Can pain intensity in osteoarthritis joint be indicator of the impairment of endothelial function?

Medical Hypotheses 94 (2016) 15–19

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Can pain intensity in osteoarthritis joint be indicator of the impairment of endothelial function? Gordana Laskarin a,b,⇑,1, Viktor Persic c,d,1, Sandra Rusac Kukic b, Drazen Massari b,d, Anita Legovic b,d, Marko Boban c,d, Rajko Miskulin c, Marija Rogoznica b, Tatjana Kehler b,d,e a

Department of Physiology and Immunology, Medical Faculty, University of Rijeka, 51000 Rijeka, B. Branchetta 20, Croatia Department of Rheumatology, Rehabilitation, and Physical Medicine, Hospital for Medical Rehabilitation of Hearth and Lung Diseases and Rheumatism ‘‘Thalassotherapia-Opatija”, 51410 Opatija, M. Tita 188, Croatia c Division of Cardiology, Hospital for Medical Rehabilitation of the Hearth and Lung Diseases and Rheumatism ‘‘Thalassotherapia – Opatija”, 51410 Opatija, M. Tita 188, Croatia d Department of Medical Rehabilitation, Medical Faculty, University of Rijeka, 51000 Rijeka, B. Branchetta 20, Croatia e Department of Physiotherapy, Faculty of Health Studies, University of Rijeka, 51000 Rijeka, V. cara Emina 5, Croatia b

a r t i c l e

i n f o

Article history: Received 4 March 2016 Accepted 2 June 2016

Keywords: Interleukin-1 Interleukin-15 Interleukin-17 Monocyte chemotactic protein-1 Endothelial dysfunction Osteoarthritis

a b s t r a c t We propose that pathological remodeling in joint tissues of osteoarthritis (OA) patients persistently stimulates local secretion of pro-inflammatory mediators, which overflow into the blood, activating leukocytes that impair endothelial function and accelerate the atherosclerotic process. During periods of pain, endothelial dysfunction progresses more aggressively due to elevated secretion of these proinflammatory mediators, which are involved in both atherosclerosis and the sensation of pain. Concentrations of pro-inflammatory cytokines and their antagonists, activating and decoy receptors of the broad interleukin (IL)-1 and IL-17 families, IL-15, and monocyte chemotactic protein-1 should be measured in peripheral blood samples of OA patients and compared with (I) OA clinical severity; (II) subclinical parameters of atherosclerosis; (III) ischemic heart disease risk factors; (IV) soluble factors indicating endothelial dysfunction; (V) degree of bone destruction; and (VI) results of a six-minute walk test. Arthroscopy and joint replacement surgery provide an opportunity to estimate mRNA and protein expression of inflammatory mediators in specimens of synovial fluid, synovial membrane, cartilage, and/or subarticular bone. A range of methods, including questionnaires, X-ray, computed tomography, ultrasound, enzyme-linked immunosorbent assay, immunohistology, immunofluorescence, and reverse transcription and in situ polymerase chain reaction are available. Understanding the inflammatory and immune mechanisms underlying OA may allow the early identification of patients at high risk of cardiovascular disease, independently of classical coronary risk factors. Pain may constitute an extrinsic indicator of currently worsening endothelial function. Ó 2016 Elsevier Ltd. All rights reserved.

Introduction Osteoarthritis (OA), the most common chronic disease affecting all joint tissues, comprises gradual progressive degradation of cartilage by chondrocyte action, secondary synovial membrane inflammation, and subchondral bone changes [1]. Pain is the leading symptom of OA and is produced by repeated or spatially clustered irritation of unmyelinated and small myelinated fibers in the joint capsule, ligaments, synovium, bone, and outer edges of the knee menisci [2]. In addition to pain, stiffness and reduced ⇑ Corresponding author at: Department of Physiology and Immunology, Medical Faculty, University of Rijeka, 51000 Rijeka, B. Branchetta 20, Croatia. E-mail address: [email protected] (G. Laskarin). 1 Gordana Laskarin and Viktor Persic equally participate in writing the manuscript. http://dx.doi.org/10.1016/j.mehy.2016.06.001 0306-9877/Ó 2016 Elsevier Ltd. All rights reserved.

range of motion result, with ultimate loss of joint function [3]. In OA patients, there is a positive correlation between pain intensity and functional limitations [4]. Moreover, pain can be positively associated with cartilage and bone destruction, as recognized by radiographic changes in joints [5]. However, in some individuals, this close connection between joint damage and pain is not observed, suggesting that other factors participate in determining OA clinical manifestations [6]. Primary OA is a disease of unknown pathogenesis, while secondary OA usually occurs following intraarticular fracture, soft tissue weakness, or congenital or developmental anomalies, where joint impairment is chiefly determined by mechanical causes rather than inflammation [3]. Neuropathic diseases, noninfectious inflammatory rheumatic diseases, joint infection, and

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epiphysitis induce secondary OA with a greater degree of inflammation. Biochemical, metabolic, and endocrine imbalances [3], together with immutable factors such as age, sex, and family history [7,8], encourage the progression of primary and secondary OA by systemic [3] and local pro-inflammatory pathways [9]. Studies in various experimental models and human tissues have illustrated the potential importance of cytokine balance in local tissue changes during the development of OA [1,10,11]. Lately, the nature of systemic inflammation of varying degrees of severity has also been acknowledged in OA patients [3,8], and many similarities have been found in the immune cell profiles of patients with OA and those suffering rheumatoid arthritis (RA), representing typical inflammatory rheumatic disease [11,12]. According to serum and/or local joint cytokine and chemokine profiles, interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor alpha (TNF-a), IL-12, IL-15, IL-17, IL-18, and monocyte chemotactic protein-1 (MCP-1) have been recognized as mediating both RA [11,13] and OA [1,14–16]. Members of the large IL-1 family, including IL-1b and IL-18, play pivotal roles in the initiation of inflammation and immunity by regulating innate immune cell functions and affecting the differentiation and activity of IL-1b-polarized T lymphocytes [17]. In OA-affected joints, increased numbers of IL-1b- and IL-18expressing cells are found, including synoviocytes, chondrocytes, and osteocytes [1,15]. Both of these cytokines suppress aggrecan synthesis and collagen type II-deposition by inhibition of both mitogen-activated protein (MAP) kinase and caspase-3 activation in chondrocytes [18]. In addition, they are capable of stimulating production of matrix metalloproteinases (MMP)-1, -3, and -13 by activation of the transcription factor nuclear factor kappa B (NFjB) [1], inducing catabolic reactions in cartilage. Importantly, IL-1b also stimulates secretion of pro-inflammatory factors in joint tissue, including the cytokines TNF-a, IL-6, and IL-8, and chemokine (C-C motif) ligand 5, while inhibiting the anti-inflammatory transforming growth factor beta (TGF-b) signaling pathway [1]. Elevated IL-6 levels are associated with pain, fatigue, and depression [7,16,19], while IL-8 is involved in the amplification of pain [20]. TNF-a increases the likelihood of damage to joint cells and structure [1] by cell-mediated cytotoxicity [21], and its elevated levels in serum due to pain [1] may cause major depressive disorder [19] in OA patients. IL-18 also promotes the secretion of harmful TNF-a, and the production of cyclooxygenase-2 and prostaglandin E2 in synoviocytes and chondrocytes [22]. Changes mediated by the action of IL-1b, IL-18, and TNF-a induce rapid aging and apoptosis of chondrocytes, accompanied by pain [18]. The local inflammatory conditions in OA joints also encourage secretion of the chemokine MCP-1 in chondrocytes and synovial fibroblasts in an autocrine manner [23]. MCP-1 is highly chemotactic for inflammatory CC chemokine receptor type 2-positive immune effectors, principally monocytes, but also CD4+ and CD8+ T, natural killer (NK), and dendritic cells [24], probably participating in their recruitment to the synovia, sustaining inflammation and pain in the affected joint [20]. Indeed, a chronic progressive immune response in OA patients has been confirmed by the presence of infiltrating immune cells in the synovial membrane [25]. T cells and their Th1-oriented CD4+ subset are less numerous in joints of OA patients than in those affected by RA, but show similar activation marker expression [11]. Pro-inflammatory IL-15 is elevated in synovial fluid and synovial membranes in early knee OA [14], suggesting that this cytokine could be responsible for the observed local neovascularization, and chemotaxis, specific in situ activation of T and NK cells. Indeed, this has been demonstrated during the mild pro-inflammatory response in early-pregnancy decidua [26], and in viable cardiomyocytes surrounding a necrotic infarction zone [27]. IL-15 increases mRNA and protein expression of perforin,

Fas ligand [28], and granulysin, even in early-pregnancy tolerogenic uterine NK cells, and increases their cytotoxicity [29]. This suggests that tissue-infiltrating NK cells might harm chondrocytes and other joint tissue cells in OA patients, causing pain. The IL-17 family, which includes proteins with inflammatory properties, has also been found to participate in joint destruction in OA patients [13]. IL-17 stimulates the expression of many inflammatory biomarkers, such as IL-1, IL-6, TNF-a, chemokine (C-X-C motif) ligand 1, MCP-1, IL-8, MMP-1, MMP-3, MMP-9, and C-reactive protein, promoting recruitment of neutrophils, T cells, and monocytes to sites of local inflammation in proportion to pain intensity [30]. However, clinical analysis of ongoing immune processes in OA joints is problematic, due to the lack of their specific and sensitive biomarker and the largely unknown immune pathogenesis of this disease. Hypothesis We propose that persistent pathological remodeling and destruction of joint tissues (synovial membrane, cartilage, and bones) in OA patients stimulates local production and secretion of pro-inflammatory mediators, such as cytokines, chemokines, and/or growth factors, which overflow into the blood in proportion to pain severity, and accordingly engender a systemic inflammatory milieu. In such circumstances, specific peripheral blood lymphocyte subsets become activated, and may impair endothelial function independently or in concert with classical metabolic risk factors to accelerate the atherosclerotic process underlying cardiovascular diseases. During periods of pain, endothelial dysfunction may progress faster and more aggressively due to a greater abundance of pro-inflammatory mediators, which play roles in both atherosclerosis and sensation of pain in the affected joint. Hence, the pain experienced by OA patients may constitute a key indicator for currently worsening endothelial function due to the following considerations: (I) prolonged duration and/or intensity of pain correlates with pro-inflammatory IL-1b and IL-6 levels in acute myocardial infarction [31]; (II) disuse of joints due to pain increases levels of pro-inflammatory cytokines [9]; (III) pain leads to a tendency for abdominal obesity owing to reduction of daily activity, fostering a strong pro-inflammatory microenvironment mediated by IL-1, IL-6, IL-8, and TNF-a, and added mechanical stress [32]; (IV) the increase in primary OA incidence with age is associated with elevated production of pro-inflammatory cytokines [9]; and (V) heightened pain intensity is connected to greater anxiety and depressive episodes, which have been found to be mediated by the inflammatory cytokines IL-1, TNF-a, IL-6, and IL18, and soluble IL-2 receptor in individuals not exhibiting overt inflammation [19,33]. Endothelial dysfunction and OA may be two sides of the same coin, consisting of the dominance of proover anti-inflammatory cytokines. Evaluation of hypothesis The most suitable subjects for examination would be patients with knee OA. OA of the knee joint, a common site of this condition, causes severe pain and demonstrates the most adverse effects on functional status [34] in accordance with its location and the natural course of the disease. Approximately 80% of patients with knee OA exhibit limitations in movement, 25% cannot participate in daily activities, and 11% need help in personal care [35]. Pain in this joint should be assessed in OA patients using (I) a visual analog scale of pain and the Western Ontario and McMaster Universities Arthritis Index questionnaire, designed to assess clinical severity of the disease based on assessment of pain, stiffness, and function in everyday life [36]; and (II) the Short Form-36 Health Survey, a

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patient-reported health assessment [37] consisting of eight subscales: vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health. In addition, using peripheral blood samples from OA patients, concentrations of pro-inflammatory cytokines, their antagonists, and the expression of their activating and decoy receptors, particularly of the broad IL-1 and IL-17 families, IL-15, and MCP-1, should be measured and compared with (I) subclinical parameters of atherosclerosis such as (a) central arterial stiffness determined by carotid-femoral pulse wave velocity measured by simultaneous ultrasound and applanation tonometry, flow-mediated dilation following cold-water hand immersion, or after ergospirometry; (b) coronary artery calcium content estimated by Agatson score, or possibly using a non-invasive technique for detection of coronary stenoses such as multislice computed tomography, depending on clinical indications; (c) carotid artery parameters, including intima/media thickness ratio, flow velocity, and degree of stenosis; and (d) assessment of abdominal arteries, such as the abdominal aorta and renal and common iliac arteries by ultrasound or angiography; (II) cardiovascular risk assessed by the Framingham Risk Score, based on age, sex, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, and smoking, or Systematic Coronary Risk Evaluation, which employs high and low risk charts; (III) soluble indicators of endothelial dysfunction, such as MMP-1, MMP-4, MMP-9, vascular cell adhesion molecule 1, von Willebrand factor (vWF), heat shock protein 90, endothelial nitric oxide synthase, and vascular endothelial growth factor alpha; (IV) the degree of bone destruction estimated by X-ray of the affected joint; and (V) results of a six-minute walk test. In the later stages of OA, it is possible to sample various tissues during surgical replacement of the joint. Using synovial fluid and biopsy specimens of synovial membrane, cartilage, and subarticular bone, mRNA and protein expression of IL-1 and IL-17 family members, IL-15, and MCP-1 can be quantitatively or semiquantitatively estimated by enzyme-linked immunosorbent assay, immunohistology, immunofluorescence, or reverse transcription or in situ polymerase chain reaction. The results of such tests could be correlated with pain intensity parameters, cytokine and chemokine concentrations in peripheral blood, and the abovementioned indicators of endothelial dysfunction and subclinical signs of atherosclerosis. Aging and pro-inflammatory comorbidities should always be taken into consideration. Consequences of the hypothesis and discussion Mediators of the pro-inflammatory immune reaction (cytokines and chemokines) are greatly involved in the pathogenesis of OA according to many research groups [3,8,9,16]. However, the relationship between OA-related pain intensity and cytokine production or secretion at local and systemic levels is largely unknown, although elevated levels of proinflammatory cytokines are involved to some degree in OA progression and pain [16]. Inflammation lowers the threshold for nociception [2], and the resulting pain disrupts sleep, causes fatigue, anxiety, and depressive episodes [6], and significantly reduces quality of life [38,19]. Cytokines that mediate low mood states and aversion to activity [IL-1, TNF-a, IL-6, and IL-18] are actively transported into the brain by endothelial cell transporters or diffuse through blood-brain barrier-deficient areas [21]. The extent to which they amplify and maintain clinical pain, and their role in central sensitization in the form of hyperexcitability in nociceptive pathways is currently under investigation [6]. In approximately 90% of patients, OA coexists with diseases and conditions associated with advanced age, such as endothelial dysfunction. This latter is the basis of atherosclerosis, with its

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diverse clinical manifestations, including arterial hypertension and myocardial infarction [39]. IL-17, interferon (IFN)-c, TNF-a, and IL-6 are released from activated T cells in hypertensive patients and promote vascular dysfunction [40]. These same proinflammatory cytokines are also involved in the pathogenesis of OA, and together with MCP-1, are expressed abundantly in joint tissues [1]. MCP-1 is also increased in the plasma of patients at high risk of cardiovascular disease [41], and those having suffered acute myocardial infarction [42]. This chemokine recruits monocytes and promotes their maturation in the arterial wall during the early inflammatory phase after acute myocardial infarction [43], inducing them to secrete IL-1 and IL-6 [15]. Similarly, IL-1b has been detected in the myocardium directly after a heart attack, and its serum levels have been observed to increase within the first few hours following onset of chest pain [31]. This cytokine is also released from synovial chondrocytes and osteocytes and is found in the peripheral blood of OA patients [1,44]. These data support our reasoning that changes at the systemic level might reflect local events relating to myocardial infarction [27] and OA. Soluble factors in circulation directly affect reciprocal cell-cell interaction and have the ability to activate innate and acquired cellmediated immune responses, regardless of their tissue of origin. It is of particular importance that during activation, lymphocytes multiply, express cytotoxic mediators [27,45,46], and secrete cytokines [16,1], potentially leading to harmful immune activity directed toward cells at sites of inflammation after recruitment into the tissue, such as in atheroma [42]. The significance of this process is supported by the fact that local T lymphocyte activity greatly determines atherosclerotic plaque rupture, in which activated T cells kill smooth muscle cells by TNF-related apoptosisinducing ligand (TRAIL)-mediated apoptosis [47]. The efficient binding of IL-18 by T lymphocytes is brought about by the increased expression of its receptor induced by IL-12. IFN-c production by these cells is then strongly enhanced [17]. IL-18 also increases the production of IL-1b, IL-8, and TNF-a [48], and in conjunction with IL-6, contributes to plaque instability and causes pain [7,15,16]. Moreover, it can exacerbate the inflammatory response within the myocardium during unstable angina and acute myocardial infarction [49]. In the serum of conservatively treated patients with non-ST elevation myocardial infarction (NSTEMI), higher levels of IL-18 are evident during the month following the acute coronary event. This is in comparison to patients with STEMI, in whom the inflammatory response is significantly decreased by primary percutaneous coronary intervention (our unpublished data). In OA patients, high serum levels of IL-18 promote overexpression of this same cytokine in synovial fluid and articular chondrocytes. Its concentration also correlates with the radiographic severity of OA [15], possibly due to lymphokine-activated killing mediated by recruited lymphocytes. In peripheral blood, 90% of CD3 CD56+dim NK cells show strong killing capacity and are able to colonize inflamed tissue, such as atherosclerotic plaque [50]. Pro-inflammatory MCP-1 [24] and IL15 [51] direct NK cells towards locally thickened intima during the formation of early atherosclerotic lesions. The same mechanism may be active in OA patients, as MCP-1 [23] and IL-15 [25] are present in chondrocytes and the synovial membrane, where they induce inflammation-related pain [20]. NK cells are the predominant synovia-infiltrating lymphocytes in affected joints. They have the ability to be further activated at inflammatory sites, including atheroma and infarcted myocardium, by the same stimulating factors, and to kill target cells without prior sensitization using perforin, granulysin, or cytotoxic mediators of the TNF protein family (Fas ligand, TNF-a, and TRAIL) [26,27,46,52–54]. According to our previous results, compared to healthy controls, the numbers of CD56+bright NK cells and cytotoxic CD8+ T cells are significantly reduced in the peripheral blood of conservatively

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treated patients during the second week after NSTEMI [27]. NKT cells, which produce immune-regulatory cytokines, are generally less cytotoxic, but are able to participate in the killing of target cells after stimulation by IL-15, IL-18, IL-12, and IL-2 during the pro-inflammatory response [53]. In apolipoprotein E-knockout mice, the classical model of atherosclerosis, neutralizing anti-IL17 antibody reduces early plaque lesions and stabilizes plaque [55], confirming the pro-atherogenic effects of IL-17. In patients with acute coronary syndrome (ACS), the number of circulating Th17 cells is elevated, and increased serum concentration of IL17 correlates positively with that of IL-6 and negatively with TGF-b [56]. IL-17 also promotes the secretion of vWF by endothelial cells and induces their apoptosis, which may be involved in ACS pathogenesis in humans [56]. However, low serum levels of IL-17 have been independently associated with all-cause mortality and recurrent myocardial infarction [57]. IL-17A-producing mast cells, CD3+CD4+ Th17 cells, NK cells, and antigen-presenting cells [58] that infiltrate the synovial membrane support the recruitment to local sites of inflammation of neutrophils, which negatively affect cartilage structure and function [22]. Moreover, IL-17 receptors A and C are abundantly expressed on chondrocytes, fibroblasts, and endothelial cells [15], which bind IL-17A, and activate NF-jB and MAP kinase pathways to produce pro-inflammatory mediators, such as IL-1b, IL-6, IL-8, TNF-a, MCP-1, and MMPs, involved in the pathogenesis of both OA and atherosclerosis [30]. It is therefore of relevance to investigate the involvement and mechanism of action of pro-inflammatory, pain-inducing, jointdestructive, and OA-related circulating cytokines and chemokines in endothelial dysfunction. Understanding the inflammatory mechanisms and immune regulation underlying OA might allow early identification of patients at high risk of cardiovascular disease, independently of classical coronary risk factors and erythrocyte sedimentation rate and high sensitive C-reactive protein. A preponderance of inflammatory cytokines in circulation seems to be atherogenic, regardless of their tissue of origin. Our hope is that greater comprehension of this process will result in better targeted clinical treatment and care for OA patients, who currently suffer a significantly impaired quality of life. Conflict of interest statement We as the authors of the manuscript disclose any financial and personal relationships with other people or organizations that could inappropriately influence our work in respect of employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. Acknowledgments The preliminary experiments supporting this hypothesis were financed by Hospital for Medical Rehabilitation of the Hearth and Lung Diseases and Rheumatism ‘‘Thalassotherapia- Opatija”, Opatija, Croatia. We would like to thank Editage (www.editage. com) for English language editing. References [1] Wojdasiewicz P, Poniatowski ŁA, Szukiewicz D. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediators Inflammation 2014;2014:561459. [2] Felson DT. The sources of pain in knee osteoarthritis. Curr Opin Rheumatol 2005;17:624–8. [3] Malemud CJ. Biologic basis of osteoarthritis: state of the evidence. Curr Opin Rheumatol 2015;27:289–94. [4] Miller GD, Nicklas BJ, Loeser RF. Inflammatory biomarkers and physical function in older, obese adults with knee pain and self-reported osteoarthritis after intensive weight-loss therapy. J Am Geriatr Soc 2008;56:644–51.

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