Osteoarthritis and Cartilage 18 (2010) 876e882

Review

The infrapatellar fat pad should be considered as an active osteoarthritic jointtissue: 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 yyUniversity of Antwerp, Department of Medicine, Belgiumz Erasmus MC, University Medical Center Rotterdam, The Netherlands

a r t i c l e i n f o

Article history:Received 8 December 2009Accepted 22 March 2010

Keywords:Infrapatellar fat padKnee osteoarthritisAdipose tissueInflammation

* Address correspondence and reprint requests to:Hospital of Antwerp, Department of OrthopaedicWilrijkstraat 10, 2650 Edegem, Belgium. Tel: 0032-48

E-mail address: stefan.clockaerts@ua.ac.be (S. Cloc

1063-4584/$ e see front matter � 2010 Osteoarthritidoi:10.1016/j.joca.2010.03.014

s u m m a r y

Introduction: Osteoarthritis (OA) of the knee joint is caused by genetic and hormonal factors and byinflammation, in combination with biomechanical alterations. It is characterized by loss of articularcartilage, synovial inflammation and subchondral bone sclerosis. Considerable evidence indicates thatthe 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 anadditional 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 keywordsInFrapatellar fat pad, Hoffa fat pad, intraarticular adipose tissue, knee, cartilage, bone, cytokine, adipo-kine, inflammation, growth factor, arthritis, and OA.Results: The IPFP is situated intracapsularly and extrasynovially in the knee joint. Besides adipocytes, theIPFP from patients with knee-OA contains macrophages, lymphocytes and granulocytes, which are ableto contribute to the disease process of knee-OA. Furthermore, the IPFP contains nociceptive nerve fibersthat 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 edemaand extravasation of the immune cells.The IPFP secretes cytokines, interleukins, growth factors and adipokines that influence cartilage byupregulating the production of matrix metalloproteinases (MMPs), stimulating the expression of pro-inflammatory cytokines and inhibiting the production of cartilage matrix proteins. They may alsostimulate 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 tissuecapable of modulating inflammatory and destructive responses in knee-OA.

� 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Introduction

In the recent past, knee osteoarthritis (OA) was considered asa pathologic condition that affects cartilage and bone. We nowappreciate 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 adiposetissue: the infrapatellar fat pad (IPFP)2. Although it has been knownthat adipose tissue secretes inflammatory mediators that are ableto influence cartilage and synovium, a theoretical framework fora role of the IPFP in knee-OA has not been described3.

Stefan Clockaerts, UniversitySurgery and Traumatology,6-62-76-84.kaerts).

s Research Society International. P

Considering the intraarticular location of the IPFP, the metabolicproperties of adipose tissue and the fact that the OA disease processinvolves all the joint tissues, it is likely that the IPFP could also beinvolved in knee-OA. Our hypothesis is that immune cells couldinfiltrate IPFP as a result of knee-OA and that the combination ofimmune cells, nerve fibers and adipocytes could then contribute tothe disease process by producing and releasing inflammatorymediators, capable of modifying inflammatory and destructiveresponses in cartilage and synovium (Fig. 1). In this article, anoverview is given of literature that supports this hypothesis.

Methods

A literature search was performed in Pubmed from 1948 untilOctober 2009 using keywords intrapatellar fat pad, Hoffa fat pad,inFrapatellar adipose tissue, knee, cartilage, bone, cytokine,

ublished by Elsevier Ltd. All rights reserved.

INFLAMMATION

Articular cartilage

Fat pad edema

Extravasation of WBC

Adipocytes

Sensory nerve(C-fibre)

Blood vessel

Infrapatellar

fat pad

Synovial

fluid

InterleukinsGrowth factorsNitric oxideLeukotrienesProstaglandines

LeptinAdiponectinNAMPTResistin

monocytes

lymphocytesgranulocytes

Substance P

Articular cartilage

Synovial layer

Osteophytosis

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 adipocytesand 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 alsopresent 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 isalso 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.

S. Clockaerts et al. / Osteoarthritis and Cartilage 18 (2010) 876e882 877

adipokine, inflammation, growth factor, arthritis, OA. We excludedpapers that were not written in English. Cadaver knee joints weredissected to make photographs and figures.

Results

Inflammation in OA

Considerable evidence indicates that OA has a multifactorialetiology with a combination of biomechanical, genetic, inflamma-tory and hormonal factors4e7. Abnormal biomechanical loading isan etiological factor in OA that can be caused by partial or totalmeniscectomy, malalignement, joint instability, muscle weaknessor peripheral neuropathy, and obesity5,8. In addition to tissuedamage or wear, repeated overloading of joints activates mecha-noreceptors in chondrocytes and osteoblasts, which in turn acti-vates inflammatory pathways that lead to the production ofcartilage degradation mediators9e12.

Several lines of evidence indicate that genetic abnormalities canresult in an early initiation of OA. For knee-OA, the influence ofgenetics on the onset of OA is believed to be between 39 and 65%.Many of these genes affect extracellular cartilage matrix andcartilage signaling molecules7.

Inflammatory pathways are known to play a role in the devel-opment of OA. Clinical features of inflammation, such as joint pain,swelling and stiffness, are indeed present during clinical exami-nation13. 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 ofinducing matrix metalloproteinases (MMPs), aggrecanases andother catabolic genes5,14. This causes remodeling of the extracel-lular cartilage matrix. These inflammatory mediators induce theproduction of prostaglandin E2 by stimulating the expression oractivity of cyclooxygenase (COX)2, microsomal prostaglandin E2synthase 1 (mPGES1), and soluble phospholipase A2 (sPLA2)14.They also upregulate the production of nitric oxide via induciblenitric oxide synthetase (iNOS) and induce pro-inflammatory cyto-kines such as IL1, TNFa, IL6, leukemia inhibitory factor (LIF), IL17,IL18, and chemokines, including IL8. The expression of a number ofgenes associated with a differentiated chondrocyte phenotype,including collagen type II is suppressed by inflammatory mecha-nisms5,14,15. Transforming growth factor (TGF)b produced bysynovial macrophages, is shown able to induce the formation ofosteophytes in animal studies16,17. Inflammatory events in thesubchondral bone layer may induce hypertropic differentiation ofchondrocytes or stimulate chondrocytes in a paracrine man-ner18e20. However, it is not known whether the subchondral boneinflammation is partly caused or stimulated by inflammatorymediators present in osteoarthritic joints.

Obesity is associated with OA

Obesity and high body mass index are associated with a higherincidence risk of OA9. Changed kinetics of weight-bearing joints can

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 showthe joint facing surface of the patella and the IPFP. The IPFP is located in the knee jointand closely to the articulating cartilage surfaces and the synovium. Notice theattachments of the IPFP at the lower border of the patella (black arrows). Theattachment at the intercondylar region with the ligamentum mucosum (white arrow)is located before the anterior cruciate ligament.

S. Clockaerts et al. / Osteoarthritis and Cartilage 18 (2010) 876e882878

lead to the initiation and progression of OA, and obesity couldenhance this mechanism by increasing the loading forces21,22.However, non-weight-bearing joints such as joints of the hand alsohave higher incidence risk for OA in obese people compared tohealthy people23e27. Furthermore, Toda et al. showed that the lossof body fat is more beneficial for symptomatic relief in knee-OAthan the loss of body weight28. Wang reported a correlationbetween the risk of primary knee or hip replacement for OA andcentral obesity or adipose mass. The latter could be explained bythe higher amount of visceral adipose tissue, which is known tosecrete more pro-inflammatory cytokines compared to peripheralsubcutaneous adipose tissue29. These data suggest that adiposetissue is an endocrine organ that is able to exert metabolic effectson 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 in190430. It is situated in the knee underneath the patella, betweenthe patellar tendon, femoral condyle and tibial plateau, where itcompletely fills the potential spaces between these structures(Fig. 2). Therefore, it is located closely to the synovial layers andcartilage surfaces of the knee joint (Figs. 2 and 3). The IPFP iscomposed of a fibrous scaffold, on which constitutional fat tissue isembedded, which is developed under the influence of sexhormones. The joint facing surface is covered by the antero-inferiorsynovial membrane, thus the IPFP localization can be described asintracapsular and extrasynovial31,32. It attaches to the lower borderof the inner non-articulating surface of the patella, to the notchbetween the two condyles of the femur by running continuouslywith the infrapatellar plica posterosuperiorly, and to the perios-teum of the tibia and the anterior part of the menisci2 (Fig. 3). Anextensive anastomotic network of vessels protects the IPFP against

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 islocated inferior from the patella and posterior from the patella tendon. It is covered bythe joint capsule (white arrow) from anterior and the synovium (black arrow) on hisjoint facing surface. Thus it is located intracapsular, but extrasynovial. Also notice itsclose contact with articulating cartilage surfaces.

necrosis during extensive surgical exposures or arthroscopicprocedures33. Only the central portion of the IPFP has a morelimited vascular network. It is supplied by branches of the superiorand inferior genicular artery. The inferior portion of the anasto-motic ring passes through the IPFP and supplies part of thepatella31,34,35. Many studies mention that the IPFP is innervated bythe posterior articular branch of the tibial nerve36e38. However, inone of the most detailed studies about innervation of the knee,Gardner39 describes branches rising from the saphenous, tibial andobturator nerves, and the nerve to the vastus medialis, innervatingthe anteromedial portion of the IPFP. The anterolateral part of theIPFP is innervated by articular branches from the nerve to thevastus lateralis, the tibial nerve, recurrent peroneal nerve andcommon peroneal nerve. These branches accompany blood vesselsthroughout the IPFP39.

IPFP facilitates the distribution of synovial fluid and may act toabsorb forces through the knee joint. Other functions of the IPFPhave not yet been determined. Pathologic processes that occurwithin the IPFP are Hoffa disease, chondromas, nodular synovitisand surgery related complications. Other small fat pads of the kneejoint have been mentioned: a posterior knee fat pad, an anteriorsuprapatellar fat pad (quadriceps) and a posterior suprapatellar fatpad (prefemoral) (Fig. 2)40.

The IPFP contains cells capable of modifying the OA disease process

Once it was thought that white adipose tissue acted only asa reservoir for excess calories that are stored as triacylglycerols. Afterthe discovery of leptin in 1994 it became tangible that the whiteadipose tissue could play an active role in physiologic and pathologicprocesses, including immunology and inflammation41,42. Theadipose tissue is considered as a specialized form of connectivetissue, which contains large numbers of adipocytes, fibroblasts,macrophages, leukocytes, and other cells involved in inflammation.These cells are present in an intercellular matrix consisting ofcollagen and elastic fibers, on which network epithelial structurescan rest and muscle and nervous tissue are embedded41.

The IPFP is a very sensitive structure together with the syno-vium43. This is due to the presence of peptidergic C-fibers, nerve

S. Clockaerts et al. / Osteoarthritis and Cartilage 18 (2010) 876e882 879

fibers staining positive for substance P44. The human OA IPFPcontains even more small sized nerves compared to medium- orlarge sized substance P nerves45. This suggests that the IPFPcontains part of the terminal sensory innervation for the knee jointand could be an important source of pain in knee-OA.

The highest rates of substance P nerves are found around vesselsof IPFP: substance P causes vasodilation that leads to extravasationof immune cells and causes IPFP edema. In turn, edema leads to softtissue impingement, ischemia and lipomatous tissue necrosis44.The presence of IPFP edema was investigated in vivo by Lawsonet al. on MRI in patients with Lyme arthritis. Results of this studyindicate 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 ofautostimulation may cause chronicity of inflammation of the IPFPin joint diseases44. O’Shaughnessy et al. showed that substance Pinduces the production of nitric oxide in rheumatoid synoviocytesand experimental models of inflammation47. Furthermore, itstimulates IL1b, TNFa, nuclear factor kB and superoxide anionproduction in various cell types. Substance P has also a strong effecton fibroblast activation and extracellular matrix production45.

Sympathetic nerve fibers are known to secrete anti-inflamma-tory norepinephrine and endogenous opiods that are able to inhibitpain perception in a bidirectional cross talk with substance Pfibers45. In healthy synovium the density of sensory vs sympatheticnerve fibers is balanced at 1:148. In synovium from rheumatoidarthritis patients, the preponderance of the substance P positivenerve fibers over sympathetic nerve fibers is approximately 8:1. Forthe IPFP, the ratio of sensory vs sympathetic nerve fibers is higher inpatients with anterior knee pain after total knee arthroplasty thenin patients with knee-OA45. Whether the density of sensory nervefibers was higher than normal in the IPFP of knee-OA patients hasnot yet been established. Based on these findings, we conclude thatsubstance P nerves are present in IPFP and can act as inflammatorycells, besides the well described sensory function of these nerves.

An increased amount of immune cells, edema, fat necrosis andfibrosis was reported in subsynovial IPFP in animal models ofinduced arthritis, together with signs of alterations in joint diseasesthat involve synovial proliferation on MRI images31,49e52. Inflam-matory cell infiltrations were present in 36% of Hoffa fat padspecimens collected from patients with knee-OA while severefibrosis was present in 33% of cases53. An OA animal model revealedthat the wet weight of IPFP in monoiodoacetate injected joints wastwo-fold higher than the vehicle controls. Numbers of neutrophils,eosinophils and basophils, and in particular monocytes wereincreased37. Jedrzejczyk et al. also found lymphocytes in the IPFP54.

The infiltration of immune cells in synovium could contribute tothe OA disease process by the production of pro-inflammatory and/or pro-fibrotic cytokines16,17,55,56. Based on the anatomical locationof the IPFP, it is possible that similar processes exist for immune cellsin the IPFP. Cartilage breakdownmoleculesmay activatemonocytesby binding to receptors that are associated with receptors of innateimmunity57. Activated macrophages produce various growthfactors, cytokines and enzymes that enhance osteophyte formation,mitigate cartilage breakdown byMMP activity, induce joint effusionby vasodilation andmight influence subchondral bonemetabolism.Neutrophils play a role in cartilage breakdown and necrosis ofadipose tissue by the production of cytokines such as IL1, IL8 andMMP837,58. Eosinophils and basophils release histamine thatincreases production of matrix degrading enzymes and pro-inflammatory mediators in synovial fibroblasts and cartilage59.Lymphocytes from OA joints express Th1 cytokines which candirectly degrade cartilage or activatemacrophages through cellecellinteraction to produce cartilage degrading mediators60.

We conclude that IPFP contains inflammatory cells andsubstance P nerve cells that could be able to influence inflamma-tory and destructive responses in knee-OA. Substance P nerve cellsin the IPFP could also play a role in the pain pathophysiology ofknee-OA.

Adipose tissue as an endocrine organ

Adipose tissue secretes cytokines, ILs, growth factors and adi-pokines in an endocrine, autocrine or paracrine manner. Theseinflammatory mediators are found in synovial fluid and are able toinfluence the cartilage and synovium metabolism3,61,62. Theimmune cells present in the adipose tissue could be responsible formost of the production and release of inflammatory mediators,except for leptin and adiponectin, which are mainly secreted byadipocytes41 (Fig. 1).

Interesting adipokines are leptin and adiponectin, as they aresecreted in high amounts by adipose tissue41,61,63. Leptin wasthought to be beneficial for OA, because injection of leptin in a kneejoint upregulated proteoglycan synthesis, production of growthfactors and stimulated its own synthesis in different jointtissues3,61. However, recent research has contradicted this idea. Atpresent, leptin is known to stimulate IL1b production, to increasethe effect of pro-inflammatory cytokines and induce the expressionof MMPs in the OA cartilage3,64e68. Leptin is able to activate nitricoxide synthase synergistically with interferon-g or to enhanceactivation of nitric oxide synthase 2 by IL165. Leptin also facilitatesthe activation of macrophages, neutrophils, dendritic cells, naturalkillers cells and Th1 cells69.

Adiponectin has been cited as a protective adipokine againstobesity and vascular diseases, but might act as a pro-inflammatoryagent in joint diseases70. Adiponectin induces MMP1 and IL6production in synovial fibroblasts, which are known to have adi-ponectin receptors71. The presence of adiponectin receptors inchondrosarcoma cells, capable of inducing type 2 nitric oxidesynthase, suggests that adiponectin receptors are also present innormal or OA chondrocytes72. Indeed, adiponectin treated chon-drocytes produce IL6, MMP3, MMP9 and monocyte chemo-attractant protein (MCP)163.

Other adipokines are resistin and nicotinamide phosphor-ibosyltransferase (NAMPT). Resistin is elevated after traumatic jointinjuries and induces production of inflammatory cytokines and lossof proteoglycans in cartilage. The injection of resistin into micejoints induces arthritis-like conditions70,73. NAMPT seems to havea pro-inflammatory effect on chondrocytes and synovial fibro-blasts70,74,75. The role of adipokines on bone is not yet clarified.Leptin and resistin may stimulate bone formation and adiponectinmight have an inhibitory effect76.

Many other inflammatory mediators such as IL1a and b, TNFa,IL4, IL6, IL8, IL10, IL18, IL1 receptor antagonist, MCP1, prostaglandinE2, nitric oxide and growth factors such as vascular endothelialgrowth factor (VEGF), TGFb and fibroblast growth factor (FGF)2 areproduced by adipose tissue and have shown to be involved in jointdiseases3,41.

IPFP produces and releases inflammatory mediators in the knee joint

The adipokines leptin, resistin and adiponectin are found in thesynovial fluid61,62,67,77. The concentration of adipokines in thesynovial fluid differs from serum levels. Resistin and adiponectinare present in lower amounts in the synovial fluid than in circu-lating blood, while leptin is present in higher amounts66,77. Acorrelation between leptin concentration in the synovial fluid andseverity of knee-OA has been shown by Ku et al.78.

S. Clockaerts et al. / Osteoarthritis and Cartilage 18 (2010) 876e882880

The presence of adipokines in the knee joint cannot beexplained by a higher permeability of the inflamed synovium alone,because resistin is present in lower concentration in synovial fluidthan leptin, although its molecular weight is similar79,80. Leptin ispresent 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 higherfor women then for men. This effect cannot be explained by thehigher serum levels of leptin in woman, caused by influence of sexhormones, because the synovium fluid/serum level ratios betweenmen and women are also different66.

Ushiyama et al. showed that the human OA IPFP containedsignificant protein levels of FGF2, VEGF, TNFa and IL6. These cyto-kines were also measured in the synovial fluid. Although synovialfluid levels and IPFP content did not correlate, a similar distributionof FGF2 and VEGF content was found in human OA synoviumcompared to IPFP81. Presle showed that cultured explants of IPFPproduced large amounts of adiponectin and leptin, althoughsurprisingly explants obtained from osteophytes produced evenmore leptin66.

The amount of IL6, soluble IL6 receptor and adiponectin that isproduced by the IPFP is higher than in subcutaneous adipose tissuefrom obese people, although the production of leptin is lower.These data, together with a decrease of genes related to lipidmetabolism in the IPFP, indicate that the IPFP should be regarded asadipose tissue with its own characteristics82.

Intraarticular production of inflammatory mediators can occurin different joint tissues such as cartilage, synovium, menisci orosteophytes66. Based on these findings, we conclude that IPFP isalso able to produce and excrete important inflammatory media-tors directly into the knee joint.

Discussion

This article reviews some significant points that could explainthe role of the IPFP in the disease process of knee-OA.

Inflammation plays an important role in the etiopathogenesis ofOA. The association between obesity and OA cannot only beexplained by biomechanical alterations, but also by the inflam-matory properties of adipose tissue. The IPFP can be regarded asa special form of adipose tissue due to its location, which is in closecontact with synovial layers and articulating cartilage.

Infiltration of immune cells has been demonstrated in the IPFPin human OA joints and in animal models for arthritis and OA.Furthermore, nociceptive nerve fibers are present that can causeanterior pain and are capable of maintaining inflammation by therelease of substance P. The combination of adipocytes, immune andnerve cells IPFP produces and secretes adipokines, but also cyto-kines, chemokines and growth factors that are capable of alteringcartilage and synovium.

Further in vitro and in vivo studies should be performed toconfirm the release of inflammatory mediators in the synovialcompartment. It should be investigated whether the IPFP fromknee-OA patients produces more inflammatory mediators thanhealthy IPFP and whether IPFP from obese people differs fromnon-obese people in content or production of cytokines.Furthermore, adipose tissue secretes anti-inflammatory media-tors such as FGF2, IL4 or IL10, which could have beneficial effectson cartilage and synovium41. Therefore, effects of the combina-tion of all factors secreted by the IPFP on cartilage should beexplored. It should be investigated whether substance P fibersare present in higher amounts in the IPFP from osteoarthriticknees as compared to healthy knee joints. Furthermore, theirpotential role in pain and inflammation in knee-OA should beelucidated.

We conclude that IPFP could play an important role in theinitiation and progression of knee-OA and should be furtherinvestigated in search for new therapeutic strategies.

Conflict of interestAll authors disclose any financial and personal relationships withother people or organizations that could inappropriately influencethis work.

Acknowledgments

The authors would like to thank D. Malan and F. Van Glabbeekfor providing anatomical figures and photographs. The research ofYvonne Bastiaansen-Jenniskens is funded by the Dutch ArthritisAssociation and Top Institute Pharma.

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