonstrated its ability to suppress M1 macrophage infiltration and polarization in the synovium via the Ca 2+ /CaMKII/Nuclear factor erythroid 2Related Factor 2 (NRF2) signaling pathway, thereby alleviating OA progression in a rat model [127]. Ca 2+ -related mitochondrial dysfunction also plays a fundamental role in OA, leading to Ca 2+ overaccumulation, stimulation of ROS production, mitochondrial membrane depolarization, and apoptosis. These further damage cellular structures, accelerating ECM degradation and promoting disease progression [128]. Therefore, targeting mitochondrial Ca 2+ homeostasis and oxidative stress may represent promising treatments for OA. Intracellular esterase and low pH-responsive nanoparticles have been shown to sequester mitochondrial Ca 2+ , thereby regulating mitochondrial Ca 2+ flux and inhibiting the Wnt/β-catenin pathway, ultimately preventing mitochondrial dysfunction and mitophagy while physiologically restoring mesenchymal stem cells’ mitochondrial function [76]. Recently, TMA-MSN-TPP-EGTA-PEG (METP) nanoparticles have been developed as mitochondrial Ca 2+ nanoregulators, specifically designed to control mitochondrial Ca 2+ overload and reduce the pro-inflammatory phenotype of macrophages in both in vitro and in vivo OA models [75]. Furthermore, poly-lactic/ glycolic acid nanoparticle-mediated delivery of cyclosporine has been shown to inhibit the opening of the mitochondrial permeability transition pore, protecting mitochondria from Ca 2+ overload-induced damage in myocardial ischemia-reperfusion injury, suggesting a potential applicability in OA treatment [128,129]. Similarly, administration of edaravone, a potent hydroxyl radical scavenger, reduced ROS overproduction and Ca 2+ overload, thus protecting rat nucleus pulposus cells from compression-induced mitochondrial damage [130]. In addition to Ca 2+ modulators, mitochondria-targeted antioxidants represent another promising therapeutic strategy to inhibit ROS accumulation and protect mitochondria from Ca 2+ overload-induced damage. For instance, mitoquinone has been shown to reduce ROS levels, suppress inflammation, and prevent ECM degradation by activating the NRF2/Parkin signaling pathway in IL-1β-induced OA chondrocytes [131]. Moreover, overexpression of the mitochondrial antioxidant protein peroxiredoxin 3 has been shown to reduce the severity of age-related OA in mice by preserving mitochondrial membrane integrity and inhibiting p38 phosphorylation under elevated H 2 O 2 , further supporting the therapeutic potential of targeting mitochondrial dysfunction in OA [132]. Although these approaches have demonstrated promising results in preclinical models, a comprehensive clinical validation is essential to confirm their efficacy and safety. Successful outcomes from clinical trials will be critical to fully realize the therapeutic potential of these emerging strategies in the treatment of OA. 6.2. Emerging targets in RA Similarly to OA, several Ca 2+ -targeted therapies have been investigated in RA, including modulators of SOCE and TRPV1 channels, both of which regulate the intracellular Ca 2+ levels and contribute to RA pathogenesis. Recent studies have highlighted the therapeutic potential of TRPV1-targeted interventions in arthritic diseases, due to their antiinflammatory and analgesic effects [36,133]. TRPV1 channels are expressed not only in sensory neurons involved in inflammatory pain transmission but also in non-neuronal cells such as FLSs, dendritic cells, macrophages, and T cells [36]. In particular, in CD4 + T cells, TRPV1 knockdown or genetic deletion has been shown to suppress the activation of p38 and c-Jun N-terminal kinase signaling pathways. Additionally, TRPV1 antagonists have been shown to reduce the production of various cytokines, including interferon gamma (IFN-γ), IL-17A, IL-2, IL10, IL-4, and TNFα in CD4 + T cells [36,134]. Similarly, TRPV1 inhibition in murine macrophages suppresses the release of pro-inflammatory cytokines such as IL-6, IL-1β, and IL-18, as well as the expression of COX2 [135]. TRPV1-targeted therapies are also commonly used for the management of arthritis pain. TRPV1 antagonists such as A-889425 and JNJ17203212 have been reported to reduce joint pain by attenuating pain-related signal transduction and neuropeptide release [133]. In contrast, TRPV1 agonists can induce channel desensitization, decrease neuropeptide levels, and provide long-term pain relief [133]. However, the development of TRPV1 modulators remains challenging, as their use may unintentionally raise the threshold for heat perception, cause hyperthermia, and involve complex regulatory mechanisms [36]. Despite these issues, several strategies are being investigated to enhance the efficacy of TRPV1 modulators. Region-specific TRPV1 antagonists have been developed, offering analgesic effects without the side effect of hyperthermia [36]. In addition, non-stimulatory TRPV1 agonists, such as olvanil and MRD-652, have shown potential in inflammatory pain models [36]. In parallel with TRPV1, SOCE has emerged as a promising therapeutic target in RA due to its well-known contribution to immune response in inflammatory diseases. In a collagen-induced arthritis murine model, systemic lentivirus-mediated delivery of short hairpin RNA moderately suppresses Ca 2+ entry via gene silencing of ORAI3, leading to a reduction in synovitis, downregulation of Th1-mediated T.D. Nguyen et al. Autoimmunity Reviews 24 (2025) 103923 9