- Email: [email protected]
Initiating pain in osteoarthritis (OA): is it the mast cell?
Accepted Manuscript Initiating pain in osteoarthritis: is it the mast cell? A. Ioan-Facsinay PII:
S1063-4584(17)31245-1
DOI:
10.1016/j.joca.2017.10.005
Reference:
YJOCA 4098
To appear in:
Osteoarthritis and Cartilage
Received Date: 2 October 2017 Accepted Date: 9 October 2017
Please cite this article as: Ioan-Facsinay A, Initiating pain in osteoarthritis: is it the mast cell?, Osteoarthritis and Cartilage (2017), doi: 10.1016/j.joca.2017.10.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Initiating pain in osteoarthritis: is it the mast cell?
2
A.Ioan-Facsinay
3 4 5 6 7 8 9
Address correspondence to: Andreea Ioan-Facsinay Department of Rheumatology, Leiden University Medical Centre P.O. Box 9600, 2300 RC Leiden, The Netherlands Tel: +31-71-5264665 E-mail: [email protected]
RI PT
ACCEPTED MANUSCRIPT
Mast cells are myeloid cells present in low numbers in most connective tissues in the body. Although mostly investigated in relationship with type 2 immune responses such as parasitic infections and allergic diseases, mast cells are versatile cells involved in various physiological and pathological conditions. The physiological role of mast cells includes regulation of angiogenesis, vasodilation, vascular permeability and protection against various pathogens 1. However, they have also been involved in inflammatory pathologies of the lung, intestine, adipose tissue and joint 2. Their pleiotropic function relies on their capacity to secrete a large number of soluble mediators that can in turn target a variety of cells, including several innate and adaptive immune cells, endothelial cells, fibroblasts and other somatic cells. Mast cells possess the unique ability to release pre-formed soluble mediators, such as histamine, heparine, proteases, various cytokines that are stored in intracellular granules, thereby initiating a cascade of events leading to full-blown inflammation. Besides this quick response, mast cells can also synthesize several cytokines, chemokines and lipid mediators such as prostaglandins and leukotrienes de novo, which can modulate ongoing inflammatory responses. The response of the mast cell is determined by the activating stimulus. For example, activation through the IgE receptor, FcɛRI, or through complement receptor C5aR induces degranulation followed by de novo synthesis and release of other soluble mediators, while activation through toll-like receptors (TLR) does not induce degranulation 3.
27 28 29 30 31 32
Mast cells are derived from hematopoietic precursors that enter the tissue and develop into mature mast cells under the influence of stem cell factor and other growth factors secreted by local tissue resident cells. In the human synovium, between 1-5% of all hematopoietic cells are typically mast cells 4 5. Although synovial mast cells are present in low numbers in healthy individuals, they are enriched in certain pathological conditions such as rheumatoid arthritis (RA) and osteoarthritis (OA) 4 .
33 34 35 36 37 38 39 40 41
The role of synovial mast cells in osteoarthritis is largely unknown. However, the presence of mast cell-derived factors, such as histamine, in the synovial fluid of OA patients indicates their activation and their potential involvement in the disease 6. Moreover, their abundance correlates with the degree of synovial inflammation and is associated with more structural damage 7. Studies in mice showed that proteinase-activated receptor 2 (PAR2)-deficient mice are protected against osteoarthritis-related pain, cartilage degradation and osteophyte formation in the destabilization of medial meniscus (DMM) model of OA in mice 8. Because mast cells are a rich source of proteases that can activate PAR2 receptor, these data support the hypothesis that mast cells could contribute to pain and structural damage in osteoarthritis.
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ACCEPTED MANUSCRIPT In the current issue of Osteoarthritis and Cartilage, Sousa-Valente and colleagues 9 offer further insights into the possible contribution of mast cells to pain in OA. The authors used genetically modified mice carrying a mutated form of the TrkA receptor rendering them more sensitive to nerve growth factor (NGF) signalling. This mutation has no consequences on mechanical pain perception, but leads to an increase in the number of dorsal root ganglia neurons. Induction of osteoarthritis by intra-articular injection of monoiodoacetate (MIA) results in an increased mechanical hypersensitivity and hyperactivation of the neurons and microglia in the spinal cord of the mutated mice (TrkA KI mice) compared to wild-type mice. Blocking NGF signalling using a tanezumab-like antibody (i.e. anti-NGF) significantly reduced the mechanical hypersensitivity, confirming that the NGF-TrkA axis is involved in this pain response. In order to investigate the possible contribution of synovial inflammation to this process, the authors characterized the inflammatory cell composition of the synovium in TrkA KI or wild-type mice. Although synovial volume was similarly increased in the mutant and wild-type mice upon MIA induction, the expression of the calcitonin gene-related peptide (CGRP) in the dorsal root ganglia neurons, which can be induced by peripheral inflammation, was higher in the mutant mice compared to wild-type mice both in the untreated and MIA joints. Indeed, a more detailed analyses of synovial inflammation showed a higher number of inflammatory cells present in the MIA joints of TrkA KI mice than wild-type joints. This was also reflected by a higher number of macrophages and mast cells. Interestingly, the number of mast cells in the vicinity of nociceptive fibres was higher both in control and MIA joints of TrkA KI mice compared to wildtype mice, indicating that the presence of the mutant TrkA receptor is associated with a stronger clustering of mast cells with nerve fibres in the synovium and this is even more increased upon MIA administration.
64 65 66 67 68 69 70 71 72 73 74
These results prompted the authors to further investigate the interaction between mast cells and nociceptive fibres, in particular the hypothesis that NGF can stimulate mast cells to secrete mediators that can sensitise nociceptive fibres. Using a model mast cell line, the authors showed that NGF can increase prostaglandin D2 (PGD2) release upon FcɛRI-mediated activation. The release of PGD2 was dependent on cytoplasmic phospholipase A2 (cPLA2) and cPLA2 was involved in upregulation of cyclooxygenase 2 (COX-2). In vivo, increased concentrations of PGD2 were observed in synovial fluid of MIA TrkA KI knees compared to MIA wild-type knees. The relevance of PGD2 for the mechanical hypersensitivity observed in TrkA KI mice was further confirmed using a PGD2 synthase inhibitor in vivo. At lower concentrations, this inhibitor was more effective in the mutant mice than in wild-type mice both at reducing PGD2 levels in affected joints and in reducing mechanical hypersensitivity.
75 76 77 78 79 80 81 82 83 84
Collectively, the data presented in the article support a contribution of mast cells to pain in osteoarthritis in the MIA model and indicate PGD2 as effector molecule. Interestingly, recent findings in two other models of osteoarthritis in mice, age-induced and destabilization of the medial meniscus (DMM) models of osteoarthritis, indicated that mice deficient in DP1, one of the receptors for PGD2, showed increased progression of structural damage 10. The authors did not report any effects on pain. These seemingly contrasting data add to the wealth of evidence that PGD2 can have both pro- and anti-inflammatory actions mediated by at least two distinct receptors, DP1 (antiinflammatory) and DP2 (pro-inflammatory). They also indicate that one has to be cautious in targeting PGD2, as it can have contrasting effects on disease-specific outcomes, and that targeting PGD2 receptors instead could be a more refined therapeutic approach.
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ACCEPTED MANUSCRIPT Several interesting questions remain, however, to be addressed. One of the most important is whether PGD2 is indeed secreted in OA and can be detected in synovial fluid of OA patients and whether synovial mast cells from OA patients can be a source of PGD2. Current data does not report the presence of PGD2 in OA patients, although it has been reported in RA serum and synovial cells 11. However, human mast cells are known to secrete PGD2, depending on their activating stimulus. As the authors used a cell line and IgE-antigen immune complexes as model stimulus in vitro, the question remains which stimuli present in OA synovial joint could activate synovial mast cells to secrete PGD2. Thus far, IgE, bacterial components, stem cell factor (SCF) and leukotriene E4 (LTE4) have been shown to induce PGD2 in human mast cells 3. Of these, only SCF has been reported in the OA synovium 12 and its involvement in the pathophysiology of OA remains to be determined. Moreover, as local tissue-derived factors are involved in the full differentiation of mast cells, it is conceivable that mast cells residing in various tissues are different and have a different response to stimuli. It would therefore be important to study specifically synovial mast cells and their response to stimuli present in the joint for a better understanding of their role in disease.
99 100 101 102 103 104 105 106 107
Besides PGD2, mast cells can secrete other bioactive molecules that could be involved in mechanical hypersensitivity. One of the most prominent ones is TNFα, which is stored in mast cells granules and could be released upon degranulation. As the presented data suggests the involvement of NGF in mast cells activation, one would expect an increase in mast cell degranulation upon MIA injection in the TrkA KI mice compared to wild-type, potentially resulting in increased TNFα levels and nociceptive sensitisation 13. Alternatively, other soluble factors released during degranulation, such as histamine, or at later phases of mast cells activation could also be involved in nociceptive sensitisation 14. The importance of degranulation in mechanical hypersensitivity remains to be determined.
108 109 110 111 112 113 114 115 116 117
The contribution of other immune cells to NGF-mediated pain should also receive attention in future studies. Although the authors focused on mast cells, they also described increased macrophage numbers in the TrkA KI mice in the MIA knees. Because both murine and human macrophages express TrkA and are responsive to NGF stimulation 15 16 and because they have been previously involved in mechanical hyperalgesia in models of neuropathic pain 14, their involvement in pain sensitisation in OA is a promising avenue for future research. Studies investigating the contribution of individual immune cells to development and progression of OA are warranted for a full understanding of the role of inflammation in the disease process. Mice genetically modified to lack specific cell-types represent an exquisite tool to investigate the contribution of various cells to OA pathogenesis.
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Acknowledgments: This work was supported by the Dutch Arthritis Foundation (LLP-24) and the IMI JU funded project BeTheCure (115142-2).
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The author has no conflicts of interest.
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ACCEPTED MANUSCRIPT 124 125 126 References
128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169
1. Urb M, Sheppard DC. The role of mast cells in the defence against pathogens. PLoS Pathog 2012;8(4):e1002619. doi: 10.1371/journal.ppat.1002619 2. Krystel-Whittemore M, Dileepan KN, Wood JG. Mast Cell: A Multi-Functional Master Cell. Front Immunol 2015;6:620. doi: 10.3389/fimmu.2015.00620 3. Yu Y, Blokhuis BR, Garssen J, et al. Non-IgE mediated mast cell activation. Eur J Pharmacol 2016;778:33-43. doi: 10.1016/j.ejphar.2015.07.017 4. de Lange-Brokaar BJ, Ioan-Facsinay A, van Osch GJ, et al. Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review. Osteoarthritis Cartilage 2012;20(12):1484-99. doi: 10.1016/j.joca.2012.08.027 5. Klein-Wieringa IR, de Lange-Brokaar BJ, Yusuf E, et al. Inflammatory Cells in Patients with Endstage Knee Osteoarthritis: A Comparison between the Synovium and the Infrapatellar Fat Pad. J Rheumatol 2016;43(4):771-8. doi: 10.3899/jrheum.151068 6. Buckley MG, Walters C, Wong WM, et al. Mast cell activation in arthritis: detection of alpha- and beta-tryptase, histamine and eosinophil cationic protein in synovial fluid. Clin Sci (Lond) 1997;93(4):363-70. 7. de Lange-Brokaar BJ, Kloppenburg M, Andersen SN, et al. Characterization of synovial mast cells in knee osteoarthritis: association with clinical parameters. Osteoarthritis Cartilage 2016;24(4):664-71. doi: 10.1016/j.joca.2015.11.011 8. Huesa C, Ortiz AC, Dunning L, et al. Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology. Ann Rheum Dis 2016;75(11):1989-97. doi: 10.1136/annrheumdis-2015-208268 9. Sousa-Valente J, Calvo L, Vacca V, et al. Role of TrkA signalling and mast cells in the initiation of osteoarthritis pain in the monoiodoacetate model. Osteoarthritis Cartilage 2017 doi: 10.1016/j.joca.2017.08.006 10. Ouhaddi Y, Nebbaki SS, Habouri L, et al. Exacerbation of Aging-Associated and Instability-Induced Murine Osteoarthritis With Deletion of D Prostanoid Receptor 1, a Prostaglandin D2 Receptor. Arthritis Rheumatol 2017;69(9):1784-95. doi: 10.1002/art.40160 11. Brouwers H, von Hegedus J, Toes R, et al. Lipid mediators of inflammation in rheumatoid arthritis and osteoarthritis. Best Pract Res Clin Rheumatol 2015;29(6):741-55. doi: 10.1016/j.berh.2016.02.003 12. Ceponis A, Konttinen YT, Takagi M, et al. Expression of stem cell factor (SCF) and SCF receptor (ckit) in synovial membrane in arthritis: correlation with synovial mast cell hyperplasia and inflammation. J Rheumatol 1998;25(12):2304-14. 13. Sorkin LS, Xiao WH, Wagner R, et al. Tumour necrosis factor-alpha induces ectopic activity in nociceptive primary afferent fibres. Neuroscience 1997;81(1):255-62. 14. Ren K, Dubner R. Interactions between the immune and nervous systems in pain. Nat Med 2010;16(11):1267-76. doi: 10.1038/nm.2234 15. Susaki Y, Shimizu S, Katakura K, et al. Functional properties of murine macrophages promoted by nerve growth factor. Blood 1996;88(12):4630-7. 16. Williams KS, Killebrew DA, Clary GP, et al. Differential regulation of macrophage phenotype by mature and pro-nerve growth factor. J Neuroimmunol 2015;285:76-93. doi: 10.1016/j.jneuroim.2015.05.016
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S1063-4584(17)31245-1
DOI:
10.1016/j.joca.2017.10.005
Reference:
YJOCA 4098
To appear in:
Osteoarthritis and Cartilage
Received Date: 2 October 2017 Accepted Date: 9 October 2017
Please cite this article as: Ioan-Facsinay A, Initiating pain in osteoarthritis: is it the mast cell?, Osteoarthritis and Cartilage (2017), doi: 10.1016/j.joca.2017.10.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Initiating pain in osteoarthritis: is it the mast cell?
2
A.Ioan-Facsinay
3 4 5 6 7 8 9
Address correspondence to: Andreea Ioan-Facsinay Department of Rheumatology, Leiden University Medical Centre P.O. Box 9600, 2300 RC Leiden, The Netherlands Tel: +31-71-5264665 E-mail: [email protected]
RI PT
ACCEPTED MANUSCRIPT
Mast cells are myeloid cells present in low numbers in most connective tissues in the body. Although mostly investigated in relationship with type 2 immune responses such as parasitic infections and allergic diseases, mast cells are versatile cells involved in various physiological and pathological conditions. The physiological role of mast cells includes regulation of angiogenesis, vasodilation, vascular permeability and protection against various pathogens 1. However, they have also been involved in inflammatory pathologies of the lung, intestine, adipose tissue and joint 2. Their pleiotropic function relies on their capacity to secrete a large number of soluble mediators that can in turn target a variety of cells, including several innate and adaptive immune cells, endothelial cells, fibroblasts and other somatic cells. Mast cells possess the unique ability to release pre-formed soluble mediators, such as histamine, heparine, proteases, various cytokines that are stored in intracellular granules, thereby initiating a cascade of events leading to full-blown inflammation. Besides this quick response, mast cells can also synthesize several cytokines, chemokines and lipid mediators such as prostaglandins and leukotrienes de novo, which can modulate ongoing inflammatory responses. The response of the mast cell is determined by the activating stimulus. For example, activation through the IgE receptor, FcɛRI, or through complement receptor C5aR induces degranulation followed by de novo synthesis and release of other soluble mediators, while activation through toll-like receptors (TLR) does not induce degranulation 3.
27 28 29 30 31 32
Mast cells are derived from hematopoietic precursors that enter the tissue and develop into mature mast cells under the influence of stem cell factor and other growth factors secreted by local tissue resident cells. In the human synovium, between 1-5% of all hematopoietic cells are typically mast cells 4 5. Although synovial mast cells are present in low numbers in healthy individuals, they are enriched in certain pathological conditions such as rheumatoid arthritis (RA) and osteoarthritis (OA) 4 .
33 34 35 36 37 38 39 40 41
The role of synovial mast cells in osteoarthritis is largely unknown. However, the presence of mast cell-derived factors, such as histamine, in the synovial fluid of OA patients indicates their activation and their potential involvement in the disease 6. Moreover, their abundance correlates with the degree of synovial inflammation and is associated with more structural damage 7. Studies in mice showed that proteinase-activated receptor 2 (PAR2)-deficient mice are protected against osteoarthritis-related pain, cartilage degradation and osteophyte formation in the destabilization of medial meniscus (DMM) model of OA in mice 8. Because mast cells are a rich source of proteases that can activate PAR2 receptor, these data support the hypothesis that mast cells could contribute to pain and structural damage in osteoarthritis.
AC C
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TE D
M AN U
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10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
1
ACCEPTED MANUSCRIPT In the current issue of Osteoarthritis and Cartilage, Sousa-Valente and colleagues 9 offer further insights into the possible contribution of mast cells to pain in OA. The authors used genetically modified mice carrying a mutated form of the TrkA receptor rendering them more sensitive to nerve growth factor (NGF) signalling. This mutation has no consequences on mechanical pain perception, but leads to an increase in the number of dorsal root ganglia neurons. Induction of osteoarthritis by intra-articular injection of monoiodoacetate (MIA) results in an increased mechanical hypersensitivity and hyperactivation of the neurons and microglia in the spinal cord of the mutated mice (TrkA KI mice) compared to wild-type mice. Blocking NGF signalling using a tanezumab-like antibody (i.e. anti-NGF) significantly reduced the mechanical hypersensitivity, confirming that the NGF-TrkA axis is involved in this pain response. In order to investigate the possible contribution of synovial inflammation to this process, the authors characterized the inflammatory cell composition of the synovium in TrkA KI or wild-type mice. Although synovial volume was similarly increased in the mutant and wild-type mice upon MIA induction, the expression of the calcitonin gene-related peptide (CGRP) in the dorsal root ganglia neurons, which can be induced by peripheral inflammation, was higher in the mutant mice compared to wild-type mice both in the untreated and MIA joints. Indeed, a more detailed analyses of synovial inflammation showed a higher number of inflammatory cells present in the MIA joints of TrkA KI mice than wild-type joints. This was also reflected by a higher number of macrophages and mast cells. Interestingly, the number of mast cells in the vicinity of nociceptive fibres was higher both in control and MIA joints of TrkA KI mice compared to wildtype mice, indicating that the presence of the mutant TrkA receptor is associated with a stronger clustering of mast cells with nerve fibres in the synovium and this is even more increased upon MIA administration.
64 65 66 67 68 69 70 71 72 73 74
These results prompted the authors to further investigate the interaction between mast cells and nociceptive fibres, in particular the hypothesis that NGF can stimulate mast cells to secrete mediators that can sensitise nociceptive fibres. Using a model mast cell line, the authors showed that NGF can increase prostaglandin D2 (PGD2) release upon FcɛRI-mediated activation. The release of PGD2 was dependent on cytoplasmic phospholipase A2 (cPLA2) and cPLA2 was involved in upregulation of cyclooxygenase 2 (COX-2). In vivo, increased concentrations of PGD2 were observed in synovial fluid of MIA TrkA KI knees compared to MIA wild-type knees. The relevance of PGD2 for the mechanical hypersensitivity observed in TrkA KI mice was further confirmed using a PGD2 synthase inhibitor in vivo. At lower concentrations, this inhibitor was more effective in the mutant mice than in wild-type mice both at reducing PGD2 levels in affected joints and in reducing mechanical hypersensitivity.
75 76 77 78 79 80 81 82 83 84
Collectively, the data presented in the article support a contribution of mast cells to pain in osteoarthritis in the MIA model and indicate PGD2 as effector molecule. Interestingly, recent findings in two other models of osteoarthritis in mice, age-induced and destabilization of the medial meniscus (DMM) models of osteoarthritis, indicated that mice deficient in DP1, one of the receptors for PGD2, showed increased progression of structural damage 10. The authors did not report any effects on pain. These seemingly contrasting data add to the wealth of evidence that PGD2 can have both pro- and anti-inflammatory actions mediated by at least two distinct receptors, DP1 (antiinflammatory) and DP2 (pro-inflammatory). They also indicate that one has to be cautious in targeting PGD2, as it can have contrasting effects on disease-specific outcomes, and that targeting PGD2 receptors instead could be a more refined therapeutic approach.
AC C
EP
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M AN U
SC
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42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63
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ACCEPTED MANUSCRIPT Several interesting questions remain, however, to be addressed. One of the most important is whether PGD2 is indeed secreted in OA and can be detected in synovial fluid of OA patients and whether synovial mast cells from OA patients can be a source of PGD2. Current data does not report the presence of PGD2 in OA patients, although it has been reported in RA serum and synovial cells 11. However, human mast cells are known to secrete PGD2, depending on their activating stimulus. As the authors used a cell line and IgE-antigen immune complexes as model stimulus in vitro, the question remains which stimuli present in OA synovial joint could activate synovial mast cells to secrete PGD2. Thus far, IgE, bacterial components, stem cell factor (SCF) and leukotriene E4 (LTE4) have been shown to induce PGD2 in human mast cells 3. Of these, only SCF has been reported in the OA synovium 12 and its involvement in the pathophysiology of OA remains to be determined. Moreover, as local tissue-derived factors are involved in the full differentiation of mast cells, it is conceivable that mast cells residing in various tissues are different and have a different response to stimuli. It would therefore be important to study specifically synovial mast cells and their response to stimuli present in the joint for a better understanding of their role in disease.
99 100 101 102 103 104 105 106 107
Besides PGD2, mast cells can secrete other bioactive molecules that could be involved in mechanical hypersensitivity. One of the most prominent ones is TNFα, which is stored in mast cells granules and could be released upon degranulation. As the presented data suggests the involvement of NGF in mast cells activation, one would expect an increase in mast cell degranulation upon MIA injection in the TrkA KI mice compared to wild-type, potentially resulting in increased TNFα levels and nociceptive sensitisation 13. Alternatively, other soluble factors released during degranulation, such as histamine, or at later phases of mast cells activation could also be involved in nociceptive sensitisation 14. The importance of degranulation in mechanical hypersensitivity remains to be determined.
108 109 110 111 112 113 114 115 116 117
The contribution of other immune cells to NGF-mediated pain should also receive attention in future studies. Although the authors focused on mast cells, they also described increased macrophage numbers in the TrkA KI mice in the MIA knees. Because both murine and human macrophages express TrkA and are responsive to NGF stimulation 15 16 and because they have been previously involved in mechanical hyperalgesia in models of neuropathic pain 14, their involvement in pain sensitisation in OA is a promising avenue for future research. Studies investigating the contribution of individual immune cells to development and progression of OA are warranted for a full understanding of the role of inflammation in the disease process. Mice genetically modified to lack specific cell-types represent an exquisite tool to investigate the contribution of various cells to OA pathogenesis.
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85 86 87 88 89 90 91 92 93 94 95 96 97 98
Acknowledgments: This work was supported by the Dutch Arthritis Foundation (LLP-24) and the IMI JU funded project BeTheCure (115142-2).
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The author has no conflicts of interest.
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ACCEPTED MANUSCRIPT 124 125 126 References
128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169
1. Urb M, Sheppard DC. The role of mast cells in the defence against pathogens. PLoS Pathog 2012;8(4):e1002619. doi: 10.1371/journal.ppat.1002619 2. Krystel-Whittemore M, Dileepan KN, Wood JG. Mast Cell: A Multi-Functional Master Cell. Front Immunol 2015;6:620. doi: 10.3389/fimmu.2015.00620 3. Yu Y, Blokhuis BR, Garssen J, et al. Non-IgE mediated mast cell activation. Eur J Pharmacol 2016;778:33-43. doi: 10.1016/j.ejphar.2015.07.017 4. de Lange-Brokaar BJ, Ioan-Facsinay A, van Osch GJ, et al. Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review. Osteoarthritis Cartilage 2012;20(12):1484-99. doi: 10.1016/j.joca.2012.08.027 5. Klein-Wieringa IR, de Lange-Brokaar BJ, Yusuf E, et al. Inflammatory Cells in Patients with Endstage Knee Osteoarthritis: A Comparison between the Synovium and the Infrapatellar Fat Pad. J Rheumatol 2016;43(4):771-8. doi: 10.3899/jrheum.151068 6. Buckley MG, Walters C, Wong WM, et al. Mast cell activation in arthritis: detection of alpha- and beta-tryptase, histamine and eosinophil cationic protein in synovial fluid. Clin Sci (Lond) 1997;93(4):363-70. 7. de Lange-Brokaar BJ, Kloppenburg M, Andersen SN, et al. Characterization of synovial mast cells in knee osteoarthritis: association with clinical parameters. Osteoarthritis Cartilage 2016;24(4):664-71. doi: 10.1016/j.joca.2015.11.011 8. Huesa C, Ortiz AC, Dunning L, et al. Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology. Ann Rheum Dis 2016;75(11):1989-97. doi: 10.1136/annrheumdis-2015-208268 9. Sousa-Valente J, Calvo L, Vacca V, et al. Role of TrkA signalling and mast cells in the initiation of osteoarthritis pain in the monoiodoacetate model. Osteoarthritis Cartilage 2017 doi: 10.1016/j.joca.2017.08.006 10. Ouhaddi Y, Nebbaki SS, Habouri L, et al. Exacerbation of Aging-Associated and Instability-Induced Murine Osteoarthritis With Deletion of D Prostanoid Receptor 1, a Prostaglandin D2 Receptor. Arthritis Rheumatol 2017;69(9):1784-95. doi: 10.1002/art.40160 11. Brouwers H, von Hegedus J, Toes R, et al. Lipid mediators of inflammation in rheumatoid arthritis and osteoarthritis. Best Pract Res Clin Rheumatol 2015;29(6):741-55. doi: 10.1016/j.berh.2016.02.003 12. Ceponis A, Konttinen YT, Takagi M, et al. Expression of stem cell factor (SCF) and SCF receptor (ckit) in synovial membrane in arthritis: correlation with synovial mast cell hyperplasia and inflammation. J Rheumatol 1998;25(12):2304-14. 13. Sorkin LS, Xiao WH, Wagner R, et al. Tumour necrosis factor-alpha induces ectopic activity in nociceptive primary afferent fibres. Neuroscience 1997;81(1):255-62. 14. Ren K, Dubner R. Interactions between the immune and nervous systems in pain. Nat Med 2010;16(11):1267-76. doi: 10.1038/nm.2234 15. Susaki Y, Shimizu S, Katakura K, et al. Functional properties of murine macrophages promoted by nerve growth factor. Blood 1996;88(12):4630-7. 16. Williams KS, Killebrew DA, Clary GP, et al. Differential regulation of macrophage phenotype by mature and pro-nerve growth factor. J Neuroimmunol 2015;285:76-93. doi: 10.1016/j.jneuroim.2015.05.016
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