Review ArticleReview
Open Access

The Immunological Facets of Chondrocytes in Osteoarthritis: A Narrative Review

Panjana Sengprasert, Ousakorn Kamenkit, Aree Tanavalee and Rangsima Reantragoon
The Journal of Rheumatology January 2024, 51 (1) 13-24; DOI: https://doi.org/10.3899/jrheum.2023-0816

Abstract

Osteoarthritis (OA) is a disease in which the pathogenesis affects the joint and its surrounding tissues. Cartilage degeneration is the main hallmark of OA, and chondrocytes within the cartilage regulate matrix production and degradation. In patients with OA and in animal models of OA, the pathology of the disease relates to disequilibrium between anabolic and catabolic states of the cartilage. Moreover, chondrocyte phenotype and function are also immunologically altered. Under inflammatory conditions, chondrocytes increase production levels of inflammatory cytokines and cartilage-degrading enzymes, which further drive cartilage destruction. Chondrocytes also have an innate immune function and respond to damage-associated molecular patterns (DAMPs) and cartilage fragments by innate immune receptors. In addition, chondrocytes play a role in adaptive immune responses by acting as antigen-presenting cells and presenting cartilaginous antigens to T cells. Indirectly, chondrocytes are stimulated by pathogen-associated molecular patterns (PAMPs) present in the joints, a result of the microbiota of the host. Chondrocytes have both direct and indirect relationships with immune cells and the immune compartment of patients with OA. Therefore, chondrocytes serve as a target for immunotherapeutic approaches in OA. In this narrative review, we cover the aforementioned immune-related aspects of chondrocytes in OA.

Key Indexing Terms:

Osteoarthritis (OA) is the most common multifactorial joint disorder, causing pain and chronic joint disability in millions of people worldwide.1 Many previous studies show that OA encompasses a low-grade inflammatory state.1,2 Characteristics of OA include cartilage loss and destruction, subchondral bone sclerosis, osteophyte formation, ligament degeneration, and synovial inflammation.3 Cartilage degradation, a central feature of OA, is found in both weight-bearing (knee and hip) and nonweight-bearing (hands, wrist, and shoulders) joints,4 suggesting that the pathology may be a result of other mechanisms apart from mechanical loading (eg, inflammation and changes in joint biochemistry).2 Chondrocytes, the primary cell type in cartilage, are directly responsible for cartilage homeostasis.5 Mediators and inflammation that induce changes in chondrocyte phenotype are related to OA pathogenesis.2 The contribution of chondrocytes to OA pathogenesis includes anabolic and catabolic mechanisms as well as immune-related processes.6,7 In this review, we focus on the immunological aspects of chondrocytes in OA.

Biological properties of human chondrocytes in a normal cartilage

Cartilage is a connective tissue that reduces joint friction during joint movement.8 It is composed of approximately 95% extracellular matrix (ECM) and 5% cellular content.9 In the cartilage, chondrocytes are the major cell type, with a small proportion of chondroprogenitor cells (CPCs).9,10 The cartilage is divided into 4 layers: the superficial, middle, deep, and calcified layers.3,8 Chondrocytes distributed in each cartilage layer possess different morphologies and function in ECM synthesis.3 Chondrocytes make up 1-10% of the net weight of cartilage, with collagen and proteoglycan making up approximately 12-14% and 7-9%, respectively.11 Approximately 90% of collagen is type II collagen.8 The majority of proteoglycan is aggrecan, which are macromolecules that link collagen fibrils in the cartilage.11 Other important components include hyaluronan, glycoproteins, and minerals.11 ECM components are distributed in different proportions within each cartilage layer.

Chondrocytes function in the synthesis, maintenance, and repair of the cartilaginous matrix by balancing ECM production and cartilage-degrading enzymes (in particular, matrix metalloproteinases [MMPs] and a disintegrin and metalloproteinase with thrombospondin motifs [ADAMTSs]) production.8 In terms of their physiological mechanism, chondrocytes are avascular and reside in hypoxic conditions. They remain in a resting state, where metabolic turnover and ECM-degrading enzyme production are low.3

The osteoarthritic chondrocyte

In OA, mechanical forces and biochemical changes within the joints initiate destruction of ECM in cartilage.1 As a result, cartilage damage exposes chondrocytes in the superficial layer to catabolic mediators, immune mediators, and degraded ECM components that are present in the synovial fluid.3 In the early stages of OA, these mediators stimulate chondrocytes to proliferate and produce type II collagen and proteoglycan aggrecan.12 During OA progression, chondrocytes cluster, become hypertrophic, or dedifferentiate into fibroblasts and become apoptotic.5 Chondrocytes with a hypertrophic phenotype produce type X collagen and higher levels of cartilage-degrading enzymes (MMP-1, MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5) than normal chondrocytes.5 MMP-1 and MMP-13 degrade type II collagen, whereas MMP-3, ADAMTS-4, and ADAMTS-5 digest aggrecan in the cartilaginous matrix.5 These chondrocytes have reduced ability to produce type II collagen and aggrecan.5,12 Chondrocytes dedifferentiate into a fibroblast-like phenotype that produces type I collagen instead of type II collagen.13,14 Type I collagen is predominant in fibrocartilage, which leads to joint pain and stiffness in OA.5 The imbalance between the production of ECM proteins and cartilage-degrading enzymes observed in hypertrophic chondrocytes results in increased cartilage destruction.4 The digested matrix proteins, such as cartilage oligomeric matrix protein (COMP), type I collagen, type II collagen, hyaluronan, fibulin-3, aggrecan, and chondroitin sulfate fragments are released into the synovial fluid and stimulate resident cells (eg, macrophages, synovial fibroblasts, and chondrocytes) in joint-surrounding tissues to produce inflammatory cytokines and chemokines, leading to inflammation in OA.2,15

The osteoarthritic cartilage also shows signs of chondrocyte apoptosis (ie, cell shrinkage, plasma membrane blebbing, DNA fragmentation, and chromatin condensation), notably in the calcified layer, with numerous empty lacunars.16,17 Apoptosis is a type of programmed cell death that regulates the homeostasis of several tissues16,17 and is responsible for the removal of aging, unhealthy, and unnecessary cells in damaged tissues to prevent excessive inflammation.17 Apoptosis can be induced by the mitochondrial (intrinsic) pathway and the death receptor (extrinsic) pathway before the activation of the cysteine protease caspase enzyme.16,17 Chondrocyte apoptosis may occur partly because of loss of ECM, since chondrocyte attachment to collagen or proteoglycan aggrecan network is required for its survival.16 The number of empty lacunae increase when cartilage ECM decreases.16,18 Nitric oxide (NO),19 reactive oxygen species (ROS),20 and other inflammatory cytokines found, such as interleukin (IL)-1β,21 act as apoptotic inducers, and may induce chondrocyte apoptosis through the mitochondria-dependent pathway.19-21 The death receptor induction pathway, such as Fas/Fas ligand signaling, also promotes chondrocyte apoptosis in OA.16 OA cartilage expresses higher levels of Fas than normal cartilage, and high levels of Fas expression is associated with loss in chondrocyte quantity.16,22 FasL, the specific ligand of the Fas receptor, is present in synovial fluid of patients with OA and can reach Fas receptors on chondrocytes through cartilage cracks.18 Ligation of Fas with its ligand induces caspase-8 and caspase-3 activation in patients with OA and destabilization of the medial meniscus (DMM)–induced OA mice.22,23 A lack of Fas expression in DMM-induced OA mice limited cartilage degradation and reduced chondrocyte apoptosis.23

Chondrocytes as a producer and responder of cytokines and chemokines in OA

OA is a low-grade chronic inflammatory disease with many inflammatory mediators in the synovial fluid that stimulate chondrocytes to produce proinflammatory cytokines and cartilage-degrading enzymes.2,24-26 Those cartilage-degrading enzymes and proinflammatory cytokines produced from chondrocytes induce cartilage breakdown and joint inflammation (Figure 1). We provide a comprehensive summary of the downstream effects that chondrocytes have in response to important cytokine and chemokine stimulation (Table 1), as well as cytokine and chemokine production by chondrocytes in response to extracellular stimuli (Table 2).

Figure 1.
Figure 1.

Chondrocyte response to cytokines in OA. Resident cells in joint-surrounding tissues, such as macrophages and fibroblast-like synoviocytes, secrete inflammatory cytokines into the synovial fluid. Those cytokines stimulate chondrocytes, particularly the superficial layer of cartilage, to produce inflammatory mediators and ECM-degrading enzymes. Both inflammatory mediators and ECM-degrading enzymes increase the severity of OA by promoting inflammatory progression and cartilage degeneration, respectively. In addition, the inflammatory mediators secreted from chondrocytes act in an autocrine fashion on chondrocyte stimulation, leading to increase of MMPs/ADAMTS and inflammatory cytokine production, chondrocyte hypertrophy, chondrocyte senescence, and chondrocyte apoptosis, and decrease of ECM production and chondrocyte proliferation. ADAMTS: a disintegrin and metalloproteinase with thrombospondin motifs; CCL: chemokine (C-C motif) ligand; CXCL: chemokine (C-X-C motif) ligand; ECM: extracellular matrix; IFN-γ: interferon γ; IL: interleukin; MMP: matrix metalloproteinase; NO: nitric oxide; OA: osteoarthritis; PGE2: prostaglandin E2; ROS: reactive oxygen species; TGF-β: transforming growth factor beta; TNF-α: tumor necrosis factor α.

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Table 1.

Downstream effects of chondrocytes in response to important chemokines and cytokines.

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Table 2.

Cytokine, chemokine, and immune mediator production by chondrocytes in OA.

It is shown here that cytokines and chemokines involved in OA are soluble protein adapters that function in communicating signals among chondrocytes themselves, between chondrocytes and immune cells, and between chondrocytes and other potential cells that will respond to these mediators.

Chondrocytes as a potential antigen and target of the immune system in OA

The cartilage ECM prevents chondrocytes from contact with immune cells.56,57 In OA, the cartilage matrix is compromised; this exposes chondrocytes to immune cells, degraded ECM, matrix-degrading enzymes, and soluble mediators.56 Such exposure shifts the chondrocyte into a vulnerable state, prone to being stimulated by such molecules, making chondrocytes a potential target for attack. There is much evidence of adaptive immune stimulation by components of the cartilage.58-60 Cocultures of isolated chondrocytes and lymphocytes from patients with OA, and from rat and mice models, in the presence of interferon-γ (IFN-γ) increased T cell proliferation and induced T cell cytotoxicity toward chondrocytes.59,60 In patients with OA, autoantibodies against chondrocyte-associated proteins (ie, antitype II collagen, anti-COMP, antiosteopontin, antifibulin antibodies, and antiaggrecan G1 domain) were found in the serum.61-65 Many studies reported that peripheral blood T cells of patients with OA respond to cartilaginous peptides, suggesting there may be cartilage antigen-specific T cells in patients with OA.66,67 Stimulation of isolated peripheral blood T cells from patients with OA with human cartilage glycoprotein-39 (HC gp-39) increased cell proliferation when compared to peripheral blood of healthy individuals.58 Aggrecan, a cartilage protein, is also recognized by T cells.66,67 Link proteins and the G1 domain of aggrecan contain several T cell epitopes that can stimulate peripheral blood T cells from patients with OA to proliferate.66,67 These aggrecan peptides induce inflammatory cytokine production in T cells isolated from both peripheral blood and infrapatellar fat pads.67,68 Surface chondrocyte extracted protein injection can induce antibody responses against COMP in immunized mice, suggesting immunogenicity of chondrocyte antigens.69 These results suggest complete stimulation of the adaptive immune system in both humoral and cell-mediated compartments by chondrocyte proteins. Animal models of rheumatoid arthritis also demonstrated this.70-73 Specificity of autoantibodies and T cells toward COMP and chondrocyte-associated peptides, respectively, suggest that chondrocytes serve as an antigenic target of the immune system in patients with OA.

Cartilage-specific regulatory T cells can be stimulated with cartilaginous matrix proteins to treat OA.74 In a DMM-induced OA mice model, intradermal injection of lipid nanoparticles loaded with type II collagen and rapamycin induced type II collagen–specific regulatory T cells.74 This induction increased the production of IL-10 and transforming growth factor-β (TGF-β), decreased the number of macrophages and helper T cells, and reduced inflammatory cytokines (ie, IFN-γ, IL-1β, and tumor necrosis factor [TNF]) in the synovium.74 Moreover, type II collagen production also increased while diminishing MMP-13 production in chondrocytes.74 Further, adoptive transfer of type II collagen–specific regulatory T cells improved the Osteoarthritis Research Society International (OARSI) score and reduced cartilage destruction in an OA mice model.74

Innate immune function of chondrocytes

Innate antigen receptors (eg, toll-like receptors [TLRs]), can be found on chondrocytes.4 TLRs are the first line of immune receptors that respond to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) that result in initiation of the immune response and inflammation (Figure 2).4 Chondrocytes in the cartilage express all types of TLRs.4 Their expression patterns differ between large and small joints. For example, TLR4 expression was higher in chondrocytes from patients with knee OA than from patients with thumb basal OA, whereas TLR3 expression was higher in chondrocytes from patients with thumb basal OA than in patients with knee OA.75 The difference in TLR expression patterns between large and small joints may contribute to the different immune mechanisms that drive the pathology.75 TLRs bind to DAMPs that are present in the synovial fluid.4 These accumulated DAMPs include fibronectin fragments, advanced glycation end products, serum amyloid A (SAA), members of the calcium-binding proteins (S100A8 and S100A9), biglycan, decoran, and genomic fragments (ssRNA and dsRNA).4

Figure 2.
Figure 2.

Schematic of innate and adaptive immune functions of chondrocytes. In OA, the cartilage is exposed to high concentrations of MMPs and ADAMTS continuously, digesting the ECM into small fragments. ECM fragments are released into the synovial fluid and act as DAMPs to stimulate immune cells and chondrocytes. Also, chondrocytes are also able to uptake and present ECM fragments to T cells. Downstream effects of chondrocyte stimulation by DAMPs and ECM antigens are shown. ADAMTS: a disintegrin and metalloproteinase with thrombospondin motifs; COMP: cartilage oligomeric matrix protein; DAMP: damage-associated molecular pattern; ECM: extracellular matrix; IFN-γ: interferon γ; MAPK: mitogen-activated protein kinase; MHC: major histocompatibility complex; MMP: matrix metalloproteinase; MyD88: myeloid differentiation primary response 88; NFEmbedded ImageB: nuclear factor kappa B; NO: nitric oxide; OA: osteoarthritis; ROS: reactive oxygen species; TLR: toll-like receptor; TRIF: Toll/IL-1 receptor domain-containing adapter-inducing interferon β.

TLR4 and TLR2 are the most widely studied among all TLRs expressed on chondrocytes.15,76-88 Stimulation of TLR2 and TLR4 by various DAMPs present in the joints induces the production of inflammatory cytokines and catabolic mediators (Table 3). In a rat OA model, intraarticular injection of TLR4 inhibitors reduced macrophage, neutrophil, and lymphocyte infiltration in the synovial tissues and decreased TLR4, TNF, and IL-1β expression in cartilage tissues.76 Inhibition of downstream TLR4 signaling resulted in increased collagen type II production and decreased MMP-13 production in rat OA chondrocytes.76

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Table 3.

DAMP recognition by TLR2 and TLR4 on chondrocytes and its downstream effects.

Interestingly, TLR expression is increased in the osteoarthritic cartilage and are congregated at high expressions at the cartilage surface zone, where mechanical force and DAMP exposure occur.15 This provides the cartilage with external stimuli to the chondrocytes. TLR stimulation on chondrocytes not only triggers downstream inflammation but also induces direct apoptosis of chondrocytes. This occurs either through myeloid differentiation primary response 88 (MyD88) activation, Toll/IL-1 receptor domain-containing adapter-inducing IFN-β (TRIF) activation, or both.4 Mechanical strain induces chondrocyte apoptosis in a mechanism mediated by TLR3, TLR7, and TLR9.4

TLR3 showed high expression in the cartilage of mice and humans with OA.89 OA chondrocytes treated with lipopolysaccharide (LPS) upregulated both TLR3 and TLR7.90 Binding of TLR3 to dsRNA released by stressed mitochondria from damaged or senescent chondrocytes in the early stages of OA can accelerate the disease by increasing IL-8, IFN-β, and MMP-13 production in chondrocytes.91 In both patients with OA and DMM-induced OA mice, TLR3 ligand (poly(I:C)) treatment enhanced chondrocyte apoptosis and IFN-β production, but was reversed upon TLR3 blockade.89 Moreover, TLR3-dsRNA blockade can also minimize proteoglycan breakdown.89 Similarly, TLR7 blockade also decreases chondrocyte death and reduces IL-1β, TNF, IL-6, MMP-3, and MMP-13 production in LPS-treated chondrocytes.90

TLR expression is also further upregulated when exposed to cytokines and DAMPs.79,80 For example, TNF, IFN-γ, and IL-1β can induce TLR2 and TLR4 upregulation on chondrocyte surfaces.30,80 Chondrocytes activated by fibronectin fragments or proteoglycan fragments also showed increased levels of TLR2 expression.80 The interactions between DAMPs and TLRs expressed on chondrocytes are a 2-way cross-talk and underscore the role of innate immune receptors in driving inflammation and catabolic effects within OA joints through the chondrocytes themselves.

Antigen presentation by chondrocytes

T cell antigen recognition requires 3 signals: (1) binding of antigenic peptides to T cell receptors through major histocompatibility complex (MHC) molecules; (2) engagement between costimulatory molecules of antigen-presenting cells (APCs; ie, CD80, CD86) and T cells (ie, CD28); and (3) stimulation by secreting cytokines.92,93 Professional APCs process and present endogenous and exogenous antigens to T cells by MHC class I and MHC class II molecules, respectively, on their cell surface.56 Chondrocytes have been reported to have antigen presentation function despite their nature as a nonimmune cell.94 Chondrocytes can phagocytose dead cells, debris, and exogenous antigens, such as collagen fragments.95 In healthy individuals, articular chondrocytes express MHC class I molecules, but not MHC class II molecules.56 However, MHC class II expression on chondrocytes can be induced by proinflammatory cytokines in vitro.56 Articular chondrocytes isolated from patients with OA can stimulate autologous T cells. Blocking interaction between MHC molecules on chondrocytes results in a decrease in T cell proliferation. These findings demonstrate the functional ability of chondrocytes as APCs.30,96 Moreover, antigen presentation function has also been demonstrated in other arthritic conditions, including ankylosing spondylitis, and with nasal chondrocytes.30,96-98 Cytotoxic T cells in BALB/c mice can also recognize influenza A virus nucleoprotein (NP)-derived peptides presented on chondrocytes.60 Recognition of specific cytotoxic T cells to NP-pulsed chondrocytes increased chondrocyte lysis.60 These studies demonstrate the ability of chondrocytes to act as a professional APC. Being able to present antigens to effector cells enables chondrocytes to become targets of cytotoxic T cells.

The interplay between chondrocytes and immune cells

In an OA joint, synovial tissues and infrapatellar fat pads are sources of immune cells that predominantly contain macrophages and T cells.99,100 The number of macrophages and T cells in the OA synovium correlates with radiographic severity, suggesting their role in OA pathology.100-102 Once synovial macrophages are exposed to cartilage-degraded molecules, they release cytokines, chemokines, and metalloproteinase enzymes that enter the synovial fluid and diffuse through the cartilage fissure or by vascular penetration into the cartilage.9,99 These inflammatory mediators function in a paracrine manner between chondrocytes and the immune cells.102 In a 3-dimensional coculture system, OA chondrocytes cocultured with LPS-treated macrophages showed significantly higher expression of TNF, IL-6, IL-8, IFN-γ, MMP-1, MMP-3, MMP-9, and MMP-13 than that of OA chondrocytes cultured alone.103 Macrophage polarization between the proinflammatory phenotype (M1) and proregenerative phenotype (M2) also has the potential to regulate chondrogenesis in OA.104 Treatment of mesenchymal stem cells (MSCs) with TGF-β induces chondrogenesis of MSCs. However, when TGF-β–treated MSCs were cultured with conditioned media generated from IFN-γ/LPS-induced M1 macrophages, the MSCs showed a reduction in chondrogenesis markers, type II collagen, and aggrecan.104 However, the inhibition of chondrogenic differentiation in MSCs was not observed after treatment with conditioned media of M2-polarized macrophages.104 The interaction between T cells and chondrocytes is also observed in OA.9,30,105 Th1, Th2, and Th17 can increase MMPs and ADAMTS enzyme production in chondrocytes, whereas regulatory T cells promote the production of IL-10, IL4, and aggrecan in chondrocytes from patients with OA.9,105

Despite not being classified as an immune cell, chondrocytes express innate immune receptors and respond to PAMPs and DAMPs by releasing inflammatory cytokines that further regulate other immune compartments.4 Chondrocytes exposed to IL-1β secrete IL-6, which acts in a paracrine fashion for further induction of IL-6 and IL-8 production in macrophages through STAT3 activation. IL-1β can also promote exosome secretion from chondrocytes.106 LPS-treated macrophages cocultured with chondrocyte-secreted exosomes revealed predominant M1-polarization (ie, increase in IL-1β, TNF, IL-6, and IL-12 production) and a reduction in M2-polarization and macrophage autophagy in patients with OA and OA animal models.106,107 Chondrocytes are also able to regulate other cells by using immune mediators. Hypoxia-inducible factor-2 α (HIF-2α) is an essential catabolic regulator in an OA inflamed joint.48 HIF-2α-overexpressing chondrocytes induce MMP-3, MMP-9, MMP-12, MMP-13, ADAMTS4, PTGS2, and NOS2 upregulation in fibroblast-like synoviocytes by TNF. Conversely, HIF-2α-overexpressing fibroblast-like synoviocytes induce MMP-3, MMP-13, and NOS2 upregulation in chondrocytes by IL-6.48

In addition, chondrocytes also respond to immune cells and their mediators. In a tissue-engineered cartilage transplantation mouse model, chondrocytes reduced the viability of macrophages by inducing cell death.108 Expression levels of FasL on chondrocytes in tissue-engineered cartilage are very low but increase after exposure to macrophages. Proteomic analysis of coculture media between chondrocytes and macrophages revealed granulocyte colony-stimulating factor (G-CSF) as responsible for the increased expression of FasL on chondrocytes, which further induces cell death in macrophages by Fas/FasL interaction.108

Chondrocytes can also regulate immune cells as such in the case of allogeneic human articular cartilage implantation. The allogeneic graft needs to overcome the immunological incompatibility between the recipient and the donor graft.109 In vitro cocultures of human articular chondrocytes with T cells in the presence of various stimuli (phytohemagluttinin [PHA], staphylococcal enterotoxin B [SEB], and anti-CD3 mAb) showed inhibition of T cell proliferation by chondrocytes in a contact dependent fashion.109 Moreover, human articular chondrocytes also inhibited monocyte differentiation to dendritic cells and maturation of dendritic cells when encountered with PAMPs.109

Chondrocytes, the microbiome, and immune responses

Recent research has linked the microbiome to the development of OA.110 Studies show that components derived from microbes can be found in culture-negative joints of patients with OA.110,111 The presence of LPS and other bacterial components in the sterile joint may be a result of gut leakage or from previous infections in the host.110 In humans and mice, gut microbiota and infections promote OA development by generating low-grade inflammation, immune system activation, and inducing cartilage degeneration.110 The role of microbiota in OA progression is shown in mouse models, where there was a reduction in cartilage degeneration in cyclic compressive loading–induced OA mice receiving antibiotics, in which the gut microbiota is depleted.112 The absence of microbiota in the host correlates with a reduction in OA severity, and the presence of PAMPs is associated with the severity of cartilage destruction and clinical pathology.113,114 These findings depict the relation between the microbiota of the host and OA.

The effects of the microbiome on OA pathology can be reversed by introducing probiotics strains and nonpathogenic bacteria into the host.110 In OA mice models, oral administration of the probiotic Lactobacillus species reduced the severity of OA.110 L. casei lessened joint inflammation in monoiodoacetate (MIA)-induced OA rats by reducing inflammatory mediators (IL-1β, IL-6, TNF, and cyclooxygenase-2 [COX2]) and enhancing antiinflammatory cytokine (IL-4 and IL-10) production from helper T cells, synovial fibroblasts, and chondrocytes.115 L. rhamnosus oral feeding in MIA-induced OA rat models also reduced IL-1β levels in the synovium while increasing IL-10 levels.116 In addition, L. casei, L. rhamnosus, and L. acidophilus protected against cartilage degeneration by decreasing MMP-1, MMP-3, and MMP-13 production and increasing the expression of genes related to cartilage development, such as COL2A1, SOX9, and TIMP-1 and -3 in rat and mouse models.27,115,116 Sodium butyrate, a byproduct of Lactobacillus ssp. dietary fiber fermentation, can prevent chondrocyte cell death in an inflammatory environment by boosting autophagy and lowering necrosis factor (RIPK and MLK1).27 In humans, L. rhamnosus treatment increased the expression of cartilage development-related genes (TIMP-1, TIMP-3, SOX9, and COL2A1) and antiinflammatory cytokines (IL-10).116 Further, L. casei Shirota treatment reduced joint pain and stiffness and improved the range of motion in patients with knee OA.117

DISCUSSION

In OA, mechanical, biochemical, and immunological factors cause chondrocytes to lose their ability to maintain cartilage homeostasis, which initiates the process of cartilage destruction. Chondrocytes serve not only as target cells of the host’s immune response in OA, but also participate in driving immune-related pathology in OA.

Chondrocytes possess characteristics that allow them to behave as immune cells as well as a source of antigens. Evidence of adaptive immune responses specific to chondrocytes or chondrocyte-originated antigens suggest that chondrocytes themselves act as a source of antigens and as a target for the immune system. Their ability to present exogenous and endogenous antigens via MHC class II and MHC class I, respectively, to T cells, make them a key player in bridging innate and adaptive immune responses in the context of OA. In addition, chondrocytes themselves also behave with innate immune ability by using innate immune receptors to ligate DAMPs from the ECM that are present in the synovial fluid. When chondrocytes bind to specific DAMPs, intracellular signaling stimulates increased production of ECM-degrading enzymes and inflammatory cytokines. These ECM-degrading enzymes and inflammatory cytokines are known drivers of OA pathology and are depicted here as a common downstream pathway despite the different DAMPs that bind onto chondrocytes. Another interrelationship between chondrocytes and the immune system is their ability to regulate one another; chondrocytes and immune cells do this by secreting cytokines and chemokines and responding to extracellular cytokines and chemokines. The residing microbiome in an individual is required for immune system development and activation.118 In animal models of OA, the microbiota is shifted, and this changes the profile of PAMP distribution in the host.113,114 However, restoration of certain species of flora in the gut and managing the balance of host microbiome through probiotics help alleviate OA symptoms and improves clinical outcomes.27,115,116

The understanding of chondrocyte-immune system interaction opens up a channel of therapeutic possibilities for OA, such as using anti-TLR antagonist to block TLR ligation by DAMPs, using specific monoclonal antibodies to target T and B cells, blocking antigen presentation with anti-HLA antibodies, and using anticytokine antibodies. This can also be incorporated in engineering chondrogenic cells (CPCs) prior to administering cell-based therapies to patients.119 Potential engineering strategies for CPCs include silencing or knocking out immune receptors that would initiate or have a role in driving OA pathogenesis.

In conclusion, this review has provided an overview of chondrocytes from an immunological perspective and shows that the immunological aspects of chondrocytes in OA are intertwined with its biochemical aspects. The understanding of chondrocytes in the immunological context provides a window for developing therapeutics for patients with OA that aim at regulating immune function or using immune mediators to regulate chondrocytes.

Footnotes

  • This work was supported by the Ratchadaphiseksomphot Fund, Faculty of Medicine, Chulalongkorn University (R2566-013). PS is a postdoctoral researcher supported by the Ratchadapisek Somphot Fund for Postdoctoral Fellowship, Chulalongkorn University.

  • The authors declare no conflicts of interest relevant to this article.

  • Accepted for publication October 16, 2023.

This is an Open Access article, which permits use, distribution, and reproduction, without modification, provided the original article is correctly cited and is not used for commercial purposes.

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Keywords

ANTIGEN PRESENTATION
CHONDROCYTES
CYTOKINE
innate immune receptor
microbiota
OSTEOARTHRITIS

Keywords