Arthritis: Unraveling the mechanisms behind joint damage
A subtype of myeloid monocyte mediates the transition from autoimmunity to joint destruction in rheumatoid arthritis.
- Department of Orthopaedic Surgery, New York University Grossman School, United States
- Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, United States
Rheumatoid arthritis is an inflammatory autoimmune disease in which the immune system gradually destroys the lining of the joints, leading to pain, swelling and stiffness in the affected regions (Komatsu and Takayanagi, 2022; Weyand and Goronzy, 2021). A key part of disease progression is the transition from autoimmunity to the destruction of the joint. In this process, osteoclasts – cells that break down bone to maintain joint homeostasis – become overactive, leading to the destruction of healthy bone tissue (Fu et al., 2021; Meehan et al., 2021). A complex network of signaling mechanisms drives the formation of osteoclasts from the fusion of immune cells called monocytes. Autoimmunity increases the expression of key molecules in this process, which is thought to drive formation of mature osteoclasts and further joint destruction.
There is currently no cure for this condition, and it remains unclear what exactly triggers the immune system to attack the body, and how this leads to the progressive destruction of the joints. Understanding the mechanisms leading to joint deterioration is thus crucial for the development of effective treatments for rheumatoid arthritis (Fearon et al., 2022; Tang et al., 2011).
Now, in eLife, Xu Cao and colleagues at the Johns Hopkins University School of Medicine – including Weixin Zhang and Kathleen Noller as joint first authors – report that a specific subpopulation of monocytes drives the transition from autoimmunity to joint destruction in rheumatoid arthritis (Zhang et al., 2023).
Using a widely accepted mouse model of rheumatoid arthritis, Zhang et al. carried out a technique called single-cell RNA sequencing to take a closer look at the signaling pathways underlying this change. The experiments revealed that monocytes in these mice overexpress two receptor proteins, TLR2 and RANK, which are important for recognizing foreign substances and initiating an immune response, and for the development of osteoclasts.
Moreover, fluorescent imaging showed increased sialylation, the addition of sialic acids, at specific sites on TLR2 in these RANK+TLR2+ cells. This was driven by increased expression of enzymes responsible for sialylation in monocytes.
When either the enzymes or TLR2 were experimentally blocked, the monocytes did not transform to become osteoclasts. Consequently, the bone was not resorbed, and the destruction of the joints was mitigated (Figure 1). These findings further support the results of recent research suggesting that the sialylation of TLR2 has a role in initiating cell fusion during osteoclast formation (Dou et al., 2022).
Figure 1
Osteoclast formation in the context of rheumatoid arthritis.
Monocytes are a type of immune cell (light purple shape) that can develop into osteoclasts (dark purple shape), cells that can degrade healthy bone to initiate remodeling. In certain conditions, such as rheumatoid arthritis, the activity of osteoclasts is increased, which leads to progressive bone loss. Zhang et al. identified two subsets of monocytes. One subset (RANK+TLR2+) overexpressed two relevant signaling molecules, RANK and TLR2, and is involved in bone resorption. When RANK is activated by RANKL in this subset, the enzyme responsible for TLR2 sialylation (ST3GAL4) becomes upregulated through a molecule called c-Fos (a transcription factor critical for the regulation of osteoclast differentiation). Consequently, TLR2 undergoes sialylation, a process that adds sialic acids that enable TLR2 to bind with different molecules in order to allow fusion of cells. Blocking sialyation or TLR2 with specific molecules (C29 and soyasaponin Bb, respectively) prevents mature osteoclasts from forming and the bone remains intact. The other monocyte subset (RANK+TLR2-) exhibited high levels of RANK but low levels of TLR2. In this subset, RANKL prompts the monocytes to differentiate into pre-osteoclasts that express a molecule called TRAP+, but they fail to mature into fully-functional osteoclasts. Instead, these cells have anabolic properties and promote the production of new bone and blood vessels. This figure was generated using BioRender.com.
Single-cell RNA sequencing further revealed a previously unknown subset of myeloid monocytes, which overexpress RANK but do not express TLR2. These RANK+TLR2- monocytes were able to differentiate into precursor osteoclasts, but they were unable to fuse and mature into fully functional osteoclasts (Figure 1). They promoted, however, the expression of proteins that further the formation of new blood vessels and bones, which may explain presence of precursor osteoclasts displaying anabolic properties in bone (i.e., with the ability to promote the biosynthesis that further tissue growth).
Zhang et al. provide crucial insights into the mechanisms driving the transition from the onset of autoimmunity to joint destruction in rheumatoid arthritis. The findings emphasize the central role of myeloid monocytes that overexpress both RANK and TLR2, and the sialylation of TLR2 in driving the fusion of monocytes and consequent resorption of bone. Targeting the sialylation process in these monocytes represents a promising avenue for preventing autoimmune-mediated joint destruction and preserving bone health in patients with rheumatoid arthritis, and potentially other autoimmune disorders. Moreover, the identification of monocytes that lack TLR2 offers valuable insights into the complex cellular dynamics involved in joint destruction and may open new avenues for exploring the potential of these cells in promoting bone repair and regeneration. More research is needed to better understand if and how the two monocyte subsets interact and their clinical relevance in humans.
In summary, the potential therapeutic targets identified in this study should help with efforts to develop drugs that prevent autoimmune-mediated joint destruction and promote bone production in rheumatoid arthritis and various autoimmune diseases.
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TNFR2/14-3-3Ε signaling complex instructs macrophage plasticity in inflammation and autoimmunityThe Journal of Clinical Investigation 131:e144016.https://doi.org/10.1172/JCI144016
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Mechanisms of joint destruction in rheumatoid arthritis - immune cell-fibroblast-bone interactionsNature Reviews Rheumatology 18:415–429.https://doi.org/10.1038/s41584-022-00793-5
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Preclinical models of arthritis for studying immunotherapy and immune toleranceAnnals of the Rheumatic Diseases 80:1268–1277.https://doi.org/10.1136/annrheumdis-2021-220043
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© 2023, Fu and Liu
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Arthritis: Unraveling the mechanisms behind joint damage
eLife 12:e89778.
https://doi.org/10.7554/eLife.89778
Further reading
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- Medicine
Background:
Clonal hematopoiesis of indeterminate potential (CHIP) was initially linked to a twofold increase in atherothrombotic events. However, recent investigations have revealed a more nuanced picture, suggesting that CHIP may confer only a modest rise in myocardial infarction (MI) risk. This observed lower risk might be influenced by yet unidentified factors that modulate the pathological effects of CHIP. Mosaic loss of the Y chromosome (mLOY), a common marker of clonal hematopoiesis in men, has emerged as a potential candidate for modulating cardiovascular risk associated with CHIP. In this study, we aimed to ascertain the risk linked to each somatic mutation or mLOY and explore whether mLOY could exert an influence on the cardiovascular risk associated with CHIP.
Methods:
We conducted an examination for the presence of CHIP and mLOY using targeted high-throughput sequencing and digital PCR in a cohort of 446 individuals. Among them, 149 patients from the CHAth study had experienced a first MI at the time of inclusion (MI(+) subjects), while 297 individuals from the Three-City cohort had no history of cardiovascular events (CVE) at the time of inclusion (MI(-) subjects). All subjects underwent thorough cardiovascular phenotyping, including a direct assessment of atherosclerotic burden. Our investigation aimed to determine whether mLOY could modulate inflammation, atherosclerosis burden, and atherothrombotic risk associated with CHIP.
Results:
CHIP and mLOY were detected with a substantial prevalence (45.1% and 37.7%, respectively), and their occurrence was similar between MI(+) and MI(-) subjects. Notably, nearly 40% of CHIP(+) male subjects also exhibited mLOY. Interestingly, neither CHIP nor mLOY independently resulted in significant increases in plasma hs-CRP levels, atherosclerotic burden, or MI incidence. Moreover, mLOY did not amplify or diminish inflammation, atherosclerosis, or MI incidence among CHIP(+) male subjects. Conversely, in MI(-) male subjects, CHIP heightened the risk of MI over a 5 y period, particularly in those lacking mLOY.
Conclusions:
Our study highlights the high prevalence of CHIP and mLOY in elderly individuals. Importantly, our results demonstrate that neither CHIP nor mLOY in isolation substantially contributes to inflammation, atherosclerosis, or MI incidence. Furthermore, we find that mLOY does not exert a significant influence on the modulation of inflammation, atherosclerosis burden, or atherothrombotic risk associated with CHIP. However, CHIP may accelerate the occurrence of MI, especially when unaccompanied by mLOY. These findings underscore the complexity of the interplay between CHIP, mLOY, and cardiovascular risk, suggesting that large-scale studies with thousands more patients may be necessary to elucidate subtle correlations.
Funding:
This study was supported by the Fondation Cœur & Recherche (the Société Française de Cardiologie), the Fédération Française de Cardiologie, ERA-CVD (« CHEMICAL » consortium, JTC 2019) and the Fondation Université de Bordeaux. The laboratory of Hematology of the University Hospital of Bordeaux benefitted of a convention with the Nouvelle Aquitaine Region (2018-1R30113-8473520) for the acquisition of the Nextseq 550Dx sequencer used in this study.
Clinical trial number:
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- Biochemistry and Chemical Biology
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