The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis

Abstract

Osteoarthritis (OA), one of the most common rheumatic disorders, is characterized by cartilage breakdown and by synovial inflammation that is directly linked to clinical symptoms such as joint swelling, synovitis and inflammatory pain. The gold-standard method for detecting synovitis is histological analysis of samples obtained by biopsy, but the noninvasive imaging techniques MRI and ultrasonography might also perform well. The inflammation of the synovial membrane that occurs in both the early and late phases of OA is associated with alterations in the adjacent cartilage that are similar to those seen in rheumatoid arthritis. Catabolic and proinflammatory mediators such as cytokines, nitric oxide, prostaglandin E2 and neuropeptides are produced by the inflamed synovium and alter the balance of cartilage matrix degradation and repair, leading to excess production of the proteolytic enzymes responsible for cartilage breakdown. Cartilage alteration in turn amplifies synovial inflammation, creating a vicious circle. As synovitis is associated with clinical symptoms and also reflects joint degradation in OA, synovium-targeted therapy could help alleviate the symptoms of the disease and perhaps also prevent structural progression.

Key Points

  • Substantial synovial inflammation can occur in early-stage osteoarthritis (OA), end-stage OA, or both

  • Synovitis triggers several symptoms and clinical signs of OA

  • OA synovitis can be assessed by MRI, ultrasonography and arthroscopy; however, the gold-standard method for detecting OA synovitis is histological analysis of biopsy-obtained samples

  • Synovial inflammation can predict cartilage breakdown in OA

  • OA synovitis perpetuates the processes of cartilage degradation

  • The OA synovium releases several soluble mediators that could hold promise as biomarkers or therapeutic targets

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Involvement of the synovium in OA pathophysiology.

References

  1. 1

    Samuels, J., Krasnokutsky, S. & Abramson, S. B. Osteoarthritis: a tale of three tissues. Bull. NYU Hosp. Jt Dis. 66, 244–250 (2008).

  2. 2

    Sellam, J., Herrero-Beaumont, G. & Berenbaum, F. Osteoarthritis: pathogenesis, clinical aspects and diagnosis. In EULAR Compendium on Rheumatic Diseases (ed. Bijlsma, H.) 444–463 (BMJ Publishing Group Ltd, London, 2009).

  3. 3

    Dougados, M. Synovial fluid cell analysis. Baillieres Clin. Rheumatol. 10, 519–534 (1996).

  4. 4

    Goldring, M. B. & Goldring, S. R. Osteoarthritis. J. Cell. Physiol. 213, 626–634 (2007).

  5. 5

    Krasnokutsky, S., Attur, M., Palmer, G., Samuels, J. & Abramson, S. B. Current concepts in the pathogenesis of osteoarthritis. Osteoarthritis Cartilage 16 (Suppl. 3), S1–S3 (2008).

  6. 6

    Ayral, X. et al. Arthroscopic evaluation of post-traumatic patellofemoral chondropathy. J. Rheumatol. 26, 1140–1147 (1999).

  7. 7

    Lindblad, S. & Hedfors, E. Intraarticular variation in synovitis. Local macroscopic and microscopic signs of inflammatory activity are significantly correlated. Arthritis Rheum. 28, 977–986 (1985).

  8. 8

    Benito, M. J., Veale, D. J., FitzGerald, O., van den Berg, W. B. & Bresnihan, B. Synovial tissue inflammation in early and late osteoarthritis. Ann. Rheum. Dis. 64, 1263–1267 (2005).

  9. 9

    Loeuille, D. et al. Macroscopic and microscopic features of synovial membrane inflammation in the osteoarthritic knee: correlating magnetic resonance imaging findings with disease severity. Arthritis Rheum. 52, 3492–3501 (2005).

  10. 10

    Iagnocco, A. & Coari, G. Usefulness of high resolution US in the evaluation of effusion in osteoarthritic first carpometacarpal joint. Scand. J. Rheumatol. 29, 170–173 (2000).

  11. 11

    Dougados, M. Clinical assessment of osteoarthritis in clinical trials. Curr. Opin. Rheumatol. 7, 87–91 (1995).

  12. 12

    Sellam, J. & Berenbaum, F. Clinical features of osteoarthritis. In Kelley's Textbook of Rheumatology, 8th edn Vol. 1 (ed. Firestein, G. S.) 1547–1560 (Saunders/Elsevier, Philadelphia, 2008).

  13. 13

    Ayral, X., Pickering, E. H., Woodworth, T. G., Mackillop, N. & Dougados, M. Synovitis: a potential predictive factor of structural progression of medial tibiofemoral knee osteoarthritis—results of a 1 year longitudinal arthroscopic study in 422 patients. Osteoarthritis Cartilage 13, 361–367 (2005).

  14. 14

    Ledingham, J., Regan, M., Jones, A. & Doherty, M. Factors affecting radiographic progression of knee osteoarthritis. Ann. Rheum. Dis. 54, 53–58 (1995).

  15. 15

    Fernandez-Madrid, F. et al. Synovial thickening detected by MR imaging in osteoarthritis of the knee confirmed by biopsy as synovitis. Magn. Reson. Imaging 13, 177–183 (1995).

  16. 16

    Ostergaard, M. et al. Magnetic resonance imaging-determined synovial membrane and joint effusion volumes in rheumatoid arthritis and osteoarthritis: comparison with the macroscopic and microscopic appearance of the synovium. Arthritis Rheum. 40, 1856–1867 (1997).

  17. 17

    Hill, C. L. et al. Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis. Ann. Rheum. Dis. 66, 1599–1603 (2007).

  18. 18

    Roemer, F. W. et al. Tibiofemoral joint osteoarthritis: risk factors for MR-depicted fast cartilage loss over a 30-month period in the multicenter osteoarthritis study. Radiology 252, 772–780 (2009).

  19. 19

    Pelletier, J. P. et al. A new non-invasive method to assess synovitis severity in relation to symptoms and cartilage volume loss in knee osteoarthritis patients using MRI. Osteoarthritis Cartilage 16 (Suppl. 3), S8–S13 (2008).

  20. 20

    Meenagh, G. et al. Ultrasound imaging for the rheumatologist VIII. Ultrasound imaging in osteoarthritis. Clin. Exp. Rheumatol. 25, 172–175 (2007).

  21. 21

    Kristoffersen, H. et al. Indications of inflammation visualized by ultrasound in osteoarthritis of the knee. Acta Radiol. 47, 281–286 (2006).

  22. 22

    Fiocco, U. et al. Long-term sonographic follow-up of rheumatoid and psoriatic proliferative knee joint synovitis. Br. J. Rheumatol. 35, 155–163 (1996).

  23. 23

    Walther, M. et al. Correlation of power Doppler sonography with vascularity of the synovial tissue of the knee joint in patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum. 44, 331–338 (2001).

  24. 24

    Iagnocco, A. et al. High resolution ultrasonography in detection of bone erosions in patients with hand osteoarthritis. J. Rheumatol. 32, 2381–2383 (2005).

  25. 25

    D'Agostino, M. A. et al. EULAR report on the use of ultrasonography in painful knee osteoarthritis. Part 1: prevalence of inflammation in osteoarthritis. Ann. Rheum. Dis. 64, 1703–1709 (2005).

  26. 26

    Keen, H. I. et al. An ultrasonographic study of osteoarthritis of the hand: synovitis and its relationship to structural pathology and symptoms. Arthritis Rheum. 59, 1756–1763 (2008).

  27. 27

    Conaghan, P. G. et al. Clinical and ultrasonographic predictors of joint replacement for knee osteoarthritis: results from a large, 3 year, prospective EULAR study. Ann. Rheum. Dis. 69, 644–647 (2009).

  28. 28

    Ayral, X. Efficacy and role of topical treatment of gonarthrosis [French]. Presse Med. 28, 1195–1200 (1999).

  29. 29

    Ayral, X. et al. Arthroscopic evaluation of potential structure-modifying drug in osteoarthritis of the knee. A multicenter, randomized, double-blind comparison of tenidap sodium vs piroxicam. Osteoarthritis Cartilage 11, 198–207 (2003).

  30. 30

    Ayral, X., Mayoux-Benhamou, A. & Dougados, M. Proposed scoring system for assessing synovial membrane abnormalities at arthroscopy in knee osteoarthritis. Br. J. Rheumatol. 35 (Suppl. 3), 14–17 (1996).

  31. 31

    Pearle, A. D. et al. Elevated high-sensitivity C-reactive protein levels are associated with local inflammatory findings in patients with osteoarthritis. Osteoarthritis Cartilage 15, 516–523 (2007).

  32. 32

    Uson, J. et al. Soluble interleukin 6 (IL-6) receptor and IL-6 levels in serum and synovial fluid of patients with different arthropathies. J. Rheumatol. 24, 2069–2075 (1997).

  33. 33

    Sharif, M., Shepstone, L., Elson, C. J., Dieppe, P. A. & Kirwan, J. R. Increased serum C reactive protein may reflect events that precede radiographic progression in osteoarthritis of the knee. Ann. Rheum. Dis. 59, 71–74 (2000).

  34. 34

    Spector, T. D. et al. Low-level increases in serum C-reactive protein are present in early osteoarthritis of the knee and predict progressive disease. Arthritis Rheum. 40, 723–727 (1997).

  35. 35

    Sturmer, T., Brenner, H., Koenig, W. & Gunther, K. P. Severity and extent of osteoarthritis and low grade systemic inflammation as assessed by high sensitivity C reactive protein. Ann. Rheum. Dis. 63, 200–205 (2004).

  36. 36

    Wolfe, F. The C-reactive protein but not erythrocyte sedimentation rate is associated with clinical severity in patients with osteoarthritis of the knee or hip. J. Rheumatol. 24, 1486–1488 (1997).

  37. 37

    Engstrom, G., Gerhardsson de Verdier, M., Rollof, J., Nilsson, P. M. & Lohmander, L. S. C-reactive protein, metabolic syndrome and incidence of severe hip and knee osteoarthritis. A population-based cohort study. Osteoarthritis Cartilage 17, 168–173 (2009).

  38. 38

    Livshits, G. et al. Interleukin-6 is a significant predictor of radiographic knee osteoarthritis: The Chingford Study. Arthritis Rheum. 60, 2037–2045 (2009).

  39. 39

    Conrozier, T. et al. Serum levels of YKL-40 and C reactive protein in patients with hip osteoarthritis and healthy subjects: a cross sectional study. Ann. Rheum. Dis. 59, 828–831 (2000).

  40. 40

    Charni-Ben Tabassi, N. & Garnero, P. Monitoring cartilage turnover. Current Rheumatol. Rep. 9, 16–24 (2007).

  41. 41

    Masuhara, K., Nakai, T., Yamaguchi, K., Yamasaki, S. & Sasaguri, Y. Significant increases in serum and plasma concentrations of matrix metalloproteinases 3 and 9 in patients with rapidly destructive osteoarthritis of the hip. Arthritis Rheum. 46, 2625–2631 (2002).

  42. 42

    Myers, S. L. et al. Synovial inflammation in patients with early osteoarthritis of the knee. J. Rheumatol. 17, 1662–1669 (1990).

  43. 43

    Smith, M. D., Triantafillou, S., Parker, A., Youssef, P. P. & Coleman, M. Synovial membrane inflammation and cytokine production in patients with early osteoarthritis. J. Rheumatol. 24, 365–371 (1997).

  44. 44

    Neame, R. L., Carr, A. J., Muir, K. & Doherty, M. UK community prevalence of knee chondrocalcinosis: evidence that correlation with osteoarthritis is through a shared association with osteophyte. Ann. Rheum. Dis. 62, 513–518 (2003).

  45. 45

    Walsh, D. A. et al. Angiogenesis in the synovium and at the osteochondral junction in osteoarthritis. Osteoarthritis Cartilage 15, 743–751 (2007).

  46. 46

    Walsh, D. A. Angiogenesis in osteoarthritis and spondylosis: successful repair with undesirable outcomes. Curr. Opin. Rheumatol. 16, 609–615 (2004).

  47. 47

    Hutton, C. W., Hinton, C. & Dieppe, P. A. Intra-articular variation of synovial changes in knee arthritis: biopsy study comparing changes in patellofemoral synovium and the medial tibiofemoral synovium. Br. J. Rheumatol. 26, 5–8 (1987).

  48. 48

    Shibakawa, A. et al. Presence of pannus-like tissue on osteoarthritic cartilage and its histological character. Osteoarthritis Cartilage 11, 133–140 (2003).

  49. 49

    Sutton, S. et al. The contribution of the synovium, synovial derived inflammatory cytokines and neuropeptides to the pathogenesis of osteoarthritis. Vet. J. 179, 10–24 (2009).

  50. 50

    Furuzawa-Carballeda, J., Macip-Rodriguez, P. M. & Cabral, A. R. Osteoarthritis and rheumatoid arthritis pannus have similar qualitative metabolic characteristics and pro-inflammatory cytokine response. Clin. Exp. Rheumatol. 26, 554–560 (2008).

  51. 51

    Yuan, G. H. et al. Characterization of cells from pannus-like tissue over articular cartilage of advanced osteoarthritis. Osteoarthritis Cartilage 12, 38–45 (2004).

  52. 52

    Nakamura, H., Yoshino, S., Kato, T., Tsuruha, J. & Nishioka, K. T-cell mediated inflammatory pathway in osteoarthritis. Osteoarthritis Cartilage 7, 401–402 (1999).

  53. 53

    Haywood, L. et al. Inflammation and angiogenesis in osteoarthritis. Arthritis Rheum. 48, 2173–2177 (2003).

  54. 54

    Sakkas, L. I., Koussidis, G., Avgerinos, E., Gaughan, J. & Platsoucas, C. D. Decreased expression of the CD3zeta chain in T cells infiltrating the synovial membrane of patients with osteoarthritis. Clin. Diagn. Lab. Immunol. 11, 195–202 (2004).

  55. 55

    Sakkas, L. I. & Platsoucas, C. D. The role of T cells in the pathogenesis of osteoarthritis. Arthritis Rheum. 56, 409–424 (2007).

  56. 56

    Sakkas, L. I. et al. T cells and T-cell cytokine transcripts in the synovial membrane in patients with osteoarthritis. Clin. Diagn. Lab. Immunol. 5, 430–437 (1998).

  57. 57

    Williams, W. V. et al. Restricted heterogeneity of T cell receptor transcripts in rheumatoid synovium. J. Clin. Invest. 90, 326–333 (1992).

  58. 58

    Alsalameh, S. et al. Cellular immune response toward human articular chondrocytes. T cell reactivities against chondrocyte and fibroblast membranes in destructive joint diseases. Arthritis Rheum. 33, 1477–1486 (1990).

  59. 59

    Kim, H. Y. et al. Enhanced T cell proliferative response to type II collagen and synthetic peptide CII (255–274) in patients with rheumatoid arthritis. Arthritis Rheum. 42, 2085–2093 (1999).

  60. 60

    Kotzin, B. L. et al. Use of soluble peptide-DR4 tetramers to detect synovial T cells specific for cartilage antigens in patients with rheumatoid arthritis. Proc. Natl Acad. Sci. USA 97, 291–296 (2000).

  61. 61

    Martel-Pelletier, J., Alaaeddine, N. & Pelletier, J. P. Cytokines and their role in the pathophysiology of osteoarthritis. Front. Biosci. 4, D694–D703 (1999).

  62. 62

    Tan, L. C. et al. Specificity of T cells in synovial fluid: high frequencies of CD8+ T cells that are specific for certain viral epitopes. Arthritis Res. Ther. 2, 154–164 (2000).

  63. 63

    Jasin, H. E. Autoantibody specificities of immune complexes sequestered in articular cartilage of patients with rheumatoid arthritis and osteoarthritis. Arthritis Rheum. 28, 241–248 (1985).

  64. 64

    Smith, M. D. et al. Immunohistochemical analysis of synovial membranes from inflammatory and non-inflammatory arthritides: scarcity of CD5 positive B cells and IL2 receptor bearing T cells. Pathology 24, 19–26 (1992).

  65. 65

    Shi, K. et al. Lymphoid chemokine B cell-attracting chemokine-1 (CXCL13) is expressed in germinal center of ectopic lymphoid follicles within the synovium of chronic arthritis patients. J. Immunol. 166, 650–655 (2001).

  66. 66

    Cooke, T. D., Bennett, E. L. & Ohno, O. The deposition of immunoglobulins and complement in osteoarthritic cartilage. Int. Orthop. 4, 211–217 (1980).

  67. 67

    Radstake, T. R. et al. Expression of Toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon-gamma. Arthritis Rheum. 50, 3856–3865 (2004).

  68. 68

    Bonnet, C. S. & Walsh, D. A. Osteoarthritis, angiogenesis and inflammation. Rheumatology (Oxford) 44, 7–16 (2005).

  69. 69

    Walsh, D. A., Wade, M., Mapp, P. I. & Blake, D. R. Focally regulated endothelial proliferation and cell death in human synovium. Am. J. Pathol. 152, 691–702 (1998).

  70. 70

    Lee, S. S. et al. Vascular endothelial growth factor levels in the serum and synovial fluid of patients with rheumatoid arthritis. Clin. Exp. Rheumatol. 19, 321–324 (2001).

  71. 71

    Koch, A. E. et al. Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J. Immunol. 152, 4149–4156 (1994).

  72. 72

    Koch, A. E. et al. Immunolocalization of endothelial and leukocyte adhesion molecules in human rheumatoid and osteoarthritic synovial tissues. Lab. Invest. 64, 313–320 (1991).

  73. 73

    Farahat, M. N., Yanni, G., Poston, R. & Panayi, G. S. Cytokine expression in synovial membranes of patients with rheumatoid arthritis and osteoarthritis. Ann. Rheum. Dis. 52, 870–875 (1993).

  74. 74

    Furuzawa-Carballeda, J. & Alcocer-Varela, J. Interleukin-8, interleukin-10, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression levels are higher in synovial tissue from patients with rheumatoid arthritis than in osteoarthritis. Scand. J. Immunol. 50, 215–222 (1999).

  75. 75

    Sadouk, M. B. et al. Human synovial fibroblasts coexpress IL-1 receptor type I and type II mRNA. The increased level of the IL-1 receptor in osteoarthritic cells is related to an increased level of the type I receptor. Lab. Invest. 73, 347–355 (1995).

  76. 76

    Alaaeddine, N. et al. Osteoarthritic synovial fibroblasts possess an increased level of tumor necrosis factor-receptor 55 (TNF-R55) that mediates biological activation by TNF-alpha. J. Rheumatol. 24, 1985–1994 (1997).

  77. 77

    Bondeson, J., Wainwright, S. D., Lauder, S., Amos, N. & Hughes, C. E. The role of synovial macrophages and macrophage-produced cytokines in driving aggrecanases, matrix metalloproteinases, and other destructive and inflammatory responses in osteoarthritis. Arthritis Res. Ther. 8, R187 (2006).

  78. 78

    Honorati, M., Neri, S., Cattini, L. & Facchini, A. Interleukin-17, a regulator of angiogenic factor release by synovial fibroblasts. Osteoarthritis Cartilage 14, 345–352 (2005).

  79. 79

    Honorati, M., Bovara, M., Cattini, L., Piacentini, A. & Facchini, A. Contribution of interleukin-17 to human cartilage degradation and synovial inflammation in osteoarthritis. Osteoarthritis Cartilage 10, 799–807 (2002).

  80. 80

    Chabaud, M. et al. Human interleukin-17: a T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum. 42, 963–970 (1999).

  81. 81

    Scanzello, C. R. et al. Local cytokine profiles in knee osteoarthritis: elevated synovial fluid interleukin-15 differentiates early from end-stage disease. Osteoarthritis Cartilage 17, 1040–1048 (2009).

  82. 82

    Brentano, F. et al. Pre-B cell colony-enhancing factor/visfatin, a new marker of inflammation in rheumatoid arthritis with proinflammatory and matrix-degrading activities. Arthritis Rheum. 56, 2829–2839 (2007).

  83. 83

    Presle, N. et al. Differential distribution of adipokines between serum and synovial fluid in patients with osteoarthritis. Contribution of joint tissues to their articular production. Osteoarthritis Cartilage 14, 690–695 (2006).

  84. 84

    Suri, S. et al. Neurovascular invasion at the osteochondral junction and in osteophytes in osteoarthritis. Ann. Rheum. Dis. 66, 1423–1428 (2007).

  85. 85

    Felson, D. T. The sources of pain in knee osteoarthritis. Curr. Opin. Rheum. 17, 624–628 (2005).

  86. 86

    Nissalo, S., Hukkanen, M., Imai, S., Törnwall, J. & Konttinen, Y. T. Neuropeptides in experimental and degenerative arthritis. Ann. NY Acad. Sci. 966, 384–399 (2002).

  87. 87

    Kidd, B. L., Photiou, A. & Inglis, J. J. The role of inflammatory mediators on nociception and pain in arthritis. Novartis Found. Symp. 260, 122–133 (2004).

  88. 88

    Meini, S. & Maggi, C. A. Knee osteoarthritis: a role for bradykinin? Inflamm. Res. 57, 351–361 (2008).

  89. 89

    Perrot, S. & Guilbaud, G. Pathophysiology of joint pain. Rev. Rhum. Engl. Ed. 63, 485–492 (1996).

  90. 90

    Mapp, P. I. et al. Substance P-, calcitonin gene-related peptide- and C-flanking peptide of neuropeptide Y-immunoreactive fibres are present in normal synovium but depleted in patients with rheumatoid arthritis. Neuroscience 37, 143–153 (1990).

  91. 91

    Fortier, L. A. & Nixon, A. J. Distributional changes in substance P nociceptive fiber patterns in naturally osteoarthritic articulations. J. Rheumatol. 24, 524–530 (1997).

  92. 92

    Lotz, M., Carson, D. A. & Vaughan, J. H. Substance P activation of rheumatoid synoviocytes: neural pathway in pathogenesis of arthritis. Science 235, 893–895 (1987).

  93. 93

    Mousa, S. A., Straub, R. H., Schafer, M. & Stein, C. Beta-endorphin, Met-enkephalin and corresponding opioid receptors within synovium of patients with joint trauma, osteoarthritis and rheumatoid arthritis. Ann. Rheum. Dis. 66, 871–879 (2007).

  94. 94

    Seidel, M. F., Herguijuela, M., Forkert, R. & Otten, U. Nerve growth factor in rheumatic diseases. Semin. Arthritis Rheum. doi: 10.1016/j.semarthrit.2009.03.002.

  95. 95

    Raychaudhuri, S. P. & Raychaudhuri, S. K. The regulatory role of nerve growth factor and its receptor system in fibroblast-like synovial cells. Scand. J. Rheumatol. 38, 207–215 (2009).

  96. 96

    Lane, N. E., Schnitser, T. J., Smith, M. D. & Brown, M. T. Tanezumab relieves moderate to severe pain due to osteoarthritis (OA) of the knee: a phase 2 trial [abstract 1989]. Arthritis Rheum. 58 (Suppl.), S896–S897 (2008).

  97. 97

    Wittenberg, R. H., Willburger, R. E., Kleemeyer, K. S. & Peskar, B. A. In vitro release of prostaglandins and leukotrienes from synovial tissue, cartilage, and bone in degenerative joint diseases. Arthritis Rheum. 36, 1444–1450 (1993).

  98. 98

    Okada, Y. et al. Localization of matrix metalloproteinase 3 (stromelysin) in osteoarthritic cartilage and synovium. Lab. Invest. 66, 680–690 (1992).

  99. 99

    Clegg, P. D., Burke, R. M., Coughlan, A. R., Riggs, C. M. & Carter, S. D. Characterisation of equine matrix metalloproteinase 2 and 9; and identification of the cellular sources of these enzymes in joints. Equine Vet. J. 29, 335–342 (1997).

  100. 100

    Blom, A. B. et al. Crucial role of macrophages in matrix metalloproteinase-mediated cartilage destruction during experimental osteoarthritis: involvement of matrix metalloproteinase 3. Arthritis Rheum. 56, 147–157 (2007).

  101. 101

    Dreier, R., Grassel, S., Fuchs, S., Schaumburger, J. & Bruckner, P. Pro-MMP-9 is a specific macrophage product and is activated by osteoarthritic chondrocytes via MMP-3 or a MT1-MMP/MMP-13 cascade. Exp. Cell Res. 297, 303–312 (2004).

  102. 102

    Blom, A. B. et al. Synovial lining macrophages mediate osteophyte formation during experimental osteoarthritis. Osteoarthritis Cartilage 12, 627–635 (2004).

  103. 103

    van Lent, P. L. et al. Crucial role of synovial lining macrophages in the promotion of transforming growth factor beta-mediated osteophyte formation. Arthritis Rheum. 50, 103–111 (2004).

  104. 104

    Pelletier, J. P., Martel-Pelletier, J. & Abramson, S. B. Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. Arthritis Rheum. 44, 1237–1247 (2001).

  105. 105

    Adamopulos, I. et al. Synovial fluid macrophages are capable of osteoclast formation and resorption. J. Pathol. 1, 35–43 (2006).

  106. 106

    Ogawa, K. et al. Mature and activated osteoclasts exist in the synovium of rapidly destructive coxarthrosis. J. Bone Miner. Metab. 25, 354–360 (2007).

  107. 107

    Iovu, M., Dumais, G. & du Souich, P. Anti-inflammatory activity of chondroitin sulfate. Osteoarthritis Cartilage 16 (Suppl. 3), S14–S18 (2008).

  108. 108

    Berenbaum, F. Targeted therapies in osteoarthritis: a systematic review of the trials on www.clinicaltrials.gov. Best Pract. Res. Clin. Rheumatol. 24, 107–119 (2010).

  109. 109

    Abdiche, Y. N., Malashock, D. S. & Pons, J. Probing the binding mechanism and affinity of tanezumab, a recombinant humanized anti-NGF monoclonal antibody, using a repertoire of biosensors. Protein Sci. 17, 1326–1335 (2008).

  110. 110

    Roach, H. I., Aigner, T., Soder, S., Haag, J. & Welkerling, H. Pathobiology of osteoarthritis: pathomechanisms and potential therapeutic targets. Curr. Drug Targets 8, 271–282 (2007).

  111. 111

    Krasnokutsky, S., Samuels, J. & Abramson, S. B. Osteoarthritis in 2007. Bull. NYU Hosp. Jt Dis. 65, 222–228 (2007).

  112. 112

    Malemud, C. J. Anticytokine therapy for osteoarthritis: evidence to date. Drugs Aging 27, 95–115 (2010).

  113. 113

    Chevalier, X. et al. Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 61, 344–352 (2009).

  114. 114

    Ley, C., Ekman, S., Roneus, B. & Eloranta, M. L. Interleukin-6 and high mobility group box protein-1 in synovial membranes and osteochondral fragments in equine osteoarthritis. Res. Vet. Sci. 86, 490–497 (2009).

  115. 115

    Sanchez, C., Gabay, O., Salvat, C., Henrotin, Y. E. & Berenbaum, F. Mechanical loading highly increases IL-6 production and decreases OPG expression by osteoblasts. Osteoarthritis Cartilage 17, 473–481 (2009).

  116. 116

    Keen, H. I. et al. Can ultrasonography improve on radiographic assessment in osteoarthritis of the hands? A comparison between radiographic and ultrasonographic detected pathology. Ann. Rheum. Dis. 67, 1116–1120 (2008).

Download references

Author information

J. Sellam and F. Berenbaum contributed equally to researching data for the article, discussion of content, writing and review/editing of the manuscript before submission.

Correspondence to Francis Berenbaum.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sellam, J., Berenbaum, F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol 6, 625–635 (2010). https://doi.org/10.1038/nrrheum.2010.159

Download citation

Further reading