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The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: a narrative review
Osteoarthritis and Cartilage 18 (2010) 876e882
Review
The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: a narrative review S. Clockaerts yz *, Y.M. Bastiaansen-Jenniskens z, J. Runhaar z, G.J.V.M. Van Osch z, J.F. Van Offel y, J.A.N. Verhaar z, L.S. De Clerck y, J. Somville y y University of Antwerp, Department of Medicine, Belgium z Erasmus MC, University Medical Center Rotterdam, The Netherlands
a r t i c l e i n f o
s u m m a r y
Article history: Received 8 December 2009 Accepted 22 March 2010
Introduction: Osteoarthritis (OA) of the knee joint is caused by genetic and hormonal factors and by inflammation, in combination with biomechanical alterations. It is characterized by loss of articular cartilage, synovial inflammation and subchondral bone sclerosis. Considerable evidence indicates that the menisci, ligaments, periarticular muscles and the joint capsule are also involved in the OA process. This paper will outline the theoretical framework for investigating the infrapatellar fat pad (IPFP) as an additional joint tissue involved in the development and progression of knee-OA. Methods: A literature search was performed in Pubmed from 1948 until October 2009 with keywords InFrapatellar fat pad, Hoffa fat pad, intraarticular adipose tissue, knee, cartilage, bone, cytokine, adipokine, inflammation, growth factor, arthritis, and OA. Results: The IPFP is situated intracapsularly and extrasynovially in the knee joint. Besides adipocytes, the IPFP from patients with knee-OA contains macrophages, lymphocytes and granulocytes, which are able to contribute to the disease process of knee-OA. Furthermore, the IPFP contains nociceptive nerve fibers that could in part be responsible for anterior pain in knee-OA. These nerve fibers secrete substance P, which is able to induce inflammatory responses and cause vasodilation, which may lead to IPFP edema and extravasation of the immune cells. The IPFP secretes cytokines, interleukins, growth factors and adipokines that influence cartilage by upregulating the production of matrix metalloproteinases (MMPs), stimulating the expression of proinflammatory cytokines and inhibiting the production of cartilage matrix proteins. They may also stimulate the production of pro-inflammatory mediators, growth factors and MMPs in synovium. Conclusion: These data are consistent with the hypothesis that the IPFP is an osteoarthritic joint tissue capable of modulating inflammatory and destructive responses in knee-OA. Ó 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Keywords: Infrapatellar fat pad Knee osteoarthritis Adipose tissue Inflammation
Introduction In the recent past, knee osteoarthritis (OA) was considered as a pathologic condition that affects cartilage and bone. We now appreciate that all joint tissues, including the synovium, menisci, ligaments, periarticular muscles and the joint capsule are involved1. In addition to these structures, the knee joint also contains adipose tissue: the infrapatellar fat pad (IPFP)2. Although it has been known that adipose tissue secretes inflammatory mediators that are able to influence cartilage and synovium, a theoretical framework for a role of the IPFP in knee-OA has not been described3.
Considering the intraarticular location of the IPFP, the metabolic properties of adipose tissue and the fact that the OA disease process involves all the joint tissues, it is likely that the IPFP could also be involved in knee-OA. Our hypothesis is that immune cells could infiltrate IPFP as a result of knee-OA and that the combination of immune cells, nerve fibers and adipocytes could then contribute to the disease process by producing and releasing inflammatory mediators, capable of modifying inflammatory and destructive responses in cartilage and synovium (Fig. 1). In this article, an overview is given of literature that supports this hypothesis. Methods
* Address correspondence and reprint requests to: Stefan Clockaerts, University Hospital of Antwerp, Department of Orthopaedic Surgery and Traumatology, Wilrijkstraat 10, 2650 Edegem, Belgium. Tel: 0032-486-62-76-84. E-mail address: [email protected] (S. Clockaerts).
A literature search was performed in Pubmed from 1948 until October 2009 using keywords intrapatellar fat pad, Hoffa fat pad, inFrapatellar adipose tissue, knee, cartilage, bone, cytokine,
1063-4584/$ e see front matter Ó 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.joca.2010.03.014
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877
Synovial layer
Articular cartilage Infrapatellar fat pad INFLAMMATION Fat pad edema Extravasation of WBC lymphocytes granulocytes monocytes Blood vessel
Substance P
Synovial fluid Interleukins Growth factors Nitric oxide Leukotrienes Prostaglandines
Leptin Adiponectin NAMPT Resistin Adipocytes
Sensory nerve (C-fibre)
Osteophytosis Articular cartilage
Fig. 1. A schematic overview of the IPFP as an active osteoarthritic joint tissue. The IPFP shows signs of inflammation secondary to OA of the knee joint. The IPFP contains adipocytes and has an increased number of immune cells such as lymphocytes, monocytes and granulocytes that have migrated from the blood circulation. Substance P nerve fibers are also present in the IPFP and contribute to the immune regulation within the IPFP by the secretion of substance P. Substance P is able to induce extravasation of white blood cells and is also known to enhance inflammation in white blood cells. The combination of these cells is able to secrete adipokines such as leptin, adiponectin, NAMPT and resistin, but also ILs, growth factors, nitric oxide, leukotrienes and prostaglandins which have shown to influence cartilage, synovium and osteophyte formation.
adipokine, inflammation, growth factor, arthritis, OA. We excluded papers that were not written in English. Cadaver knee joints were dissected to make photographs and figures. Results Inflammation in OA Considerable evidence indicates that OA has a multifactorial etiology with a combination of biomechanical, genetic, inflammatory and hormonal factors4e7. Abnormal biomechanical loading is an etiological factor in OA that can be caused by partial or total meniscectomy, malalignement, joint instability, muscle weakness or peripheral neuropathy, and obesity5,8. In addition to tissue damage or wear, repeated overloading of joints activates mechanoreceptors in chondrocytes and osteoblasts, which in turn activates inflammatory pathways that lead to the production of cartilage degradation mediators9e12. Several lines of evidence indicate that genetic abnormalities can result in an early initiation of OA. For knee-OA, the influence of genetics on the onset of OA is believed to be between 39 and 65%. Many of these genes affect extracellular cartilage matrix and cartilage signaling molecules7. Inflammatory pathways are known to play a role in the development of OA. Clinical features of inflammation, such as joint pain, swelling and stiffness, are indeed present during clinical examination13. Inflammatory mediators, such as interleukin (IL)1b and
tumor necrosis factor (TNF)a, are released by cartilage, bone, synovium and other surrounding joint tissues and are capable of inducing matrix metalloproteinases (MMPs), aggrecanases and other catabolic genes5,14. This causes remodeling of the extracellular cartilage matrix. These inflammatory mediators induce the production of prostaglandin E2 by stimulating the expression or activity of cyclooxygenase (COX)2, microsomal prostaglandin E2 synthase 1 (mPGES1), and soluble phospholipase A2 (sPLA2)14. They also upregulate the production of nitric oxide via inducible nitric oxide synthetase (iNOS) and induce pro-inflammatory cytokines such as IL1, TNFa, IL6, leukemia inhibitory factor (LIF), IL17, IL18, and chemokines, including IL8. The expression of a number of genes associated with a differentiated chondrocyte phenotype, including collagen type II is suppressed by inflammatory mechanisms5,14,15. Transforming growth factor (TGF)b produced by synovial macrophages, is shown able to induce the formation of osteophytes in animal studies16,17. Inflammatory events in the subchondral bone layer may induce hypertropic differentiation of chondrocytes or stimulate chondrocytes in a paracrine manner18e20. However, it is not known whether the subchondral bone inflammation is partly caused or stimulated by inflammatory mediators present in osteoarthritic joints.
Obesity is associated with OA Obesity and high body mass index are associated with a higher incidence risk of OA9. Changed kinetics of weight-bearing joints can
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lead to the initiation and progression of OA, and obesity could enhance this mechanism by increasing the loading forces21,22. However, non-weight-bearing joints such as joints of the hand also have higher incidence risk for OA in obese people compared to healthy people23e27. Furthermore, Toda et al. showed that the loss of body fat is more beneficial for symptomatic relief in knee-OA than the loss of body weight28. Wang reported a correlation between the risk of primary knee or hip replacement for OA and central obesity or adipose mass. The latter could be explained by the higher amount of visceral adipose tissue, which is known to secrete more pro-inflammatory cytokines compared to peripheral subcutaneous adipose tissue29. These data suggest that adipose tissue is an endocrine organ that is able to exert metabolic effects on the joint tissues. The IPFP or Hoffa’s fat pad is located in the knee joint The IPFP or Hoffa fat pad was first described by Albert Hoffa in 190430. It is situated in the knee underneath the patella, between the patellar tendon, femoral condyle and tibial plateau, where it completely fills the potential spaces between these structures (Fig. 2). Therefore, it is located closely to the synovial layers and cartilage surfaces of the knee joint (Figs. 2 and 3). The IPFP is composed of a fibrous scaffold, on which constitutional fat tissue is embedded, which is developed under the influence of sex hormones. The joint facing surface is covered by the antero-inferior synovial membrane, thus the IPFP localization can be described as intracapsular and extrasynovial31,32. It attaches to the lower border of the inner non-articulating surface of the patella, to the notch between the two condyles of the femur by running continuously with the infrapatellar plica posterosuperiorly, and to the periosteum of the tibia and the anterior part of the menisci2 (Fig. 3). An extensive anastomotic network of vessels protects the IPFP against
Fig. 3. A dissection of a left knee in flexion showing the IPFP from an anterior view (broken lines). The patella tendon has been dissected proximally and retracted to show the joint facing surface of the patella and the IPFP. The IPFP is located in the knee joint and closely to the articulating cartilage surfaces and the synovium. Notice the attachments of the IPFP at the lower border of the patella (black arrows). The attachment at the intercondylar region with the ligamentum mucosum (white arrow) is located before the anterior cruciate ligament.
necrosis during extensive surgical exposures or arthroscopic procedures33. Only the central portion of the IPFP has a more limited vascular network. It is supplied by branches of the superior and inferior genicular artery. The inferior portion of the anastomotic ring passes through the IPFP and supplies part of the patella31,34,35. Many studies mention that the IPFP is innervated by the posterior articular branch of the tibial nerve36e38. However, in one of the most detailed studies about innervation of the knee, Gardner39 describes branches rising from the saphenous, tibial and obturator nerves, and the nerve to the vastus medialis, innervating the anteromedial portion of the IPFP. The anterolateral part of the IPFP is innervated by articular branches from the nerve to the vastus lateralis, the tibial nerve, recurrent peroneal nerve and common peroneal nerve. These branches accompany blood vessels throughout the IPFP39. IPFP facilitates the distribution of synovial fluid and may act to absorb forces through the knee joint. Other functions of the IPFP have not yet been determined. Pathologic processes that occur within the IPFP are Hoffa disease, chondromas, nodular synovitis and surgery related complications. Other small fat pads of the knee joint have been mentioned: a posterior knee fat pad, an anterior suprapatellar fat pad (quadriceps) and a posterior suprapatellar fat pad (prefemoral) (Fig. 2)40.
The IPFP contains cells capable of modifying the OA disease process
Fig. 2. A midsagittal plane of the knee joint. This figure shows the location of the IPFP (1) and also the presence of other smaller fat pads in the knee joint: posterior fat pad (2), anterior suprapatellar fat pad (3) and posterior suprapatellar fat pad (4). The IPFP is located inferior from the patella and posterior from the patella tendon. It is covered by the joint capsule (white arrow) from anterior and the synovium (black arrow) on his joint facing surface. Thus it is located intracapsular, but extrasynovial. Also notice its close contact with articulating cartilage surfaces.
Once it was thought that white adipose tissue acted only as a reservoir for excess calories that are stored as triacylglycerols. After the discovery of leptin in 1994 it became tangible that the white adipose tissue could play an active role in physiologic and pathologic processes, including immunology and inflammation41,42. The adipose tissue is considered as a specialized form of connective tissue, which contains large numbers of adipocytes, fibroblasts, macrophages, leukocytes, and other cells involved in inflammation. These cells are present in an intercellular matrix consisting of collagen and elastic fibers, on which network epithelial structures can rest and muscle and nervous tissue are embedded41. The IPFP is a very sensitive structure together with the synovium43. This is due to the presence of peptidergic C-fibers, nerve
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fibers staining positive for substance P44. The human OA IPFP contains even more small sized nerves compared to medium- or large sized substance P nerves45. This suggests that the IPFP contains part of the terminal sensory innervation for the knee joint and could be an important source of pain in knee-OA. The highest rates of substance P nerves are found around vessels of IPFP: substance P causes vasodilation that leads to extravasation of immune cells and causes IPFP edema. In turn, edema leads to soft tissue impingement, ischemia and lipomatous tissue necrosis44. The presence of IPFP edema was investigated in vivo by Lawson et al. on MRI in patients with Lyme arthritis. Results of this study indicate that IPFP edema can develop as a result of arthritis46. Ischemia induces the release of neuro-tropin neural growth factor, which in turn activates the release of substance P. This type of autostimulation may cause chronicity of inflammation of the IPFP in joint diseases44. O’Shaughnessy et al. showed that substance P induces the production of nitric oxide in rheumatoid synoviocytes and experimental models of inflammation47. Furthermore, it stimulates IL1b, TNFa, nuclear factor kB and superoxide anion production in various cell types. Substance P has also a strong effect on fibroblast activation and extracellular matrix production45. Sympathetic nerve fibers are known to secrete anti-inflammatory norepinephrine and endogenous opiods that are able to inhibit pain perception in a bidirectional cross talk with substance P fibers45. In healthy synovium the density of sensory vs sympathetic nerve fibers is balanced at 1:148. In synovium from rheumatoid arthritis patients, the preponderance of the substance P positive nerve fibers over sympathetic nerve fibers is approximately 8:1. For the IPFP, the ratio of sensory vs sympathetic nerve fibers is higher in patients with anterior knee pain after total knee arthroplasty then in patients with knee-OA45. Whether the density of sensory nerve fibers was higher than normal in the IPFP of knee-OA patients has not yet been established. Based on these findings, we conclude that substance P nerves are present in IPFP and can act as inflammatory cells, besides the well described sensory function of these nerves. An increased amount of immune cells, edema, fat necrosis and fibrosis was reported in subsynovial IPFP in animal models of induced arthritis, together with signs of alterations in joint diseases that involve synovial proliferation on MRI images31,49e52. Inflammatory cell infiltrations were present in 36% of Hoffa fat pad specimens collected from patients with knee-OA while severe fibrosis was present in 33% of cases53. An OA animal model revealed that the wet weight of IPFP in monoiodoacetate injected joints was two-fold higher than the vehicle controls. Numbers of neutrophils, eosinophils and basophils, and in particular monocytes were increased37. Jedrzejczyk et al. also found lymphocytes in the IPFP54. The infiltration of immune cells in synovium could contribute to the OA disease process by the production of pro-inflammatory and/ or pro-fibrotic cytokines16,17,55,56. Based on the anatomical location of the IPFP, it is possible that similar processes exist for immune cells in the IPFP. Cartilage breakdown molecules may activate monocytes by binding to receptors that are associated with receptors of innate immunity57. Activated macrophages produce various growth factors, cytokines and enzymes that enhance osteophyte formation, mitigate cartilage breakdown by MMP activity, induce joint effusion by vasodilation and might influence subchondral bone metabolism. Neutrophils play a role in cartilage breakdown and necrosis of adipose tissue by the production of cytokines such as IL1, IL8 and MMP837,58. Eosinophils and basophils release histamine that increases production of matrix degrading enzymes and proinflammatory mediators in synovial fibroblasts and cartilage59. Lymphocytes from OA joints express Th1 cytokines which can directly degrade cartilage or activate macrophages through cellecell interaction to produce cartilage degrading mediators60.
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We conclude that IPFP contains inflammatory cells and substance P nerve cells that could be able to influence inflammatory and destructive responses in knee-OA. Substance P nerve cells in the IPFP could also play a role in the pain pathophysiology of knee-OA. Adipose tissue as an endocrine organ Adipose tissue secretes cytokines, ILs, growth factors and adipokines in an endocrine, autocrine or paracrine manner. These inflammatory mediators are found in synovial fluid and are able to influence the cartilage and synovium metabolism3,61,62. The immune cells present in the adipose tissue could be responsible for most of the production and release of inflammatory mediators, except for leptin and adiponectin, which are mainly secreted by adipocytes41 (Fig. 1). Interesting adipokines are leptin and adiponectin, as they are secreted in high amounts by adipose tissue41,61,63. Leptin was thought to be beneficial for OA, because injection of leptin in a knee joint upregulated proteoglycan synthesis, production of growth factors and stimulated its own synthesis in different joint tissues3,61. However, recent research has contradicted this idea. At present, leptin is known to stimulate IL1b production, to increase the effect of pro-inflammatory cytokines and induce the expression of MMPs in the OA cartilage3,64e68. Leptin is able to activate nitric oxide synthase synergistically with interferon-g or to enhance activation of nitric oxide synthase 2 by IL165. Leptin also facilitates the activation of macrophages, neutrophils, dendritic cells, natural killers cells and Th1 cells69. Adiponectin has been cited as a protective adipokine against obesity and vascular diseases, but might act as a pro-inflammatory agent in joint diseases70. Adiponectin induces MMP1 and IL6 production in synovial fibroblasts, which are known to have adiponectin receptors71. The presence of adiponectin receptors in chondrosarcoma cells, capable of inducing type 2 nitric oxide synthase, suggests that adiponectin receptors are also present in normal or OA chondrocytes72. Indeed, adiponectin treated chondrocytes produce IL6, MMP3, MMP9 and monocyte chemoattractant protein (MCP)163. Other adipokines are resistin and nicotinamide phosphoribosyltransferase (NAMPT). Resistin is elevated after traumatic joint injuries and induces production of inflammatory cytokines and loss of proteoglycans in cartilage. The injection of resistin into mice joints induces arthritis-like conditions70,73. NAMPT seems to have a pro-inflammatory effect on chondrocytes and synovial fibroblasts70,74,75. The role of adipokines on bone is not yet clarified. Leptin and resistin may stimulate bone formation and adiponectin might have an inhibitory effect76. Many other inflammatory mediators such as IL1a and b, TNFa, IL4, IL6, IL8, IL10, IL18, IL1 receptor antagonist, MCP1, prostaglandin E2, nitric oxide and growth factors such as vascular endothelial growth factor (VEGF), TGFb and fibroblast growth factor (FGF)2 are produced by adipose tissue and have shown to be involved in joint diseases3,41. IPFP produces and releases inflammatory mediators in the knee joint The adipokines leptin, resistin and adiponectin are found in the synovial fluid61,62,67,77. The concentration of adipokines in the synovial fluid differs from serum levels. Resistin and adiponectin are present in lower amounts in the synovial fluid than in circulating blood, while leptin is present in higher amounts66,77. A correlation between leptin concentration in the synovial fluid and severity of knee-OA has been shown by Ku et al.78.
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The presence of adipokines in the knee joint cannot be explained by a higher permeability of the inflamed synovium alone, because resistin is present in lower concentration in synovial fluid than leptin, although its molecular weight is similar79,80. Leptin is present in higher amount in synovial fluid from female OA patients, but interestingly not in male OA patients. Except for adiponectin, the synovial fluid levels of resistin and leptin appears to be higher for women then for men. This effect cannot be explained by the higher serum levels of leptin in woman, caused by influence of sex hormones, because the synovium fluid/serum level ratios between men and women are also different66. Ushiyama et al. showed that the human OA IPFP contained significant protein levels of FGF2, VEGF, TNFa and IL6. These cytokines were also measured in the synovial fluid. Although synovial fluid levels and IPFP content did not correlate, a similar distribution of FGF2 and VEGF content was found in human OA synovium compared to IPFP81. Presle showed that cultured explants of IPFP produced large amounts of adiponectin and leptin, although surprisingly explants obtained from osteophytes produced even more leptin66. The amount of IL6, soluble IL6 receptor and adiponectin that is produced by the IPFP is higher than in subcutaneous adipose tissue from obese people, although the production of leptin is lower. These data, together with a decrease of genes related to lipid metabolism in the IPFP, indicate that the IPFP should be regarded as adipose tissue with its own characteristics82. Intraarticular production of inflammatory mediators can occur in different joint tissues such as cartilage, synovium, menisci or osteophytes66. Based on these findings, we conclude that IPFP is also able to produce and excrete important inflammatory mediators directly into the knee joint. Discussion This article reviews some significant points that could explain the role of the IPFP in the disease process of knee-OA. Inflammation plays an important role in the etiopathogenesis of OA. The association between obesity and OA cannot only be explained by biomechanical alterations, but also by the inflammatory properties of adipose tissue. The IPFP can be regarded as a special form of adipose tissue due to its location, which is in close contact with synovial layers and articulating cartilage. Infiltration of immune cells has been demonstrated in the IPFP in human OA joints and in animal models for arthritis and OA. Furthermore, nociceptive nerve fibers are present that can cause anterior pain and are capable of maintaining inflammation by the release of substance P. The combination of adipocytes, immune and nerve cells IPFP produces and secretes adipokines, but also cytokines, chemokines and growth factors that are capable of altering cartilage and synovium. Further in vitro and in vivo studies should be performed to confirm the release of inflammatory mediators in the synovial compartment. It should be investigated whether the IPFP from knee-OA patients produces more inflammatory mediators than healthy IPFP and whether IPFP from obese people differs from non-obese people in content or production of cytokines. Furthermore, adipose tissue secretes anti-inflammatory mediators such as FGF2, IL4 or IL10, which could have beneficial effects on cartilage and synovium41. Therefore, effects of the combination of all factors secreted by the IPFP on cartilage should be explored. It should be investigated whether substance P fibers are present in higher amounts in the IPFP from osteoarthritic knees as compared to healthy knee joints. Furthermore, their potential role in pain and inflammation in knee-OA should be elucidated.
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54. Jedrzejczyk T. The infrapatellar adipose body in humans of various age groups. Folia morphologica 1996;55:51e5. 55. Blom AB, van Lent PL, Libregts S, Holthuysen AE, van der Kraan PM, van Rooijen N, et al. Crucial role of macrophages in matrix metalloproteinase-mediated cartilage destruction during experimental osteoarthritis: involvement of matrix metalloproteinase 3. Arthritis Rheum 2007;56:147e57. 56. Haynes MK, Hume EL, Smith JB. Phenotypic characterization of inflammatory cells from osteoarthritic synovium and synovial fluids. Clin Immunol 2002;105:315e25. 57. Kaisho T, Akira S. Toll-like receptors and their signaling mechanism in innate immunity. Acta Odontol Scand 2001;59:124e30. 58. Abbink JJ, Kamp AM, Nieuwenhuys EJ, Nuijens JH, Swaak AJ, Hack CE. Predominant role of neutrophils in the inactivation of alpha 2-macroglobulin in arthritic joints. Arthritis Rheum 1991;34:1139e50. 59. Tetlow LC, Woolley DE. Effect of histamine on the production of matrix metalloproteinases-1, -3, -8 and -13, and TNFalpha and PGE(2) by human articular chondrocytes and synovial fibroblasts in vitro: a comparative study. Virchows Arch 2004;445:485e90. 60. Sakkas LI, Platsoucas CD. The role of T cells in the pathogenesis of osteoarthritis. Arthritis Rheum 2007;56:409e24. 61. Dumond H, Presle N, Terlain B, Mainard D, Loeuille D, Netter P, et al. Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum 2003;48:3118e29. 62. Schaffler A, Ehling A, Neumann E, Herfarth H, Tarner I, Scholmerich J, et al. Adipocytokines in synovial fluid. Jama 2003;290:1709e10. 63. Lago R, Gomez R, Otero M, Lago F, Gallego R, Dieguez C, et al. A new player in cartilage homeostasis: adiponectin induces nitric oxide synthase type II and pro-inflammatory cytokines in chondrocytes. Osteoarthritis Cartilage 2008;16:1101e9. 64. Iliopoulos D, Malizos KN, Tsezou A. Epigenetic regulation of leptin affects MMP-13 expression in osteoarthritic chondrocytes: possible molecular target for osteoarthritis therapeutic intervention. Ann Rheum Dis 2007;66:1616e21. 65. Otero M, Gomez Reino JJ, Gualillo O. Synergistic induction of nitric oxide synthase type II: in vitro effect of leptin and interferon-gamma in human chondrocytes and ATDC5 chondrogenic cells. Arthritis Rheum 2003;48:404e9. 66. Presle N, Pottie P, Dumond H, Guillaume C, Lapicque F, Pallu S, 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 2006;14:690e5. 67. Simopoulou T, Malizos KN, Iliopoulos D, Stefanou N, Papatheodorou L, Ioannou M, et al. Differential expression of leptin and leptin’s receptor isoform (Ob-Rb) mRNA between advanced and minimally affected osteoarthritic cartilage; effect on cartilage metabolism. Osteoarthritis Cartilage 2007;15:872e83.
68. Vuolteenaho K, Koskinen A, Kukkonen M, Nieminen R, Paivarinta U, Moilanen T, et al. Leptin enhances synthesis of proinflammatory mediators in human osteoarthritic cartilagemediator role of NO in leptin-induced PGE2, IL-6, and IL-8 production. Mediators Inflamm 2009;2009:345838. 69. Matarese G, Leiter EH, La Cava A. Leptin in autoimmunity: many questions, some answers. Tissue Antigens 2007;70:87e95. 70. Gomez R, Lago F, Gomez-Reino J, Dieguez C, Gualillo O. Adipokines in the skeleton: influence on cartilage function and joint degenerative diseases. J Mol Endocrinol 2009;43:11e8. 71. Tang CH, Chiu YC, Tan TW, Yang RS, Fu WM. Adiponectin enhances IL-6 production in human synovial fibroblast via an AdipoR1 receptor, AMPK, p38, and NF-kappa B pathway. J Immunol 2007;179:5483e92. 72. Ehling A, Schaffler A, Herfarth H, Tarner IH, Anders S, Distler O, et al. The potential of adiponectin in driving arthritis. J Immunol 2006;176:4468e78. 73. Lee JH, Ort T, Ma K, Picha K, Carton J, Marsters PA, et al. Resistin is elevated following traumatic joint injury and causes matrix degradation and release of inflammatory cytokines from articular cartilage in vitro. Osteoarthritis Cartilage 2009;17:613e20. 74. Brentano F, Schorr O, Ospelt C, Stanczyk J, Gay RE, Gay S, 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 2007;56:2829e39. 75. Gosset M, Berenbaum F, Salvat C, Sautet A, Pigenet A, Tahiri K, et al. Crucial role of visfatin/pre-B cell colony-enhancing factor in matrix degradation and prostaglandin E2 synthesis in chondrocytes: possible influence on osteoarthritis. Arthritis Rheum 2008;58:1399e409. 76. Reid IR. Relationships between fat and bone. Osteoporos Int 2008;19:595e606. 77. Chen TH, Chen L, Hsieh MS, Chang CP, Chou DT, Tsai SH. Evidence for a protective role for adiponectin in osteoarthritis. Biochim Biophys Acta 2006;1762:711e8. 78. Ku JH, Lee CK, Joo BS, An BM, Choi SH, Wang TH, et al. Correlation of synovial fluid leptin concentrations with the severity of osteoarthritis. Clin Rheumatol 2009. 79. Shine B, Bourne JT, Begum Baig F, Dacre J, Doyle DV. C reactive protein and immunoglobulin G in synovial fluid and serum in joint disease. Ann Rheum Dis 1991;50:32e5. 80. Wallis WJ, Simkin PA, Nelp WB. Protein traffic in human synovial effusions. Arthritis Rheum 1987;30:57e63. 81. Ushiyama T, Chano T, Inoue K, Matsusue Y. Cytokine production in the infrapatellar fat pad: another source of cytokines in knee synovial fluids. Ann Rheum Dis 2003;62:108e12. 82. Distel E, Cadoudal T, Durant S, Poignard A, Chevalier X, Benelli C. The infrapatellar fat pad in knee osteoarthritis: an important source of interleukin-6 and its soluble receptor. Arthritis Rheum 2009;60:3374e7.
Review
The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: a narrative review S. Clockaerts yz *, Y.M. Bastiaansen-Jenniskens z, J. Runhaar z, G.J.V.M. Van Osch z, J.F. Van Offel y, J.A.N. Verhaar z, L.S. De Clerck y, J. Somville y y University of Antwerp, Department of Medicine, Belgium z Erasmus MC, University Medical Center Rotterdam, The Netherlands
a r t i c l e i n f o
s u m m a r y
Article history: Received 8 December 2009 Accepted 22 March 2010
Introduction: Osteoarthritis (OA) of the knee joint is caused by genetic and hormonal factors and by inflammation, in combination with biomechanical alterations. It is characterized by loss of articular cartilage, synovial inflammation and subchondral bone sclerosis. Considerable evidence indicates that the menisci, ligaments, periarticular muscles and the joint capsule are also involved in the OA process. This paper will outline the theoretical framework for investigating the infrapatellar fat pad (IPFP) as an additional joint tissue involved in the development and progression of knee-OA. Methods: A literature search was performed in Pubmed from 1948 until October 2009 with keywords InFrapatellar fat pad, Hoffa fat pad, intraarticular adipose tissue, knee, cartilage, bone, cytokine, adipokine, inflammation, growth factor, arthritis, and OA. Results: The IPFP is situated intracapsularly and extrasynovially in the knee joint. Besides adipocytes, the IPFP from patients with knee-OA contains macrophages, lymphocytes and granulocytes, which are able to contribute to the disease process of knee-OA. Furthermore, the IPFP contains nociceptive nerve fibers that could in part be responsible for anterior pain in knee-OA. These nerve fibers secrete substance P, which is able to induce inflammatory responses and cause vasodilation, which may lead to IPFP edema and extravasation of the immune cells. The IPFP secretes cytokines, interleukins, growth factors and adipokines that influence cartilage by upregulating the production of matrix metalloproteinases (MMPs), stimulating the expression of proinflammatory cytokines and inhibiting the production of cartilage matrix proteins. They may also stimulate the production of pro-inflammatory mediators, growth factors and MMPs in synovium. Conclusion: These data are consistent with the hypothesis that the IPFP is an osteoarthritic joint tissue capable of modulating inflammatory and destructive responses in knee-OA. Ó 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Keywords: Infrapatellar fat pad Knee osteoarthritis Adipose tissue Inflammation
Introduction In the recent past, knee osteoarthritis (OA) was considered as a pathologic condition that affects cartilage and bone. We now appreciate that all joint tissues, including the synovium, menisci, ligaments, periarticular muscles and the joint capsule are involved1. In addition to these structures, the knee joint also contains adipose tissue: the infrapatellar fat pad (IPFP)2. Although it has been known that adipose tissue secretes inflammatory mediators that are able to influence cartilage and synovium, a theoretical framework for a role of the IPFP in knee-OA has not been described3.
Considering the intraarticular location of the IPFP, the metabolic properties of adipose tissue and the fact that the OA disease process involves all the joint tissues, it is likely that the IPFP could also be involved in knee-OA. Our hypothesis is that immune cells could infiltrate IPFP as a result of knee-OA and that the combination of immune cells, nerve fibers and adipocytes could then contribute to the disease process by producing and releasing inflammatory mediators, capable of modifying inflammatory and destructive responses in cartilage and synovium (Fig. 1). In this article, an overview is given of literature that supports this hypothesis. Methods
* Address correspondence and reprint requests to: Stefan Clockaerts, University Hospital of Antwerp, Department of Orthopaedic Surgery and Traumatology, Wilrijkstraat 10, 2650 Edegem, Belgium. Tel: 0032-486-62-76-84. E-mail address: [email protected] (S. Clockaerts).
A literature search was performed in Pubmed from 1948 until October 2009 using keywords intrapatellar fat pad, Hoffa fat pad, inFrapatellar adipose tissue, knee, cartilage, bone, cytokine,
1063-4584/$ e see front matter Ó 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.joca.2010.03.014
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877
Synovial layer
Articular cartilage Infrapatellar fat pad INFLAMMATION Fat pad edema Extravasation of WBC lymphocytes granulocytes monocytes Blood vessel
Substance P
Synovial fluid Interleukins Growth factors Nitric oxide Leukotrienes Prostaglandines
Leptin Adiponectin NAMPT Resistin Adipocytes
Sensory nerve (C-fibre)
Osteophytosis Articular cartilage
Fig. 1. A schematic overview of the IPFP as an active osteoarthritic joint tissue. The IPFP shows signs of inflammation secondary to OA of the knee joint. The IPFP contains adipocytes and has an increased number of immune cells such as lymphocytes, monocytes and granulocytes that have migrated from the blood circulation. Substance P nerve fibers are also present in the IPFP and contribute to the immune regulation within the IPFP by the secretion of substance P. Substance P is able to induce extravasation of white blood cells and is also known to enhance inflammation in white blood cells. The combination of these cells is able to secrete adipokines such as leptin, adiponectin, NAMPT and resistin, but also ILs, growth factors, nitric oxide, leukotrienes and prostaglandins which have shown to influence cartilage, synovium and osteophyte formation.
adipokine, inflammation, growth factor, arthritis, OA. We excluded papers that were not written in English. Cadaver knee joints were dissected to make photographs and figures. Results Inflammation in OA Considerable evidence indicates that OA has a multifactorial etiology with a combination of biomechanical, genetic, inflammatory and hormonal factors4e7. Abnormal biomechanical loading is an etiological factor in OA that can be caused by partial or total meniscectomy, malalignement, joint instability, muscle weakness or peripheral neuropathy, and obesity5,8. In addition to tissue damage or wear, repeated overloading of joints activates mechanoreceptors in chondrocytes and osteoblasts, which in turn activates inflammatory pathways that lead to the production of cartilage degradation mediators9e12. Several lines of evidence indicate that genetic abnormalities can result in an early initiation of OA. For knee-OA, the influence of genetics on the onset of OA is believed to be between 39 and 65%. Many of these genes affect extracellular cartilage matrix and cartilage signaling molecules7. Inflammatory pathways are known to play a role in the development of OA. Clinical features of inflammation, such as joint pain, swelling and stiffness, are indeed present during clinical examination13. Inflammatory mediators, such as interleukin (IL)1b and
tumor necrosis factor (TNF)a, are released by cartilage, bone, synovium and other surrounding joint tissues and are capable of inducing matrix metalloproteinases (MMPs), aggrecanases and other catabolic genes5,14. This causes remodeling of the extracellular cartilage matrix. These inflammatory mediators induce the production of prostaglandin E2 by stimulating the expression or activity of cyclooxygenase (COX)2, microsomal prostaglandin E2 synthase 1 (mPGES1), and soluble phospholipase A2 (sPLA2)14. They also upregulate the production of nitric oxide via inducible nitric oxide synthetase (iNOS) and induce pro-inflammatory cytokines such as IL1, TNFa, IL6, leukemia inhibitory factor (LIF), IL17, IL18, and chemokines, including IL8. The expression of a number of genes associated with a differentiated chondrocyte phenotype, including collagen type II is suppressed by inflammatory mechanisms5,14,15. Transforming growth factor (TGF)b produced by synovial macrophages, is shown able to induce the formation of osteophytes in animal studies16,17. Inflammatory events in the subchondral bone layer may induce hypertropic differentiation of chondrocytes or stimulate chondrocytes in a paracrine manner18e20. However, it is not known whether the subchondral bone inflammation is partly caused or stimulated by inflammatory mediators present in osteoarthritic joints.
Obesity is associated with OA Obesity and high body mass index are associated with a higher incidence risk of OA9. Changed kinetics of weight-bearing joints can
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lead to the initiation and progression of OA, and obesity could enhance this mechanism by increasing the loading forces21,22. However, non-weight-bearing joints such as joints of the hand also have higher incidence risk for OA in obese people compared to healthy people23e27. Furthermore, Toda et al. showed that the loss of body fat is more beneficial for symptomatic relief in knee-OA than the loss of body weight28. Wang reported a correlation between the risk of primary knee or hip replacement for OA and central obesity or adipose mass. The latter could be explained by the higher amount of visceral adipose tissue, which is known to secrete more pro-inflammatory cytokines compared to peripheral subcutaneous adipose tissue29. These data suggest that adipose tissue is an endocrine organ that is able to exert metabolic effects on the joint tissues. The IPFP or Hoffa’s fat pad is located in the knee joint The IPFP or Hoffa fat pad was first described by Albert Hoffa in 190430. It is situated in the knee underneath the patella, between the patellar tendon, femoral condyle and tibial plateau, where it completely fills the potential spaces between these structures (Fig. 2). Therefore, it is located closely to the synovial layers and cartilage surfaces of the knee joint (Figs. 2 and 3). The IPFP is composed of a fibrous scaffold, on which constitutional fat tissue is embedded, which is developed under the influence of sex hormones. The joint facing surface is covered by the antero-inferior synovial membrane, thus the IPFP localization can be described as intracapsular and extrasynovial31,32. It attaches to the lower border of the inner non-articulating surface of the patella, to the notch between the two condyles of the femur by running continuously with the infrapatellar plica posterosuperiorly, and to the periosteum of the tibia and the anterior part of the menisci2 (Fig. 3). An extensive anastomotic network of vessels protects the IPFP against
Fig. 3. A dissection of a left knee in flexion showing the IPFP from an anterior view (broken lines). The patella tendon has been dissected proximally and retracted to show the joint facing surface of the patella and the IPFP. The IPFP is located in the knee joint and closely to the articulating cartilage surfaces and the synovium. Notice the attachments of the IPFP at the lower border of the patella (black arrows). The attachment at the intercondylar region with the ligamentum mucosum (white arrow) is located before the anterior cruciate ligament.
necrosis during extensive surgical exposures or arthroscopic procedures33. Only the central portion of the IPFP has a more limited vascular network. It is supplied by branches of the superior and inferior genicular artery. The inferior portion of the anastomotic ring passes through the IPFP and supplies part of the patella31,34,35. Many studies mention that the IPFP is innervated by the posterior articular branch of the tibial nerve36e38. However, in one of the most detailed studies about innervation of the knee, Gardner39 describes branches rising from the saphenous, tibial and obturator nerves, and the nerve to the vastus medialis, innervating the anteromedial portion of the IPFP. The anterolateral part of the IPFP is innervated by articular branches from the nerve to the vastus lateralis, the tibial nerve, recurrent peroneal nerve and common peroneal nerve. These branches accompany blood vessels throughout the IPFP39. IPFP facilitates the distribution of synovial fluid and may act to absorb forces through the knee joint. Other functions of the IPFP have not yet been determined. Pathologic processes that occur within the IPFP are Hoffa disease, chondromas, nodular synovitis and surgery related complications. Other small fat pads of the knee joint have been mentioned: a posterior knee fat pad, an anterior suprapatellar fat pad (quadriceps) and a posterior suprapatellar fat pad (prefemoral) (Fig. 2)40.
The IPFP contains cells capable of modifying the OA disease process
Fig. 2. A midsagittal plane of the knee joint. This figure shows the location of the IPFP (1) and also the presence of other smaller fat pads in the knee joint: posterior fat pad (2), anterior suprapatellar fat pad (3) and posterior suprapatellar fat pad (4). The IPFP is located inferior from the patella and posterior from the patella tendon. It is covered by the joint capsule (white arrow) from anterior and the synovium (black arrow) on his joint facing surface. Thus it is located intracapsular, but extrasynovial. Also notice its close contact with articulating cartilage surfaces.
Once it was thought that white adipose tissue acted only as a reservoir for excess calories that are stored as triacylglycerols. After the discovery of leptin in 1994 it became tangible that the white adipose tissue could play an active role in physiologic and pathologic processes, including immunology and inflammation41,42. The adipose tissue is considered as a specialized form of connective tissue, which contains large numbers of adipocytes, fibroblasts, macrophages, leukocytes, and other cells involved in inflammation. These cells are present in an intercellular matrix consisting of collagen and elastic fibers, on which network epithelial structures can rest and muscle and nervous tissue are embedded41. The IPFP is a very sensitive structure together with the synovium43. This is due to the presence of peptidergic C-fibers, nerve
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fibers staining positive for substance P44. The human OA IPFP contains even more small sized nerves compared to medium- or large sized substance P nerves45. This suggests that the IPFP contains part of the terminal sensory innervation for the knee joint and could be an important source of pain in knee-OA. The highest rates of substance P nerves are found around vessels of IPFP: substance P causes vasodilation that leads to extravasation of immune cells and causes IPFP edema. In turn, edema leads to soft tissue impingement, ischemia and lipomatous tissue necrosis44. The presence of IPFP edema was investigated in vivo by Lawson et al. on MRI in patients with Lyme arthritis. Results of this study indicate that IPFP edema can develop as a result of arthritis46. Ischemia induces the release of neuro-tropin neural growth factor, which in turn activates the release of substance P. This type of autostimulation may cause chronicity of inflammation of the IPFP in joint diseases44. O’Shaughnessy et al. showed that substance P induces the production of nitric oxide in rheumatoid synoviocytes and experimental models of inflammation47. Furthermore, it stimulates IL1b, TNFa, nuclear factor kB and superoxide anion production in various cell types. Substance P has also a strong effect on fibroblast activation and extracellular matrix production45. Sympathetic nerve fibers are known to secrete anti-inflammatory norepinephrine and endogenous opiods that are able to inhibit pain perception in a bidirectional cross talk with substance P fibers45. In healthy synovium the density of sensory vs sympathetic nerve fibers is balanced at 1:148. In synovium from rheumatoid arthritis patients, the preponderance of the substance P positive nerve fibers over sympathetic nerve fibers is approximately 8:1. For the IPFP, the ratio of sensory vs sympathetic nerve fibers is higher in patients with anterior knee pain after total knee arthroplasty then in patients with knee-OA45. Whether the density of sensory nerve fibers was higher than normal in the IPFP of knee-OA patients has not yet been established. Based on these findings, we conclude that substance P nerves are present in IPFP and can act as inflammatory cells, besides the well described sensory function of these nerves. An increased amount of immune cells, edema, fat necrosis and fibrosis was reported in subsynovial IPFP in animal models of induced arthritis, together with signs of alterations in joint diseases that involve synovial proliferation on MRI images31,49e52. Inflammatory cell infiltrations were present in 36% of Hoffa fat pad specimens collected from patients with knee-OA while severe fibrosis was present in 33% of cases53. An OA animal model revealed that the wet weight of IPFP in monoiodoacetate injected joints was two-fold higher than the vehicle controls. Numbers of neutrophils, eosinophils and basophils, and in particular monocytes were increased37. Jedrzejczyk et al. also found lymphocytes in the IPFP54. The infiltration of immune cells in synovium could contribute to the OA disease process by the production of pro-inflammatory and/ or pro-fibrotic cytokines16,17,55,56. Based on the anatomical location of the IPFP, it is possible that similar processes exist for immune cells in the IPFP. Cartilage breakdown molecules may activate monocytes by binding to receptors that are associated with receptors of innate immunity57. Activated macrophages produce various growth factors, cytokines and enzymes that enhance osteophyte formation, mitigate cartilage breakdown by MMP activity, induce joint effusion by vasodilation and might influence subchondral bone metabolism. Neutrophils play a role in cartilage breakdown and necrosis of adipose tissue by the production of cytokines such as IL1, IL8 and MMP837,58. Eosinophils and basophils release histamine that increases production of matrix degrading enzymes and proinflammatory mediators in synovial fibroblasts and cartilage59. Lymphocytes from OA joints express Th1 cytokines which can directly degrade cartilage or activate macrophages through cellecell interaction to produce cartilage degrading mediators60.
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We conclude that IPFP contains inflammatory cells and substance P nerve cells that could be able to influence inflammatory and destructive responses in knee-OA. Substance P nerve cells in the IPFP could also play a role in the pain pathophysiology of knee-OA. Adipose tissue as an endocrine organ Adipose tissue secretes cytokines, ILs, growth factors and adipokines in an endocrine, autocrine or paracrine manner. These inflammatory mediators are found in synovial fluid and are able to influence the cartilage and synovium metabolism3,61,62. The immune cells present in the adipose tissue could be responsible for most of the production and release of inflammatory mediators, except for leptin and adiponectin, which are mainly secreted by adipocytes41 (Fig. 1). Interesting adipokines are leptin and adiponectin, as they are secreted in high amounts by adipose tissue41,61,63. Leptin was thought to be beneficial for OA, because injection of leptin in a knee joint upregulated proteoglycan synthesis, production of growth factors and stimulated its own synthesis in different joint tissues3,61. However, recent research has contradicted this idea. At present, leptin is known to stimulate IL1b production, to increase the effect of pro-inflammatory cytokines and induce the expression of MMPs in the OA cartilage3,64e68. Leptin is able to activate nitric oxide synthase synergistically with interferon-g or to enhance activation of nitric oxide synthase 2 by IL165. Leptin also facilitates the activation of macrophages, neutrophils, dendritic cells, natural killers cells and Th1 cells69. Adiponectin has been cited as a protective adipokine against obesity and vascular diseases, but might act as a pro-inflammatory agent in joint diseases70. Adiponectin induces MMP1 and IL6 production in synovial fibroblasts, which are known to have adiponectin receptors71. The presence of adiponectin receptors in chondrosarcoma cells, capable of inducing type 2 nitric oxide synthase, suggests that adiponectin receptors are also present in normal or OA chondrocytes72. Indeed, adiponectin treated chondrocytes produce IL6, MMP3, MMP9 and monocyte chemoattractant protein (MCP)163. Other adipokines are resistin and nicotinamide phosphoribosyltransferase (NAMPT). Resistin is elevated after traumatic joint injuries and induces production of inflammatory cytokines and loss of proteoglycans in cartilage. The injection of resistin into mice joints induces arthritis-like conditions70,73. NAMPT seems to have a pro-inflammatory effect on chondrocytes and synovial fibroblasts70,74,75. The role of adipokines on bone is not yet clarified. Leptin and resistin may stimulate bone formation and adiponectin might have an inhibitory effect76. Many other inflammatory mediators such as IL1a and b, TNFa, IL4, IL6, IL8, IL10, IL18, IL1 receptor antagonist, MCP1, prostaglandin E2, nitric oxide and growth factors such as vascular endothelial growth factor (VEGF), TGFb and fibroblast growth factor (FGF)2 are produced by adipose tissue and have shown to be involved in joint diseases3,41. IPFP produces and releases inflammatory mediators in the knee joint The adipokines leptin, resistin and adiponectin are found in the synovial fluid61,62,67,77. The concentration of adipokines in the synovial fluid differs from serum levels. Resistin and adiponectin are present in lower amounts in the synovial fluid than in circulating blood, while leptin is present in higher amounts66,77. A correlation between leptin concentration in the synovial fluid and severity of knee-OA has been shown by Ku et al.78.
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The presence of adipokines in the knee joint cannot be explained by a higher permeability of the inflamed synovium alone, because resistin is present in lower concentration in synovial fluid than leptin, although its molecular weight is similar79,80. Leptin is present in higher amount in synovial fluid from female OA patients, but interestingly not in male OA patients. Except for adiponectin, the synovial fluid levels of resistin and leptin appears to be higher for women then for men. This effect cannot be explained by the higher serum levels of leptin in woman, caused by influence of sex hormones, because the synovium fluid/serum level ratios between men and women are also different66. Ushiyama et al. showed that the human OA IPFP contained significant protein levels of FGF2, VEGF, TNFa and IL6. These cytokines were also measured in the synovial fluid. Although synovial fluid levels and IPFP content did not correlate, a similar distribution of FGF2 and VEGF content was found in human OA synovium compared to IPFP81. Presle showed that cultured explants of IPFP produced large amounts of adiponectin and leptin, although surprisingly explants obtained from osteophytes produced even more leptin66. The amount of IL6, soluble IL6 receptor and adiponectin that is produced by the IPFP is higher than in subcutaneous adipose tissue from obese people, although the production of leptin is lower. These data, together with a decrease of genes related to lipid metabolism in the IPFP, indicate that the IPFP should be regarded as adipose tissue with its own characteristics82. Intraarticular production of inflammatory mediators can occur in different joint tissues such as cartilage, synovium, menisci or osteophytes66. Based on these findings, we conclude that IPFP is also able to produce and excrete important inflammatory mediators directly into the knee joint. Discussion This article reviews some significant points that could explain the role of the IPFP in the disease process of knee-OA. Inflammation plays an important role in the etiopathogenesis of OA. The association between obesity and OA cannot only be explained by biomechanical alterations, but also by the inflammatory properties of adipose tissue. The IPFP can be regarded as a special form of adipose tissue due to its location, which is in close contact with synovial layers and articulating cartilage. Infiltration of immune cells has been demonstrated in the IPFP in human OA joints and in animal models for arthritis and OA. Furthermore, nociceptive nerve fibers are present that can cause anterior pain and are capable of maintaining inflammation by the release of substance P. The combination of adipocytes, immune and nerve cells IPFP produces and secretes adipokines, but also cytokines, chemokines and growth factors that are capable of altering cartilage and synovium. Further in vitro and in vivo studies should be performed to confirm the release of inflammatory mediators in the synovial compartment. It should be investigated whether the IPFP from knee-OA patients produces more inflammatory mediators than healthy IPFP and whether IPFP from obese people differs from non-obese people in content or production of cytokines. Furthermore, adipose tissue secretes anti-inflammatory mediators such as FGF2, IL4 or IL10, which could have beneficial effects on cartilage and synovium41. Therefore, effects of the combination of all factors secreted by the IPFP on cartilage should be explored. It should be investigated whether substance P fibers are present in higher amounts in the IPFP from osteoarthritic knees as compared to healthy knee joints. Furthermore, their potential role in pain and inflammation in knee-OA should be elucidated.
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