Adverse Effects of Fine-Particle Exposure on Joints and Their

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Adverse Effects of Fine-Particles Exposure on Joints and their Surrounding Cells and Microenvironment Shuping Zhang, Quanzhong Ren, Hui Qi, Sijin Liu, and Yajun Liu ACS Nano, Just Accepted Manuscript • DOI: 10.1021/acsnano.8b08517 • Publication Date (Web): 17 Feb 2019 Downloaded from http://pubs.acs.org on February 17, 2019

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Adverse Effects of Fine-Particles Exposure on Joints and their Surrounding Cells and Microenvironment

Shuping Zhang1#, Quanzhong Ren2#, Hui Qi3,4, Sijin Liu2 and Yajun Liu3*

1. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA 2. State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, P.R. China 3. Beijing Jishuitan Hospital, Peking University Health Science Center, Beijing, 100035, P.R. China 4. Beijing Research Institute of Traumatology and Orthopaedics, Beijing, 100035, P.R. China

#

These authors contributed equally to this work

* Corresponding Author: [email protected] (Y. Liu)

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Abstract Current understanding of the health risks and adverse effects upon exposure to fine particles is premised on the direct association of particles with target organs, particularly the lung; however, fine-particle exposure has also been found to have detrimental effects on sealed cavities distant to the portal-of-entry, such as joints. Moreover, the fundamental toxicological issues have been ascribed to the direct toxic mechanisms, in particular, oxidative stress and pro-inflammatory responses, without exploring the indirect mechanisms, such as compensated, adaptive, and secondary effects. In this review, we recapitulate the current findings regarding the detrimental effects of fine-particle exposure on joints, the surrounding cells and microenvironment, as well as their deteriorating impact on the progression of arthritis. We also elaborate the likely molecular mechanisms underlying the particle-induced detrimental influence on joints, not limited to direct toxicity, but also considering the other indirect mechanisms. Due to the similarities between fine air particles and engineered nanomaterials, we compare the toxicities of engineered nanomaterials to those of fine air particles. Arthritis and joint injuries are prevalent, particularly in the elderly population. Considering the severity of global exposure to fine particles and limited studies assessing the detrimental effects of fine-particle exposure on joints and arthritis, this review aims to appeal to a broad interest and to promote more research efforts in this field.

Key words: fine particles; engineered nanomaterials; joints; surrounding cells; arthritis; direct toxicity; indirect toxicity; systemic inflammation


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Air pollution and their subsequent harmful impact on human health have becoming the increasing global concerns. Particulate matter (PM) is the main component of air pollution. A range of epidemiological and toxicological studies have linked PMs, particularly fine particles (nano-sized PMs), to a variety of diseases, including respiratory diseases, cardiovascular diseases, and even cancers. Although some of the health risks and pathogenic mechanisms behind these effects have been clearly defined,1,2 there remain many questions required further study and clarification.2 The health hazard posed by fine particles has always been an important research topic in the field of environmental science. Based on their different sizes, PM can be defined as coarse particles (PM10, < 10 μm in diameter), fine particles (PM2.5, < 2.5 μm in diameter) and ultrafine particles (UFPs, < 100 nm in diameter).3 PMs can also be roughly divided into two types: Outdoor atmospheric PMs, which are derived from motor vehicle exhausts, fossil fuel burning, sand, and fire,2,4,5 and indoor PMs, which are derived from activities like cooking and smoking.6,7 Regardless of origin, both PM types adversely affect human health and are considered pathogenic. Most studies thus far have been limited to the direct impact of fine particles on organs and tissues near the portal-of-entry. However, a smaller number of studies have revealed adverse effects on distant sites, such as bones and joints. Additionally, there is a class of engineered nanomaterials that are produced with specific size, shape, surface characteristics, and functionality. These nanomaterials are intended for daily, commercial applications and are called "engineered nanoparticles" (ENPs). ENPs also cause fine-particle exposure indoors.8 Due to the high degree of similarity between ENPs and PM2.59 as well as their wide use and distribution, indoor exposure to ENPs also contributes to fine particle-induced morbidity and mortality.3,10 Furthermore, these similarities have allowed wide use of ENPs as an ideal model for studies on the effects of PM2.5. Joints are the main structures that support movement of both human and animal bodies, and therefore they are important for human health. Damage to joints and surrounding cells causes a significant pain and complications.11 Among the joint injuries, arthritis including osteoarthritis and rheumatoid arthritis, is a common disease


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and it affects a large number of adults, particularly elderly people.12 Some epidemiological investigations have also revealed that joints are one of the targets of PM2.5.13 Arthritis is one of the inflammatory diseases, thus indicating susceptibility to fine-particle exposure. To date, systemic inflammation has been shown to be responsible for most of the detrimental effects of inhaled fine particles on joints. However, it is still unknown whether there are any other mechanisms and how they interplay with systemic inflammation. Although few studies have reported direct injuries caused by ENPs to joints, it is also unknown whether PM2.5 can induce such direct impairment of joints. Here, we review the studies that assessed the detrimental effects of PM2.5 (both outdoor and indoor) and indoor ENPs on joints and their microenvironment. Both the clarified and possible mechanisms underlying these detrimental effects are discussed. The current issues and challenges are also addressed together with a discussion on the key aspects and future research directions to aid the audience to capture the essences of this field.

PMs and ENPs The toxic effects of PMs on human body depend on their size,14–16 oxygencontaining functional group17 and the environmental pollutants attached to them.18,19 Most particles with diameter > 10 μm are trapped in the nasal cavity and respiratory mucus, or they are ingested through digestive system. PM10 (diameter 2.5-10 μm) can enter the lower respiratory tract and lead to cough, asthma, and other respiratory symptoms. PM2.5 (diameter ≤ 2.5 μm) can reach the alveolar structure deep within the respiratory system and can even travel to multiple organs, including the brain, liver, spleen, kidney and testes (Fig. 1A).14–16 Since inhalation is the main exposure route of particles in humans,20,21 respiratory system-related diseases, such as chronic obstructive pulmonary disease (COPD),22,23 acute respiratory infections,24 respiratory allergies,25–27 and lung cancer,28,29 are associated with particle exposure and are a global concern. In addition to respiratory diseases, cardiovascular diseases, including fatal or non-fatal coronary artery disease30,31 and myocardial infarction,32 stroke,33 cerebrovascular occurrence and mortality34,35 are extensively linked to inhalation


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exposure of particles. Moreover, atmospheric particles have been linked to some other diseases or physiological periods, such as diabetes,36 cancers,37 gestation,38 and psychomotor development during childhood.39,40

Figure 1 Inhalation exposure to PMs and their comparison with ENPs. (A) The distribution of PMs after inhalation mainly depends on their size. The nasal cavity can trap most of the particles > 10 μm in diameter. PM10 can enter the lower respiratory tract, and PM2.5 can reach the alveolar structure. (B) Besides the widespread distribution and exposure to human, ENPs share many characteristics with PMs and they have several important merits, e.g. a simple structure and clarified properties, and ease of acquisition and modification. Thus, ENPs have become an ideal model to study the detrimental effects of PMs on human health.

ENPs are widely used commercially and are widely distributed and they have some similarities with fine particles, such as aerodynamics and nano-size properties.9 Therefore, it has been inferred that ENPs are the ideal materials for investigating the


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health effects of indoor fine particles (Fig. 1B). Moreover, since ENPs have relatively simple structures and clearly determined characteristics along with ease of acquisition and modification (Fig. 1B),41,42 they have been widely employed as models in experimental studies on indoor fine particles. In this manuscript, we review the studies that used these ENPs to reflect the adverse effects of indoor PM2.5 on joints.

Joints, arthritis, and particle exposure Histologically, there are three types of joints, fibrous joints, cartilaginous joints, and synovial joints. Fibrous joints have no joint cavity and are almost immovable, while cartilaginous joints, such as the human spine, allow limited movement. Synovial joints, such as shoulder, wrist, hip, knee and ankle joints, play an important role in human movement,11,43 and can be structurally divided into articular cartilage, synovium and subchondral bone (Fig. 2A).44,45 Collagen fibers and chondrocytes are differentially organized within the different layers of articular cartilage.46 Synovium comprises the following two layers: the intima and the sub-intima, which provide essential nutrients to the avascular cartilage. Synoviocytes constitute the main component of the intima, and fibrous connective tissue, blood vessels, and a small number of immune cells compose the sub-intima.44,47 Subchondral bone serve to maintain the articular cartilage matrix.44–46 Since osteoarthritis (OA) and rheumatoid arthritis (RA) are closely associated with fine particle exposure and they induce damage mostly in synovial joints, this review focuses on the detrimental effects of fine particles on synovial joints. OA is a common disease that affects more than 10% of the elderly people over the age of 60 years.48 Continuous degradation of articular cartilage matrix caused by apoptotic chondrocytes is one of the early features of OA.44 Hyperplasia and increased vascularization are also observed in OA synovium, which may cause more infiltration of immune cells, such as macrophages, T cells, and B cells. These pathological changes destroy adjacent articular cartilage and subchondral bone (Fig. 2B).49,50 RA is another common joint disease with a 0.5~1% prevalence.12 Typically, RA affects bilateral joints of the hand and foot, but large joints, including ankle, knee, elbow and shoulder joints, may also be affected.51 Pathological reactions, such as destruction of


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the articular cartilage, inflammation of the synovium and infiltration of immune cells can be found in both RA and OA. However, RA is considered as an autoimmune joint disease, while OA is classified as a degenerative joint disease. Synovial inflammation plays an important role in RA, and it leads to bony erosion and progressive cartilage degradation.51–53

Figure 2 The structure of synovial joints and arthritis. (A) Synovial joints consist of the following three parts: the three-layered articular cartilage differently organized by chondrocytes and collagen fibers, the synovium as composed of synoviocytes to support the cartilage, and the subchondral bone for maintenance of the cartilage matrix. (B) Being an inflammatory disease, arthritis is characterized by chondrocyte apoptosis, matrix degradation, hyperplasia and enhanced vascularization. Infiltration of immune cells is another important feature and a key cause of arthritis.

Many risk factors, including age, obesity, genetic predisposition, mechanical injuries, and environmental factors, are linked to arthritis.54,55 Recently, increasing attention has been devoted to the detrimental influence of environmental factors on synovial joints and their microenvironment, and exposure to fine particles, including PMs or commercially used ENPs, is an important environmental factor. Previous epidemiological investigations have reported that residents living near air pollution sites, e.g. airways, highways, and combustion sites, tended to have an increased occurrence of OA and RA.56–58 In addition to arthritis, atmospheric PMs, especially


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PM2.5, have been linked to osteoporosis.59 Heavy metals combined with PMs also contribute to disturbed bone metabolism.60 Nonetheless, epidemiological studies assessing the adverse effects of particles on the musculoskeletal system, including bones and joints, remain limited.

Fine particle-induced systemic inflammation and its detrimental effect on joints Acute and chronic inflammation after the inhalation of fine particles from air pollution plays a crucial role in the occurrence and progression of respiratory diseases as well as secondary effects on other organs and tissues.61 After fine particle inhalation, a large number of resident pulmonary inflammatory cells are activated and more immune cells are recruited, leading to continuous pulmonary inflammation. However, systemic inflammation is subsequently induced through stimulation of the production and activation of more immune cells, such as granulocytes, lymphocytes, and particularly, macrophages in bone marrow and spleen.62–64 As a result, complications including arthritis occur at the extra pulmonary sites. In this section, we discuss the processes and mechanisms involved in the interplay between fine particle-induced systemic inflammation and the injuries in joints. Evidence for fine particle-induced systemic inflammation Inhalation exposure to atmospheric particles, particularly fine particles, has been substantially linked to systemic inflammation in cohorts exposed to air pollution.65–68 Even in the absence of air pollution, low-level exposure to atmospheric fine particles has been found to induce systemic inflammatory responses in ischemic heart disease patients.69 The association between fine particle exposure and systemic inflammation has been shown in both children and senior adults.70–72 Although epidemiological investigation on the detrimental effects of ENPs on human health remains limited,73 experimental studies have shown

a positive

association between ENPs and the induction of systemic inflammation. Carbon nanotubes (CNTs) are typical ENPs that have been widely used in many fields, and they can be divided into single-walled carbon nanotubes (SWCNTs) and multi-walled


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carbon nanotubes (MWCNTs).74 Compared to SWCNTs, MWCNTs are more widely used. Using the exposure doses of MWCNTs based on their biomedical application as a reference, Ma et al. recently observed systemic inflammation in MWCNT-treated mice, which was indicated by a significant increase in serum pro-inflammatory cytokines and white blood cells in the bloodstream along with splenomegaly and macrophage infiltration in the spleen.75 Moreover, inhalation exposure to different commercial carbon blacks (CBs), including SB4A, Printex U, C1864 and C824455, induced systemic inflammation to different extents in mice.76 Besides CNTs, metallic nanoparticles have also been found to induce local inflammatory responses (pulmonary inflammation and asthma) and systemic inflammation. A single intratracheal instillation of titanium dioxide nanoparticles (nTiO2) induced 14-day sustained inflammatory responses in mice.77 Hussain et al. reported that exposure to gold nanoparticles (AuNPs) at low doses aggravated both pulmonary inflammation and airway hyperreactivity in a well-developed mouse model of toluene diisocyanate (TDI)-induced asthma, as demonstrated by increased airway reactivity, macrophages and neutrophils in bronchoalveolar lavage, oedema and epithelial damage. However, nTiO2 only increased the inflammatory response in these sensitised mice. These results suggested that there is an increased risk of asthma after occupational exposure to nanoparticles.78 Nickel oxide nanoparticles (NiONPs) were also found to induce inflammatory responses and toxicities in pulmonary epithelial cell lines, including a significant reduction in cell viability and an increase in apoptotic and necrotic cells due to altered cell cycle and DNA damage.79 Furthermore, quantum dots induced the greatest inflammatory responses and DNA damage followed by CB and SWCNT, while fullerenes C60 and AuNPs showed the

lowest

inflammatory

effects

and

DNA

damage.80

Additionally,

dietary

supplementation with omega-3 fatty acids was also shown to reduce both pulmonary and systemic inflammation in fine particle-exposed mice, providing a potential nutritional approach to attenuate the adverse effects of fine-particle exposure.16


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Destruction of joints and their microenvironment due to fine particle-induced systemic inflammation An early characteristic of most types of arthritis is the inflammatory response within the joints.81 Both OA and RA are chronic inflammatory diseases characterized by infiltration of immune cells, secretion of pro-inflammatory cytokines, and synovitis, both leading to destruction of the articular cartilage.82,83 Under normal conditions, the matrix in the cartilage microenvironment is maintained in a finely tuned, stable equilibrium between the generation and degradation of matrix components. However, under pathological conditions, enhanced cartilage destruction occurs due to increased matrix degradation induced by the activated inflammatory cells, synoviocytes and chondrocytes (Fig. 3). Therefore, a large number of studies have shown that systemic inflammation is tightly related to arthritis.84–86 To date, investigations on the detrimental effect of fine particles, both PMs and ENPs, on bone and joints remain limited. Recently, the adverse impact of ENPs on knee joints was systematically investigated.75,76 After exposure to MWCNTs, infiltration of pro-inflammatory cells was observed in the synovium and meniscus of mice, followed by increased thickness of the synovial membrane within the knee joints. However, intrusion of MWCNTs was not observed in knee joints, and MWCNTs mainly accumulated in the lung and liver. This finding demonstrates systemic inflammationinduced injuries in the knee joints after MWCNT exposure.75 Infiltrated proinflammatory cells into the synovium indicated synovial inflammation. Moreover, in the knee section of MWCNT-treated mice, COX-2 and MMP-9 expressions were significantly increased along with an increase in apoptotic cells, indicating arthritis syndrome.75 Pro-inflammatory cytokines play essential roles in arthritis by stimulating the secretion of enzymes, such as COX and MMP, in synoviocytes and chondrocytes.81,87 After incubation with the culture medium from MWCNT-treated macrophages, the protein levels and activities of COX and MMP enzyme family members in synoviocytes were significantly increased; however, direct treatment of synoviocytes with MWCNTs did not induce any notable enzymatic change.75 The COX and MMP families are crucial in the pathological activation of synovial cells and


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subsequent destruction of articular cartilage.88 These results suggested that activation of synovial cells together with changes in their cellular priming status was caused by MWCNT-induced pro-inflammatory cytokines. Similar to that in synoviocytes, incubation with the culture medium obtained from MWCNT-treated macrophages upregulated the expression of COX and MMP enzymes in chondrocytes, suggesting matrix degradation of articular cartilage in an autocrine-paracrine pattern under MWCNT-induced inflammation.75 Finally, blockage assay confirmed that the production of inflammatory cytokines, TNF-α and IL-1β, by macrophages prominently accounted for the activation of synovial cells upon MWCNT exposure 75. Similar to MWCNTs, inhalation exposure to CBs also induced injuries in the knee joints.76 Although no obvious impairment was found in articular cartilage, a thickened synovial membrane and an activated metabolic state of chondrocytes were induced by all four types of commercial CBs.76 This could be due to the infiltration of systemic inflammation-activated pro-inflammatory cells in synovial membrane.89,90 It is still unknown whether metallic nanoparticles and other non-CNT ENPs can induce indirect adverse effects on joints through systemic inflammation. However, inflammation induced by exposure to these particles shared several features with CNTs, thus suggesting the possibility that non-CNT ENPs may also cause indirect damage to joints through systemic inflammation. Nonetheless, these studies demonstrated an interplay between ENP-induced systemic inflammatory responses and enzymatic destruction of articular cartilage, in which pathological activation of synoviocytes and chondrocytes is the key process (Fig. 3). However, it still needs to be investigated how PM2.5 influences human joints through systemic inflammation and what processes are involved.


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Figure 3 Systemic inflammation-induced joint destruction. Local inflammation in the lung further promotes the production and activation of systemic immune cells and subsequent cytokine secretion of cytokines. Induction of systemic inflammation then leads to the infiltration of inflammatory cells and elevated concentrations of cytokines in the joints, resulting in the destruction of joints, apoptotic chondrocytes, and degraded cartilage matrix. Pathological activation of synoviocytes and chondrocytes is also essentially involved in joint destruction through secretion of MMP and COX enzymes.

Mechanisms underlying the detrimental effects of fine-particle exposure on joints through systemic inflammation Fine particle-induced inflammatory cytokines and according molecular bases Various inflammatory cytokines are secreted during fine particle-triggered pulmonary and systemic inflammation (Table 1). MWCNT exposure induced significant increases in serum IL-6 and TNF-α.75 In vitro experiments verified that TLR4-NF-κB signaling recognized the intrusion of MWCNTs and initiated pro-inflammatory responses in macrophages.75 Inhalation of CBs provoked macrophagic proinflammatory responses characterized by the reinforced secretion of IL-6 and TNF-α.76 Apolipoprotein E (ApoE) has been found to be associated with CB-induced pulmonary toxicity. Compared with wild-type mice, ApoE knockout (ApoE-/-) mice showed more lung inflammation after CB exposure through intratracheal instillation or inhalation, particularly instillation.80


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Pro-inflammatory effects of NiONPs were also revealed by MAPK cascadedependent release of IL-6 and IL-8 through induction of the NF- κ B pathway in pulmonary epithelial cells.79 Intratracheal instillation of nTiO2 significantly induced the expression of pro-inflammatory cytokines (IL-1, TNF-α, and IL-6) in a dose-dependent manner on day 1. Moreover, the levels of both Th1-type cytokines (IL-12 and IFN-γ) and Th2-type cytokines (IL-4, IL-5 and IL-10) were also induced in a dose-dependent manner. The induction of Th2-type cytokines further increased the distributions of B cell in spleen and blood as well as IgE production in bronchoalveolar lavage fluid and serum, suggesting Th2-mediated chronic inflammation induced by nTiO2.77 Negatively charged poly (acrylic acid)-conjugated AuNPs were shown to bind to and induce unfolding of fibrinogen, leading to interaction with the integrin receptor, Mac-1. Then, the NF-κB signaling pathway was up-regulated by the activated Mac-1, resulting in the release of inflammatory cytokines.91 It was found that macrophages mediated the nTiO2 and AuNP-induced inflammatory response in the TDI-sensitised mice, which was similar to that in CNT-treated mice. However, no significant increase in the TNFα level was observed in these TDI-sensitised mice when exposed to nTiO2 and AuNPs.78 nTiO2 and nSiO2, but not nZnO, were reported to activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome, leading to the release of IL-1β which further induced the release of IL-1α. It was also shown that cytoskeleton-dependent phagocytosis was not required for the activation of Nlrp3 activity by nTiO2 and IL-1α/β secretion was induced in nonphagocytic keratinocytes. Pulmonary inflammation induced by nTiO2 inhalation in mice was largely mediated by IL-1α.92 Briefly, both CNTs and non-CNTs, particularly metallic nanoparticles, provoke the secretion of inflammatory cytokines and systemic inflammation through the NF-κB pathway. MAPK cascade and unfolded fibrinogen activated Mac-1 contribute to the activation of the NF-κB pathway by non-CNTs. Moreover, non-CNTs elicit Nlrp3regulated and nonphagocytic cytokine release.


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Table 1. A brief summary of fine particle-induced inflammatory cytokines and according molecular bases Fine particles

Induction of inflammatory cytokines

MWCNT

IL-6, TNF-α

CBs

IL-6, TNF-α

NiONPs

IL-6, IL-8

nTiO2

Molecular bases NF-κB signaling

Ma et al. 201675

NF-κB signaling,

Ma et al. 201876

ApoE

Jacobsen et al. 200980

NF-κB and MAPK signaling

IL-1, TNF-α, IL-6, IL-12,

Th2-mediated

IFN-γ, IL4, IL-5, IL-10

signaling, Nlrp3 Unfolded

AuNPs

IL-6, IL-8, TNF-α

fibrinogen, Mac-1, NF-κB signaling

nSiO2

IL-1α, IL-1β

References

Nlrp3 inflammasome

Capasso et al. 201479 Park et al. 200977 Yazdi et al. 201092 Hussain et al. 201178 Deng et al. 201091 Hussain et al. 201178 Yazdi et al. 201092

Involvement of adaptive immune responses in fine particle-induced joint damage The innate immune response can activate the adaptive immune response for longer protection against pathogen invasion,93,94 and exposure to PMs can induce the adaptive immune response.95 After pathogen invasion, naïve CD4+ T cells are activated via the T-cell receptor and co-stimulatory molecules and they differentiate into three types of effector T helper (Th) cells, Th1 (against intracellular pathogens), Th2 (against parasites), or Th17 cells (against extracellular pathogens).94 However, similar to other autoimmune diseases, the development of the adaptive immune responses, including the production of autoantibodies and the activation of Th17 cells, is a common feature of RA.96 Exposure to silica was reported to increase the production of autoantibodies and CD4 T cells in mice,97 thus contributing to the pathogenesis of RA.98 Furthermore, the activation of Th17 cells that differentiated from naïve CD4+ T cells in the adaptive immune responses leads to osteoclast-mediated bone destruction in RA.99 The activated Th17 cells can also produce IL-17, IL-17F, IL21, and IL-22.100


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The aryl hydrocarbon receptor (AHR), a transcription factor belonging to the basichelix-loop-helix/Per-Arnt-sim (bHLH/PAS) family of proteins, plays an important role in the harmful effect of fine particles on bone and joints.101 Diesel exhaust particles can bind to the AHR cooperating with HSP-90 and p23 chaperone complex, leading to translocation of the AHR from the cytosol to the nucleus. Translocation of the AHR initiates the attachment of the AHR to xenobiotic response elements (XRE), thus leading to the up-regulated expression of cytokine genes. Secreted cytokines, such as IL-6, induce the differentiation of naïve CD4+ T cells into Th17 cells, resulting in the activation of adaptive immune responses and bone destruction in RA.101–103 AHR expression is higher in the synovial tissue from RA patients than from OA patients, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) derived from smoking and other exposure routes can also bind to the AHR to up-regulate the expression of inflammatory cytokines, such as IL-1 β , IL-6, and IL-8; thus resulting in exacerbated RA pathophysiology.104 AHR knockout mice showed lower incidence of arthritis as compared to the wild-type mice.105 Furthermore, fine particles have been shown to participate in modulation of the balance between osteoblasts and osteoclasts, in which the AHR is also involved.106,107 The activation of adaptive immune responses might partly accounts for the fact that both CNTs and non-CNTs pose adverse effects on joints through inflammatory response. The involvement of adaptive immune responses in fine particle-induced joint damage is illustrated in Fig. 4.


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Figure 4. An illustration of the effects and mechanisms of fine particle-activated adaptive immune responses. The innate immune response activated by pathogen invasion can further induce the adaptive immune response by promoting the differentiation of naïve CD4+ T cells into Th1, Th2 and Th17 cells. Cooperating with HSP-90 and p23 chaperone complex, fine particles bind to the AHR, leading to the AHR translocation in pro-inflammatory cells. Translocated AHR binds to the XRE element of cytokine mRNAs to induce the cytokine expression. The secreted cytokines, particularly IL-6 and TNF-β, activate adaptive immune response by promoting the differentiation of naïve CD4+ T cells into Th17 cells. Th17 cells and Th17-secreted cytokines contribute to the bone destruction in RA.

Disordered iron homeostasis, anemia and joint damage after fine particle exposure Many types of biological homeostasis can be disrupted by systemic inflammatory responses, thus increasing susceptibility to some health problems, e.g. anemia of inflammation (AI).108 Besides the systemic inflammation as previously observed,75 systemic iron homeostasis was altered through the provoked IL-6-hepcidin axis in the liver, after both short-term and long-term exposure to MWCNTs, thus resulting in AI.109 Inflammation is one of the key signaling pathways that induce the expression of hepcidin, the master regulator of iron homeostasis,110 through the IL-6-STAT3 axis.111


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Moreover, hepcidin, the main regulator of iron homeostasis, was found to be an important inducer of anemia of inflammation in patients with RA.112 Hepatic local inflammation induced by MWCNT exposure also contributed to the increase in hepcidin expression.109 MWCNT-induced AI caused several subsequent effects, including splenomegaly to support the extramedullary erythropoiesis.109 Iron is crucial for bone metabolism through two mechanisms. The first mechanism is that iron is required during the proteolytic cleavage of pro-collagen I to collagen I, which accounts for 90% of total bone protein.113 The second mechanism is that iron is essential for vitamin D metabolism.114 Iron metabolism was first associated with bone metabolism based on clinical investigations which revealed that patients with iron overload-related diseases, such as hereditary hemochromatosis, thalassemia and sickle cell disease, exhibited a higher incidence of osteoporosis and fractures.115–117 However, in the non-disease context, the relationship between iron metabolism and bone metabolism is more complex and remains controversial. For example, although a positive correlation exists between serum ferritin level and bone mineral density in elderly men, such a positive correlation was not found in women.118 Furthermore, a negative correlation was observed in women aged older than 45 years.119 On the other hand, a study by Zhao et al. reported the inhibition of osteoblast activity by iron overload, the promotion of osteoblast activity by mild iron deficiency, and inhibited osteoblast activity by severe iron deficiency.120 A recent epidemiological study revealed that maternal iron deficiency during pregnancy gave rise to higher levels of infant c-terminal-fibroblast growth factor-23 (C-FGF23), which is mainly expressed in osteocytes as an important regulator of phosphate homeostasis and vitamin D metabolism, and total alkaline phosphatase (TALP) in infants and young children.121 Thus, results from these reports suggest that disordered iron homeostasis induced by fine particle exposure may contribute to impairment of bone and joint health after fine particle exposure, and hepcidin could be a potential therapeutic target. Furthermore, hemoglobin concentration correlates to the physical disability in patients with RA.122 As a key component during erythropoiesis, iron homeostasis substantially influences hemoglobin levels during normal and pathological conditions,


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and even in the recovery from blood loss.123,124 During ischemic osteonecrosis, secretion of IL-6 from articular chondrocytes was significantly promoted in an HIF-1dependent pathway. The secreted IL-6 further resulted in significant increases in IL-1β and TNF-α expression in synovial cells, and finally initiated hip synovitis.125 HIF-1 signaling serves as the sensor of hypoxia and anemia.126,127 These intricate relationships among disrupted iron homeostasis, iron- or inflammation-induced anemia, and arthritis might be involved in fine particle-induced joint damage.

IL-6-mediated complex circuit and arthritis after fine particle exposure Both epidemiological and experimental investigations have reported that exposure to atmospheric fine particles elevates the expression and secretion of many inflammatory cytokines, such as CRP, IL-1, IL-6, IL-8, and TNF-α, in systemic inflammation.65,128–134 Among them, IL-1, IL-6, and TNF-α are the most frequently reported cytokines in fine particle-induced systemic inflammation. An elevated IL-6 level has also been noted after ENP exposure.75,76,135,136 IL-6 plays a pivotal role in promoting the transition of acute inflammation into chronic inflammation through complex mechanisms, in which it could act as a pro- or an anti-inflammatory cytokine.137,138 IL-6 is produced by a variety of cells, such as T cells, B cells, monocytes/macrophages, fibroblasts, and tumor cells.139–143 IL-6 is also potently expressed and secreted by synoviocytes, and the levels of IL-6 in synovial fluid and sera correlated with RA.144–146 IL-6 was also shown to correlate with internal derangement of the temporomandibular joints (TMJ).147,148 Fu et al. showed that IL-6 mediates the differentiation of osteoclast progenitor cells and the activity of osteoclasts.149 The finding of polymorphism (-174 G->C) in the promoter region of IL6 from some patients with RA also indicated the close relationship between IL-6 and RA susceptibility.150 Treatment with anti-IL-6R antibody was found to effectively inhibit the development of arthritis in both mice and monkeys.151,152 Recently, it was noted that the secretion of IL-6 was greater in synovial fibroblasts from obese OA patients than that in synovial fibroblasts from normal-weight patients, which was consistent with the observation of higher IL-6 level in synovial fluid from obese patients.153 Such


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increased IL-6 secretion from synovial fibroblasts was driven by chondrocyte-derived IL-6, suggesting a cross-talk between chondrocytes and synovial fibroblasts. This cross-talk was further proved to be enhanced by the obesity-related adipokine leptin.153 In RA patients, anemia of chronic disease (ACD) is the most common extra articular manifestation and IL-6-mediated bone marrow suppression was shown to be the main mechanism for the development of ACD in RA patients.154 On the other hand, the IL6-STAT3 axis is one of the two key signalings regulating the expression of hepatic hepcidin which further regulates iron homeostasis.111 Both disturbed iron homeostasis and elevated hepcidin expression were observed after ENP exposure, and they were implicated in the mechanisms of ENP-induced damage in joints. Additionally, the differentiation of Th17 cells in adaptive immune responses is induced by IL-6 and TGFβ.100 All these reports suggest a complex connection of systemic inflammatory responses, adaptive immune responses, and complications (diabetes, obesity, disordered iron metabolism, and anemia) with joint damage and arthritis after fine particle exposure, and critically, IL-6 is the pivotal point.

Direct adverse effects of fine particles on joints and their surrounding cells To date, although epidemiological studies have reported an association between atmospheric fine particles and arthritis,155,156 None of the experimental studies has directly indicated their impact on joints. Instead, few studies have been carried out using ENPs to evaluate the potential impact of atmospheric fine particles on joints. As a therapeutic approach, ENPs have been used to deliver therapeutic agents to the synovium for treating arthritis.157–159 While the number and wide variety of ENPs are growing almost daily, the side effects and even the toxicities of ENPs remain largely unknown. Fine particle-induced direct toxicity in chondrocytes and joints


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In addition to secondary toxicity after fine particle exposure through induction of systemic inflammation, fine particles can also enter the cartilage cavity and cause direct toxicityin cartilage and chondrocytes. Pascarelli et al. evaluated the detrimental effects of two categories of nanoparticles, AuNPs and silver nanoparticles (AgNPs), on chondrocytes.160 The characteristics of apoptosis and the induction of nitric oxide synthase in chondrocytes were observed for both NPs. While there was no detection of AgNPs, AuNPs were detected in the cytoplasm and in endocytotic vesicles of chondrocytes. After treatment with both NPs, the expression of MMP3 was increased.160 The deleterious impact of AuNPs was further evaluated in rabbit chondrocytes ex vivo using AuNPs of different diameters, 3, 13 and 45 nm (nanometer), and the results showed that such an impact was diameter-dependent.161 AuNPs (13 nm) caused the death of chondrocytes along with apoptotic characteristics, including mitochondrial damage, externalization of phosphatidylserine and nuclear concentration, while 3- and 45 nm AuNPs did not exhibit significant toxicity in chondrocytes. Although induction of reactive oxygen species (ROS) was observed, pretreatment with a ROS scavenger did not prevent 13 nm

AuNP-induced

cytotoxicity,

suggesting

a

ROS-independent

apoptosis

mechanism.161 Besides metal nanoparticles, CB-induced direct toxicity in chondrocytes was revealed recently. Four classes of CBs exhibited different toxicities due to different levels of induced-ROS,76 which is different from the reported ROS-independent mechanism reported by H. Huang et al..161 A switch from the normal state to the pathological state in CB-treated chondrocytes was also found, which was demonstrated by the induction and secretion of MMP proteins, consistent with metal nanoparticles160 and suggesting pathological activation of chondrocytes that can be observed in OA or RA.76 Meanwhile, differential toxicities in knee joints were also observed among the four types of CBs.76 The functional groups, basically including the hydrophobic and hydrophilic groups, essentially determine the existing state and dispersibility of nanoparticles in water and culture medium, thus influencing their bioreactivity and biocompatibility.162–164 Owing to the different functional groups and


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the different extents of oxygen-containing groups, CBs with less dispersibility exhibited greater toxicity in chondrocytes in vitro and knee joints in vivo.76 Based on the limited studies mentioned above, it can be determined that exposure to ENPs mainly impacts the viability of chondrocytes, possibly through ROS- and mitochondria-mediated apoptosis. The upregulated expression and secretion of MMP proteins from chondrocytes after ENP exposure may contribute to the destruction of knee joints (Fig. 5A).

Figure 5 Direct adverse effects of fine particles on joints. (A) Exposure to fine particles causes chondrocyte apoptosis through induction of ROS production and mitochondrial damage. Pathological activation of chondrocytes promotes the secretion of MMP enzymes which further induce destruction of cartilage matrix. (B) Additionally, fine particle exposure changes the fate of mesenchymal stem cells (MSCs) with the promoted proliferation and impaired differentiation towards to different lineages by (C) inducing mitochondrial injuries and modulating mitochondrial biogenesis, dynamic fusion and fission, and mitophagy.

Direct detrimental effect on mesenchymal stem cells after fine particle exposure Mesenchymal stem cells (MSCs) are multipotent stem cells, residing in bone marrow, and have the capacity to differentiate into multiple mesenchymal tissues,


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including cartilage.165,166 Besides matured chondrocytes, MSCs have also been considered as a potential target following exposure to fine particles. Superparamagnetic iron oxide (SPIO) is a widely used class of nanoparticles in the labeling and tracking of stem cells, but the side effects of SPIO on stem cells have not been fully elucidated. SPIO was reported to be safe for human MSCs (hMSCs), without alterations of cellular function, cell toxicity and inhibition of differentiation capacity.167 However, Roeder et al. reported a dose-dependent deleterious effect of SPIO on TGF-β1-driven chondrogenesis.168 Moreover, modified SPIO, aiming at improving biocompatibility, bio-distribution and labeling efficiency of SPIO, also showed different influences on MSCs.169 Chang et al. investigated the effects of aminesurface‐modified SPIO on the proliferation and differentiation of hMSCs. They found that the potential of hMSCs for osteogenic and chondrogenic differentiation, but not the adipogenic potential, was impaired after treatment with amine-surface‐modified SPIO, while the proliferation of hMSCs was enhanced.169 The production of growth factors, including amphiregulin, glial cell‐derived neurotrophic factor, heparin‐binding EGF‐like growth factor, vascular endothelial growth factor, and the soluble forms of macrophage colony‐stimulating factor receptor and stem cell factor receptor, was increased after modified SPIO treatment.169 Even at non-toxic concentrations, AgNPs were shown to attenuate adipogenic and osteogenic differentiation of hMSCs, but not chondrogenic differentiation.170 On the contrary, AgNPs have been shown to enhance the mineralization ability and to increase the expression of alkaline phosphatase (ALP) in an osteoblast precursor cell line.171 In addition, AuNPs have a positive effect on the osteogenic differentiation of osteoprogenitor cells172 and the differentiation of MSCs into osteoblasts.173 Shen et al. evaluated the effects of Printex 90, a commercial type of CBs, on MSCs.174 Upon exposure to low doses of Printex 90 without impairing the viability of MSCs, Printex 90 significantly down-regulated the expression of osteogenic marker genes of MSCs, including ALP, Bglap and Runx2, in which the inhibited ALP indicated impaired matrix formation of osteoblasts. It was further demonstrated that Printex 90


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inhibited the mineralization potential, thus resulting in smaller and less mineralized nodules.174 Different from matured chondrocytes, MSCs exhibit different responses to ENP exposure. While some ENPs (AgNPs and AuNPs) promote osteogenic differentiation of osteoprogenitors and MSCs, other ENPs (SPIO and CB) enhance the proliferation but impair the potential for osteogenic and chondrogenic differentiation, mineralization and matrix formation of MSCs (Fig. 5B).

Possible effects of implant-derived fine particles on joints Metal and metal alloy biomaterials (stainless steel, Co, Cr, Ti and Ti based alloys) for implants have been widely used in the fields of orthopedics and dentistry. These materials have excellent corrosion resistance, good mechanical properties and biocompatibility. However, when a metal or a metal alloy is implanted into a complex and corrosive physiological environment, the stability of the oxide may be changed, thus resulting in an increase in metal ion dissociation and/or nanoparticle release.175 For example, AgNPs and AuNPs have been considerably used in plastic surgery and dental implants. Furthermore, Ti-AuNPs can induce dental implants for formation of an osseous interface and maintenance of nascent bone formation.176 However, in a complex physiological environment, they are prone to degradation and thus they enter into the circulatory system, inducing direct or indirect detrimental effects on other cells. Studies have shown that after implantation in the human body, the implant is bound to degrade through the following two mechanisms: wear and corrosion. Wear is physical degradation of materials and particles are produced by abrasion. The resultant particles are usually nano-sized, and they can activate macrophages, thus leading to inflammation.177 These metal wear particles accumulate in the surrounding tissue and are transported to distant organs through the synovial fluid, blood, or urine. The lymphatic system transfers free or engulfed metal particles, which results in their accumulation in regional lymph nodes, liver and spleen.178 Corrosion is chemical degradation, which mainly produces dissolved metal ions by reacting with acidic substances in the body.179 The corrosion behavior of implants is affected by a number


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of factors, including the material itself (e.g. chemical composition, microstructure, surface condition), ambient conditions (e.g. pH, temperature, O2 content, proteins in plasma), and structure (e.g. presence of cracks), and the chemical environment of plasma is highly corrosive to many metals and alloys.175,180 The corrosive effects are usually synergistically combined to cause corrosion of the implant,181 and produce nano-sized particles.182 Studies have shown that these corroded particles can cause adverse inflammatory reactions and immune responses in the body.183,184 On the other hand, induced inflammatory environments due to these particulates can further increase the degree of implant corrosion, thus resulting in the release of more metal ions and/or nanoparticles.185 Additionally, systemic and local inflammation can also be induced by implants themselves.186–188 Furthermore, many studies have shown that after the implant is worn out, a large amount of ROS is produced.189–191 For example, after implantation and exposure to biological fluids, bone cells and inflammatory cells, mainly macrophages and neutrophils, are found on the titanium surface. Also, activation of macrophages induces the accumulation of ROS, which further leads to inflammatory responses.192 ROS can induce adverse effects on the osteoblast phenotype, such as decreased ALP activity and poor matrix mineralization.193,194 Moreover, nanoparticles cause direct toxicity in chondrocytes through induction of ROS,76 suggesting that implants and implant-derived nanoparticles and metal ions may reduce chondrocyte viability. It has also been shown that worn-out implant particles induce ROS production through the NOX signaling pathway, thus leading to persistent inflammation and prosthesis loosening.195 Therefore, in the context of application in orthopedics and dentistry, direct adverse effects of implantation on joints might be mostly induced by the leaked nanoparticles and metal ions. During the application in other organs, indirect adverse effects of implantation on joints might be induced by the implants themselves and the released nanoparticles. The production of ROS may contribute to joint injuries caused by implantation in most scenarios (Fig. 6).


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Figure 6. Possible adverse effects of implants, implant-derived nanoparticles, and metal ions on joints. The implants are bound to degrade through two mechanisms, wear and corrosion, which produce nanoparticles and metal ions, respectively. In the context of application of implants in orthopedics and dentistry, the leaked nanoparticles and metal ions might induce local inflammatory responses and direct toxicities in joints and their surrounding cells, including matrix degradation, chondrocyte apoptosis and impairment of the differentiation potentials of MSCs. The implants and implant-derived nanoparticles can be transported to distant organs to induce systemic inflammation. Thus, indirect adverse effects of implantation on joints might also be induced even during the application of implants in other organs. In most scenarios, the induced and accumulated ROS might be involved in contributing to the possible toxicities of the implants to joints.

Mechanisms underlying direct adverse effects of fine particles on joints and their surrounding cells Damage to mitochondria and oxidative stress induced by fine particles Shen et al. reported altered mitochondrial structure, as indicated by dissolved mitochondrial cristae, swelling and abnormal density of mitochondria in Printex 90treated MSCs. OXPHOS The damage induced by Printex 90 impaired the activity of mitochondrial respiratory chain, which in turn reduced ATP production.174 Printex 90


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administration inhibited mitochondrial biogenesis in MSCs, as shown by a dramatic decrease in TFAM, PGC-1α, and Nrf1. By measuring the expression of fusion and fission related factors, mitochondrial dynamics, including fusion and fission, were shown to be damaged by Printex 90 treatment. However, both PINK1 and Parkin were upregulated after Printex 90 treatment, showing the enhanced mitophagy in MSCs.174 Furthermore, both BMP and WNT signaling pathways were significantly inhibited by Printex 90. These two signaling cascades play important roles in osteoblastic differentiation of MSCs through promotion of mitochondrial biogenesis (Fig. 5C).174 Mitochondria are important for fulfilling the requirement of increased energy, and they are maintained through mitochondrial biogenesis, dynamic fusion and fission, and mitophagy during differentiation of MSCs.196,197 These mitochondrial processes are dynamically altered during MSC differentiation.198,199 Although a number of studies have demonstrated the detrimental effects of nanoparticles on maintenance of mitochondria,200,201 limited investigations are specific to MSCs and chondrocytes, particularly in terms of the effects on the bone and joint health. On the other hand, mitochondria are one of the main sources of ROS, and oxidative stress due to high levels of ROS is crucial for the occurrence and progression of degenerative diseases.202 Being one of the most common degenerative diseases in elderly people, OA is an age-related arthropathy with progressive joint destruction.48,203 During aging, more and more ROS are generated and accumulated, contributing to age-related mitochondrial dysfunction and promoting alteration in the senescence and apoptosis of chondrocytes in joints. Nonetheless, the ROS accumulated during aging play a minor role and only account for a small amount of the total ROS in OA.204 Indeed, a low-level of ROS helps maintain the balance between osteoclastogenesis and osteoblastogenesis to sustain bone integrity. The main ROS responsible for oxidative stress and OA are derived from inflammation and mechanical load.205 It is still unknown whether fine particle-induced systemic inflammation exacerbates the ROS generation in mitochondria. Athough no significant induction of ROS was observed in CB-treated MSCs,174 it is still unclear whether other types of ENPs and atmospheric fine particles induce ROS in MSCs. Oxidative stress triggered by a high-level of ROS results in


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chondrocyte apoptosis with subsequent cartilage degradation and hypertrophy, and induction of abnormal bone resorption and remodeling.205 Furthermore, whether fine particle-induced oxidative stress in chondrocytes76,161 significantly contributes to the accumulation of ROS and the subsequent detrimental effect on joints is another fundamental scientific question to be explored.

Disturbed epigenetics and joint damage after fine particle exposure Fine particle exposure has been reported to disturb epigenetics through alteration of DNA methylation.206–208 Recently, a crossover, placebo-controlled trial demonstrated that acute exposure to atmospheric fine particles altered the methylation of genes in peripheral CD4+ T cells, and these genes were involved in the mitochondrial oxidative energy metabolism, resulting in 11.1% depletion of mitochondrial DNA content.209 More importantly, B-vitamin supplementation was shown to attenuate the effects of fine particles on epigenetics by 102%, thus providing a potential strategy for developing preventive interventions to minimize the adverse effects of fine particles on marker genes.209 Epigenetic modification under various pathological conditions has been revealed to involve many types of bone and cartilage diseases.210–214 Oxidative stress can modify epigenetics in many diseases, such as cardiovascular diseases and cancers,215,216 suggesting the potential role of epigenetic modification in fine particleinduced adverse effect on the cartiliage through oxidative stress.

Comparison between ENPs and PMs Although ENPs are similar to PMs in several aspects, such as similar aerodynamics and nano-size, there are many differences between these two particles in real-life settings, such as different sizes, composition complex, and physicochemical characteristics. Exposure to ENPs with high purity may induce marked and acute effects, while the impurities in PMs may trigger unexpected effects. These two effects may be ascribed to different mechanisms. However, to date, there is no investigation comparing ENPs and PMs in terms of their different adverse effects and corresponding mechanisms in joints and their surrounding cells. Here, we review studies that


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assessed the detrimental effects of these fine particles on non-joint tissues and organs to infer possible different toxicities and mechanisms in joints. Currently, ENPs are widely used in biomedicine, cosmetics, electronics, clothing manufacturing and other industries.217–219 Although many ENPs can be safely used, some of them can be highly toxic to consumers upon exposure.220–222 For instance, in view of the unique magnetic and optical characteristics of ENPs, they are widely used in cancer treatment, such as photodynamic therapy. However, ENPs may induce serious toxic and detrimental effects in the human body during diagnosis, such as production of ROS, initiation of inflammation, and induction of cell apoptosis.220 During use of nTiO2, nTiO2 enter the water environment in large quantities.223 Although their chemical properties are stable, the surface of nTiO2 easily adsorbs other pollutants (such as arsenic and lead) in the water environment due to their high specific surface area, leading to increased toxicity, endangering the aquatic environment, and eventually accumulating in aquatic objects.224 Studies have shown that intake of nTiO2 may cause oxidative stress, which leads to damage to the digestive gland cell membrane.221 Studies have found that many nanomaterials used in food packaging (nZnO and nMgO) and food additives (nTiO2 and nSiO2 ) not only have toxic effects on human intestinal cells, but also cause DNA damage.222 Owing to their small sizes, they can penetrate the epithelial and endothelial barriers to enter into the lymph and blood, and they can be transfer into the brain, heart, liver, kidney, spleen, bone marrow and nervous system via the bloodstream and lymphatic flow.16,225–227 The toxicity of ENPs is highly dependent on their physical and chemical properties, such as their size, shape, specific surface area, surface charge, catalytic activity and the presence of shells and reactive groups on the surface.228 For example, small sized AgNPs are more toxic to cells as they produce 10 times higher amounts of ROS than large sized AgNPs.229 Similarly, small sized AuNPs produce 60 to 100 times more cytotoxicity than large sized AuNPs.230 However, when the particle size is larger than 100 nm, an opposite effect is observed. For example, after exposure of cells to spherical nTiO2-PEGs, it was found that the apoptotic rate increases as the nanoparticle size increases. The reason for this difference may be related to cell phagocytosis. Compared with small-


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sized, large-sized particles are more likely to be phagocytosed by cells, leading to apoptosis.231 When the size and surface area of ENPs remain the same, the shape of ENPs becomes an important factor for determining their cytotoxicity. Unlike cubic/octahedral cerium oxide nanoparticles, rod-like nanoparticles significantly and dose-dependently enhance pro-inflammatory and cytotoxicity responses.232 Rod-like nZnO are more toxic to human lung epithelial cells than spherical nZnO.233 In addition, different functional groups on the surface of ENPs can produce different charges. For example, the -COOH functionalized ENPs are considered to be positively charged, while the -NH2 functionalized ENPs are considered to be negatively charged. These functions not only change the charge but also change how these ENPs function in biological systems. Studies have found that cationic chain-functionalized AuNPs are moderately toxic, while anionic chain-functionalized AuNPs have been found to be non-toxic.234 However, compared with ENPs, the composition of PMs is more complex. The chemical composition of PMs includes organic carbon, inorganic carbon, metals, organic matter, inorganic aerosols, trace elements and bioaerosols.235 Toxic effects of PMs are related to their size, shape, and surface charge,236 as well as to the components adsorbed by the particles. Studies have shown that certain contaminants adsorbed by PMs induce more cellular oxidative stress, apoptosis and cytotoxicity than PM itself.237 Each specific toxic component of PMs affects their specific target organ. For example, exposure to lead- and manganese-adsorbing PMs can cause neurological and hematological toxicity in children.238 Exposure to polycyclic aromatic hydrocarbon-adsorbing PMs can cause skin irritation and inflammation.239 After prolonged exposure, these PMs can induce cataracts and cause kidney and liver damage and jaundice.240 Bioaerosol-adsorbing PMs can aggravate human respiratory allergies and other lung diseases.241 However, when various pollutants are added together, synergistic effects may occur. Therefore, compared to ENPs, the complex composition and adsorbed pollutants of PMs are crucial for their toxicities. These two factors are very unpredictable, causing great inconvenience to scientific research. Thus, although knowledge of ENP-induced


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detrimental effects on joints and the underlying mechanisms is crucial for evaluating the adverse impacts of PMs on joints, the differences between ENPs and PMs should always be taken into account.

Current issues, challenges, key aspects, and future directions Current issues To date, the lack of epidemiological studies assessing the detrimental effects of PM2.5 and ENPs on joints and their microenvironment is a prominent issue. There is inadequate toxicological insight into the direct effects of PMs on joints. Although some studies have been used ENPs to reflect the adverse impact of PM2.5 on joints, the knowledge is still quite limited. It is unknown whether there is a synergistic effect between them. Although increasing evidence indicates that systemic inflammation induced by fine particles plays an important role in injuries to the joints, there is little information on the details of the underlying mechanisms, particularly in terms of direct toxicities in chondrocytes and MSCs. Furthermore, it is still unknown whether there is any interaction between the indirect and direct effects of fine particle exposure on joints and how they interplay. Therefore, studies focusing on direct toxicity and corresponding specific mechanisms of fine particles on joints, with or without incorporating indirect effects and systemic mechanisms, are necessary. Most importantly, there is an urgent need to perform studies by using atmospheric fine particles.

Challenges The processes and mechanisms by which inhaled fine particles penetrate into the extra pulmonary tissues and joint cavity are still unknown. Furthermore, due to the relatively closed space of a joint cavity, the exchange of nutrients between the articular cartilage and bloodstream is limited and it functions at a slow rate. This slow exchange can protect the cells inside the cavity from the detrimental effects of fine particles. However, on the other hand, the relatively sealed joint cavity also causes difficulty in detection of fine particles inside a joint cavity, leading to underestimation of fine particle


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toxicities, particularly for in vitro experiments. Therefore, more in vivo experiments and new detection approaches with higher sensitivity and accuracy will be essential for resolving this issue. In real-life settings, similar to most of the other pollutants, exposure of humans to fine particles at low doses and the accumulation of these particles is a gradual and chronic process, particularly in joints. This increases the difficulty and cost of scientific research. Furthermore, it remains difficult to determine the complex chemical compositions and adsorbed pollutants of PMs, which results in great difficulty in evaluating their toxicities and underlying mechanisms. This challenge also exists while investigating the adverse effects of PMs on joints. Additionally, the use of new technologies, such as single cell RNA-seq as well as targeted and untargeted metabolomics, will facilitate revealing the dynamics of the affected processes, signaling pathways and cell states after fine-particle exposure. Moreover, some high-quality and structure-curated resources and databases could also be immensely useful to explore and further establish the connections between fine-particle exposure and OA/RA such as the CompTox Chemistry Dashboard,242 and the Aggregated Computational Toxicology Resource (ACToR).243

Global view of the mechanisms, key aspects, and future directions During induction of indirect adverse effects of fine particles on joints through systemic inflammation, infiltration of immune cells, particularly macrophages, is an early event. Activation of adaptive immune responses might be another early event, especially in RA. Subsequently, both indirect and direct adverse effects of fine particles on joints share some common events, including secretion of cytokines, synovitis, articular cartilage destruction, and apoptosis of chondrocytes (Fig. 7). With respect to the detailed molecular mechanisms, IL-1, IL-6, and TNF-α are the most provoked pro-inflammatory cytokines through the NF-κB pathway. Both Th1-type and Th2-type cytokines are also induced by fine particles. The AHR-XRE axismediated cytokine expression and Th17 cell activation are important for inducing adaptive immune responses after fine particle exposure. Secreted cytokines increase


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the release of COX and MMP enzymes from the activated synoviocytes and chondrocytes. COX and MMP enzyme-mediated matrix degradation and apoptosis of chondrocytes are the main subsequent outcomes. Most fine particles also cause direct detrimental effects on MSCs by enhancing proliferation, undermining the capabilities of osteogenesis and chondrogenesis, and inhibiting the mineralization potential and matrix formation of MSCs. Furthermore, IL-6 plays a pivotal role in incorporating several fine particle-induced complications (diabetes, obesity, disordered iron metabolism, and anemia) related to joint damage and arthritis.

Figure 7. A global view of fine particle-induced adverse effects on joints and the corresponding mechanisms. After pulmonary and systemic inflammation induced by exposure to fine particles, infiltration of immune cells, particularly macrophages, into joints serves as an early event to trigger the indirect detrimental effects of fine particles on joints and their surrounding cells. Mechanistically, cytokines, in particular IL-1, IL-6, and TNF-α, secreted by the infiltrated immune cells via the NF-κB pathway induce the expression and secretion of


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COX and MMP enzymes from synoviocytes and chondrocytes. Secreted COXs and MMPs cause matrix degradation. Meanwhile, chondrocyte apoptosis is induced by cytokines. Fine particle can also activate adaptive immune responses through the AHR-XRE axis to promote cytokine expression and Th17 cell activation, which might be involved in the above process. On the other hand, fine particles can penetrate into joint cavity to induce direct toxicities on MSCs, including enhanced proliferation, undermined capabilities of osteogenesis and chondrogenesis, and inhibited mineralization potential and matrix formation of MSCs. Direct exposure to fine particle also causes chondrocyte apoptosis via ROS- and mitochondrial mechanisms. Furthermore, IL-6 incorporates several fine particle-induced complications with the toxicities in joints.

Thus, infiltrated macrophages and secreted cytokines (IL-1, IL-6, and TNF-α) would be the key molecules to interrogate the initiation events. Placing the focus on COX and MMP enzyme-mediated matrix destruction would help unveil the complex regulatory mechanisms underlying the subsequent events that are responsible for the final adverse effects of fine particles on joints and their surrounding cells. Understanding the toxicities in chondrocytes and MSCs in the presence of fine particleinduced systemic and local inflammation would be another key aspect. Such an investigation is warranted in the future. In summary, the adverse effects of fine-particle exposure (both PMs and ENPs) on joints and their surrounding cells through systemic and local inflammatory responses have been well established. Although some underlying mechanisms have been proposed (Fig. 7), the understanding on the involved processes and regulatory network is still limited. Furthermore, many issues exist in this field as discussed above as follows: insufficient epidemiological studies regarding the detrimental effects of both PMs and ENPs on joints; inadequate toxicological insight into the effects on joints directly from PMs; no study on the interplay between the indirect and direct effects of fine particles on joints. Overall, the knowledge in this field is still quite preliminary. Besides the warranted studies on the key molecules (secreted cytokines, COX and MMP enzymes), investigation on the existing issues are also the future directions. In particular, research on PM-induced adverse effects on joints is the priority, including


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both

epidemiological

and

experimental

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investigations.

Strategies

targeting

dysfunctional macrophages, increased pro-inflammatory cytokines, and COX and MMP enzymes would help reduce fine particle-induced toxicities in joints and neighboring cells.

ACKNOWLEDGMENTS This work was supported by the grants from the National Natural Science Foundation of China (Grant No.: 91543124, 21425731, 21637004 and 21621064), the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB14000000), and the national “973” program (Grant No. 2014CB932000).

VOCABULARY Fine particles, also known as PM2.5, particles < 2.5 μm in diameter, which can reach the alveolar structure and subsequently travel to multiple organs; ENPs, engineered nanoparticles, a class of engineered nanomaterials that is intended for daily and commercial applications; joints, a structure to connect bones to support different various movements of body; arthritis, a common type of joint diseases characterized by

chondrocyte

apoptosis,

matrix

degradation,

hyperplasia

and

enhanced

vascularization; systemic inflammation, a chronic inflammation subsequently induced by the pro-inflammatory cytokines after local inflammation, e.g. pulmonary inflammation; leading to infiltration of immune cells in distant organs and tissues.


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