Chemokines are a class of small molecules that induce chemotaxis in a variety of cells, known for their role in transporting and recruiting immune effector cells to the sites of infection or inflammation, thus affecting the proliferation, migration, differentiation, and activation of intracellular responses [1]. CXC motif chemokine ligand 10 (CXCL10), also named interferon γ-induced protein 10 kDa (IP-10) or small-inducible cytokine 10, is a member of the CXC chemokine subfamilies [2]. CXCL10 was initially identified as a chemokine that was secreted by various cell types including neutrophils, monocytes, eosinophils, stromal cells, mesenchymal cells, and keratinocytes in response to interferon-γ (IFN-γ) [3,4]. It can also be induced by NF-κB, which plays a role in the early stage of hypoxia-induced inflammation [5]. CXCL10 specifically binds to CXCR3, a seven trans-membrane-spanning G protein-coupled receptor, and regulates immune responses by activating and recruiting leukocytes with CXCR3 such as T and B cells, eosinophils, monocytes, dendritic cells, macrophage, and natural killer (NK) cells [2,6]. Currently, CXCL10 is known to be involved in the regulation of CXCR3+ cell chemotaxis, apoptosis, migration, proliferation, and angiostasis, and also functionally categorized as an inflammatory chemokine [7].

Articular cartilage is a physiologically non-self-renewing matrix-rich, hypocellular, and vasculature-free tissue with a singular cell type, the chondrocyte [8]. Its unique connective tissue structure enables it to serve as a lubricating and load-bearing cushion in joints while restricting its intrinsic reparative ability. Meanwhile, the size, number, shape and metabolic activity of chondrocytes vary according to the layer of the cartilage plate which is quite different among joints and species [9]. Chondrocytes “sense” biomechanical and physicochemical signals transmitted by the extracellular matrix (ECM) and respond by regulating their anabolic and catabolic activity to maintain ECM homeostasis and continual internal remodeling [10]. Cytokines, which are secreted on its own or diffused from surrounding tissues into the cartilage matrix, are a large class of stimuli that affect cartilage metabolism. Inflammatory factors such as interleukin-1 (IL-1) induce matrix degradation by producing and activating protein hydrolases, such as collagenases and proteoglycanases [11,12]. Growth factors, powerful stimuli for DNA and protein synthesis, and natural inhibitors for catabolic activities, exert anabolic effects by promoting chondrocyte proliferation and synthesis of matrix macromolecules [13,14].

One of the most important causes in the pathogenesis of articular cartilage-related diseases is the tilted cytokine balance in favor of pro-inflammatory cytokines which can trigger inflammatory cascade amplification [15]. As crucial players in this unstoppable process, chemokines attract inflammatory cells to joints under the stimulation of cytokines, thereby further promoting the secretion of inflammatory factors and disease progression [11,12]. Chemokines have been confirmed to mediate the migration, activation, and functional regulation of distinct white blood cell subsets by binding to specific receptors, jointly driving the inflammatory destruction of joints. CXCL8 induces the migration of neutrophils into the joint cavity by binding to CXCR1/CXCR2, stimulating chondrocytes to secrete matrix metalloproteinases (MMPs), establishing a protease-mediated pathway that accelerates cartilage matrix degradation while concurrently amplifying synovial inflammatory responses [16]. CCL2 recruits CCR2-expressing inflammatory monocytes to the joints. Following synovial infiltration, these monocytes undergo differentiation into pro-inflammatory macrophages that produce robust quantities of inflammatory cytokines—including tumor necrosis factor-α (TNF-α), IL-1β, and IL-6—thereby perpetuating a chronic inflammatory milieu [17]. CXCL13 mediates the migration of B cells to the synovial lymphoid tissue by binding to its receptor CXCR5, thereby promoting B cell activation and inducing the production of local autoantibodies [18]. Moreover, studies have shown that CXCL13 is closely related to the formation of ectopic lymphoid-like structures (ELS) in the inflammatory tissues of rheumatoid arthritis (RA) and is considered a key regulatory factor in this pathological process [19]. CCL21 guides immature dendritic cells (DCs) from peripheral tissues to lymphoid tissues, thereby enhancing antigen-presenting capacity, activating naive T cells, and initiating autoimmune responses. Additionally, CCL21 works in concert with CXCL13 to promote the formation of tertiary lymphoid structures (TLS) in the synovium, further intensifying autoimmune reactions [20]. The CXCL12/CXCR4 axis has been demonstrated to upregulate vascular endothelial growth factor (VEGF) expression within articular cartilage, which facilitates synovial pannus progression through the induction of neovascularization, thereby exacerbating joint destruction in inflammatory arthritic conditions [21].

The levels of CXCL10 in serum, synovial membrane, and/or synovia fluid are significantly increased in arthritic diseases such as osteoarthritis (OA) [22], rheumatoid arthritis (RA) [23], psoriatic arthritis (PsA) [24], and traumatic arthritis [25]. In addition, blocking CXCL10 or its receptor CXCR3 with monoclonal antibodies can hinder the progression of arthritis [26]. Moreover, CXCL10- or CXCR3- mice have significantly mitigated arthritis symptoms compared to wild-type mice [27]. Integrating current findings, we speculate that CXCL10 has a potential role in cartilage development and disease.

Although existing researches have already demonstrated the importance of CXCL10 in cartilage physiology and pathology, relevant studies are still limited and not thorough enough. CXCL10 may be a new therapeutic target, and more in-depth research into its regulatory mechanisms will help enhance treatment efficacy and improve the prognosis of arthritis. In this review, we summarize the role of CXCL10 and its specific receptor CXCR3 in cartilage diseases, discuss the latest clinical research results and predict future challenges in this field.