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Review
Contributions of joint damage-related events to gout pathogenesis: new insights from laboratory research
  1. HanLin Xu1,2,
  2. Hengwei Qin1,
  3. YingHui Hua1,
  4. Nicola Dalbeth2
  1. 1 Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
  2. 2 Department of Medicine, The University of Auckland, Auckland, New Zealand
  1. Correspondence to Professor Nicola Dalbeth, Department of Medicine, The University of Auckland, Auckland, New Zealand; n.dalbeth{at}auckland.ac.nz; Professor YingHui Hua, Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China; hua_cosm{at}aliyun.com

Abstract

Epidemiological and imaging findings indicate that gout frequently affects damaged joints. Recent studies suggest that the relationship between gout and joint damage may be more complex than a simple unidirectional link and that joint damage may promote the development of gout at affected sites. In this article, we review the clinical associations and recent laboratory research identifying events in the setting of osteoarthritis or joint injury that can alter the intraarticular microenvironment and locally regulate monosodium urate crystallisation and deposition or amplify the inflammatory response to deposited crystals. This includes cartilage matrix proteins or fibres released into the articular space that accelerates the crystallisation process, as well as the lack of lubricin and fibroblast priming that enhances the immune response towards the deposited crystals. These findings provide new insights into gout pathogenesis and offer a possible explanation for the site preference of gout in the damaged joint.

  • Gout
  • Crystal arthropathies
  • Osteoarthritis

https://doi.org/10.1136/ard-2023-224679

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    Introduction

    Gout is caused by monosodium urate (MSU) crystal deposition in the setting of elevated urate concentrations. Hyperuricaemia is virtually always present but is not sufficient for the articular deposition of MSU crystals and the progression of gout.1 Ultrasound and dual-energy CT studies have also shown that MSU deposition is evident in around 25% of people with hyperuricaemia, without clinical evidence of gout.2 3 Long-term cohort studies have shown that most people with hyperuricaemia at baseline do not develop gout over prolonged periods of observation, even in the setting of very high serum urate.4 These findings indicate that there are several checkpoints in the development of gout, from hyperuricaemia to MSU crystal deposition, to clinically evident gout. Additionally, some people with asymptomatic hyperuricaemia with MSU crystal deposition have subclinical joint inflammation.5–8

    For both the initial deposition of MSU crystals and the gout flare, a strong site preference for MSU crystal deposition and gout has been demonstrated by clinical observations. It is well recognised that specific joints, particularly the first metatarsophalangeal (MTP1) joint, midfoot/ankle and knee are most often affected by MSU crystal deposition and gout, and that other joints, particularly in the axial skeleton, are infrequently affected.9 Similarly, certain soft tissue sites are commonly affected, such as the Achilles tendon and olecranon bursa.10 The observation that MSU crystals are preferentially deposited at specific anatomical sites suggests that local factors contribute to the formation of MSU crystals. A biomechanical analysis has demonstrated that the elevated internal tissue stress within the foot during walking is inconsistent with the pattern of MSU crystal deposition in gout, implying that biomechanical loading alone does not explain the patterns of gout presentation11 (figure 1).

    Figure 1
    Figure 1

    Patterns of MSU crystal deposition in gout and average tissue stress during normal gait. Foot maps showing the patterns of average urate deposition in feet of people with gout, measured by dual energy CT (DECT), and average tissue stress during normal gait. For each map, both the sphere diameter and colour represent the linear range from 0 to the maximum value. Adapted from Dalbeth et al.11 MSU, monosodium urate.

    In addition to mechanical stress, the role of osteoarthritis (OA) and cartilage lesions have been postulated.9 12 A cadaveric study examined 7855 human talus samples for the presence of surface and beneath-the-surface crystals and found that the presence of surface MSU crystals strongly correlated with cartilage lesions in the talus, often associated with large lesions and adjacent fibrillated lesions.12 In a community-based cross-sectional study, an association between the site of gout flares and the presence of OA was found (adjusted OR 7.94; 95% CI 6.27 to 10.05), suggesting that joints affected by previous trauma or OA are more likely to be affected by MSU crystal deposition, especially in MTP1 joint, midfoot and knee.13 The association between gout and OA seems particularly strong in small joints.14 OA is also a risk factor for the future development of gout.15 In addition, several studies have reported the coexistence of other joint trauma related events and gout, including ligament injuries,16 joint replacements17 18 and surgical procedures.19

    Here, we introduce a new concept of “joint damage-related events” in gout pathogenesis . These events are typically caused by joint injury or cartilage degeneration, including the release of cartilage matrix, exposure to fibres, lubricin deficiency and fibroblast proinflammatory priming. Although the pathophysiological mechanisms are not entirely identical, there is ample clinical evidence supporting the notion that these events are part of the environment involved in joint trauma or OA.20–25 Importantly, these events have been confirmed in the latest research to drive MSU crystal deposition and presentation of gout following joint damage.26–30 This review aims to summarise this new evidence and propose a causal link between damaged-related events and gout.

    Joint damage-related events and the development of gout

    Release of cartilage components

    Synovial fluid is a major carrier of biological factors affecting the crystallisation and deposition of MSU crystals.31 Synovial fluid collected from patients with degenerative joint disease or with gout could enhance the nucleation of MSU crystals.32 Further studies confirmed that the protein component instead of the lipid component in synovial fluid was required for MSU-induced interleukin-1β (IL-1β) production by macrophages.33 Therefore, researchers have increasingly paid attention to the protein component of synovial fluid, which is involved in the crystallisation and deposition of crystals on the surface of cartilage in damaged joints.

    To investigate the relationship between cartilage-derived proteins and MSU crystallisation, Chhana et al used human cartilage homogenates (HCH), consisting of cartilage cells and matrix proteins. HCH mimic the release of cartilage matrix proteins into the joint space.30 They found that HCH can promote MSU crystal nucleation and growth by providing a surface for MSU deposition. HCH also led to the formation of shorter MSU crystals, which are more likely to trigger the inflammatory response and apoptosis of macrophages.34–36 By measuring the level of cytokines and chemokines in monocytes stimulated by HCH and MSU crystals, they showed that HCH increased the production of interleukin-8 (IL-8) and enhanced the inflammatory response to MSU crystals.30

    Based on these findings, Xu et al further investigated the role of type II collagen (CII), a major organic component of the cartilage matrix, in MSU crystallisation and gout-related inflammation.27 37 They found that CII fragments were spatially enriched around MSU crystals in synovial fluid from patients with gout and injured cartilage in the same joint. It was also found that CII added prior to crystallisation can regulate the morphology of CII-MSU crystals. They then established a classification system of crystals by analysing the morphological parameters of crystals with or without CII and compared them with crystals, selectively phagocytosed by macrophages. CII-MSU crystals are more homogenous and more likely to be recognised and phagocytosed by macrophages. Furthermore, CII also enhanced MSU-induced inflammatory response by upregulating the expression of chemokines and proinflammatory cytokines through toll-like receptor (TLR)2/4/nuclear factor (NF)-κB signalling pathway, thereby promoting innate immune cell recruitment.

    The aforementioned studies demonstrate the impact of cartilage-derived proteins on MSU crystallisation. By altering the kinetics of crystal nucleation and growth, cartilage homogenate can accelerate this process and increase local MSU crystal accumulation. Additionally, the morphology of crystals changes in a specific manner, making it easier for recognition and phagocytosis by macrophages. It is also noteworthy that synovial fluid is highly complex and can fluctuate. Specifically, cartilage-derived protein concentration and composition can alter in response to joint injuries or OA,38 39 which may act as an additional contributing factor to MSU crystal deposition or the inflammatory response to these crystals.40

    Exposure of fibre templates

    Fibrous fragments, which regulate the formation of crystals through a structural approach, have also received attention.29 From a structural perspective, it is more feasible for crystals to form on complementary surfaces, known as heterogeneous crystallisation, rather than forming in an oversaturated solution. This process requires the lowest amount of energy and thus is preferred during primary crystallisation and subsequent crystal deposition.41

    Pascual et al analysed the deposition sites and patterns of MSU crystals in gout patients and showed that MSU crystals mainly deposited on the surface of cartilage, tendons and ligaments.29 42 By using high magnification polarising light microscopy, they showed that the crystals are neatly arranged near fibrous fragments, and they align themselves parallel to the fibres. These findings showed that MSU crystals favour template nucleation on fibres with complementary structures and that cartilage, tendon, or loose collagen in the synovial fluid provides a specific growth environment for MSU crystals.

    More importantly, on the articular surface of damaged joints, these fibrous fragments are more likely to be exposed to the crystallisation system. The potential structural complementarity, similar to other biomineralisation processes by which different beings form the mineralised structures, between detached collagen fibres and MSU crystals suggests that localised areas may require less energy for crystal nucleation, leading to the accumulation of MSU crystals.43 Moreover, in specific areas with greater focal tissue injuries or impingement such as tendon insertion sites, this phenomenon is more likely to be observed (as shown in a clinical example in figure 2).44 Although this requires further experimental studies to confirm, it provides a theoretical explanation from another perspective for the higher incidence of gout in damaged joints.

    Figure 2
    Figure 2

    MRI and pathological examination of the ankle of a man with tophaceous gout. (A) A male patient has posterior ankle impingement (between talus and Achilles tendon) due to posterolateral talus tubercle (white arrow). (B) Arthroscopic view demonstrated severe cartilage lesions andchalky material deposits at the posterior margin of the talus. (C) Postoperative pathological examination found homogeneous acellular structures surrounded by chronic inflammatory cells at the impingement site. (D) Birefringent crystals were detected in synovial fluid under polarised light microscopy (PLM), suggesting that the impaired cartilage promoted local MSU crystals deposition. Scale bar: 50 µm in (C) and 15 µm in (D). MSU, monosodium urate.

    Lubricin deficiency

    Lubricin (also known as proteoglycan 4) is a crucial molecule for joint lubrication and cartilage protection secreted by chondrocytes and synovial cells.45 Elsaid et al described lubricin deficiency in a patient with normouricaemic crystal proven gout, severe arthritis and bone erosion.26 Whole-genome sequencing and whole-blood RNA sequencing of the proband revealed susceptibility variants in two genes, NLR family pyrin domain containing 3 (NLRP3) and inter-alpha-trypsin inhibitor heavy chain 3. The latter is an inhibitor of lubricin-degrading cathepsin G.46 Consistently, quantitative serum proteomics verified that the patient had decreased levels of lubricin and lower activity of cathepsin G.

    This study also demonstrated that lubricin can inhibit MSU crystallisation by increasing the solubility of urate, reducing IL-1β-induced inflammation and relieving arthritis in a mouse model. Comparing MSU crystal weight between the proband and healthy controls indicated that lubricin deficiency facilitated MSU crystallisation. The researchers demonstrated that lubricin deficiency can amplify the IL-1β signalling pathway via NLRP3 and activate xanthine oxidase (XO) in macrophages, leading to the development and progression of gout independent of hyperuricaemia. Combined activation of cathepsin G and TLR-2 signalling pathway in synovial fibroblast (SF) is a probable cause of erosive arthritis in the setting of lubricin deficiency.

    Relative lubricant deficiency is a common damage-related event.22 26 Decreased lubricin expression has been linked to cartilage degeneration/injuries in animal models of acute joint injury or OA.20–22 In a longitudinal study of the people with acute knee injury, synovial fluid lubricin concentrations significantly reduced during injury repair.47 Therefore, it is rational to extrapolate that lubricin deficiency may increase the risk of both MSU crystal deposition and the inflammatory response to these crystals. Furthermore, previous studies have demonstrated that recombinant human lubricin has significant anti-inflammatory properties in MSU-mediated inflammation, exogenous lubricin may be a potential treatment for these patients.48–50

    Tissue-resident fibroblast priming

    Sustained inflammation and pre-programming of resident cells are pathological hallmarks of post-traumatic OA.51 In the presence of low-grade inflammation, resident tissue cells undergo intracellular reprogramming in response to external stimuli and acquire an enhanced ability for inflammatory response.

    Tissue-resident fibroblasts play a critical role in inflammatory processes.52 A single-cell sequencing study classified SF in post-traumatic arthritis and analysed their interactions with macrophages and chondrocytes.25 IL-6+ immune-interacting SF was detected after anterior cruciate ligament injury. It regulated macrophage polarisation and activated canonical Wnt/β-catenin signalling by secreting R-spondin 2.25 A recent study has confirmed that the inflammatory tissue priming is implicated in the development of gout.28 Friščić et al found that repeated inflammatory stimulation causes metabolic reprogramming of SF through complement 3 (C3) and C3a receptors. Primed SFs have altered capacity for migration, invasiveness and osteoclastogenesis, resulting in greater inflammatory response with subsequent MSU stimulation.28 These results suggest that recurrent gout flares depend on the preprogramming of SF.

    Furthermore, this inflammatory tissue priming is proved to be dependent on the transcriptional regulation by bromodomain and extra terminal motif (BET) proteins.53 Applying a BET inhibitor (I-BET151) systemically or locally in the joint could attenuate the pre-existing transcriptional, metabolic and functional inflammatory state of SF, inhibiting tissue priming and leading to reduced severity of MSU-mediated flares in both preventive and therapeutic approaches,53 making it a potential target for intervention or treatment of gout.

    These findings revealed the pathological mechanisms underlying damaged joint and its connection to gout development. Recurrent gout flares are closely linked to the preprogramming of SF, which exhibit altered migration, invasiveness and osteoclastogenesis capacity. Interestingly, transcriptional regulation by BET proteins has been identified as a key factor in inflammatory tissue priming. Targeting this mechanism using BET inhibitors has shown promising results in reducing the severity of MSU-mediated flares, offering potential therapeutic approaches for gout intervention. These insights into the molecular processes and potential intervention strategies may pave the way for better management of gout.

    Conclusions

    Various joint damage-related events, such as the release of cartilage matrix proteins, exposure to tissue fibres, lubricin deficiency and fibroblast priming, play significant roles in MSU crystal deposition and the inflammatory response to deposited crystals (figure 3). Combining these findings with previous studies that MSU crystals could lead to joint structure damage, this provides a potential basis for theory of a vicious cycle between damaged joint and crystal deposition. Furthermore, additional research is necessary to explore the prevalence and frequency of damage-related events in the presence of joint injury or OA. Investigating how changes in downstream events, such as crystal deposition and inflammation, contribute to altering the symptoms and site preference of gout is also needed. In conclusion, advancing our understanding of the interaction between joint damage and gout could enhance insights into gout pathogenesis and potentially explain the site-preference of gout.

    Figure 3
    Figure 3

    Gout manifests different pathophysiological mechanisms between healthy and damaged joints. Release of cartilage matrix, exposure of fibres, lubricin deficiency and fibroblast priming in the damaged joint may directly or indirectly promote MSU crystallisation or inflammation in response to deposited crystals. MSU, monosodium urate.

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    Footnotes

    • Handling editor Josef S Smolen

    • HX and HQ contributed equally.

    • Contributors YH and ND designed and supervised the research project; HX and HQ completed literature search, paper writing and figure design; YH, HX and ND revised the draft.

    • Funding The study was supported by CSC grant (ID 202106100140) to HX.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.