ARTHRITIS & RHEUMATISM
Vol. 60, No. 11, November 2009, pp 3374–3377
© 2009, American College of Rheumatology
The Infrapatellar Fat Pad in Knee Osteoarthritis
An Important Source of Interleukin-6 and Its Soluble Receptor
Emilie Distel,1Thomas Cadoudal,1Sylvie Durant,1Alexandre Poignard,2
Xavier Chevalier,2and Chantal Benelli1
Objective. Obesity is a potent risk factor in knee
osteoarthritis (OA). It has been suggested that adipo-
kines, secreted by adipose tissue (AT) and largely found
in the synovial fluid of OA patients, derive in part from
the infrapatellar fat pad (IFP), also known as Hoffa’s
fat pad. The goal of this study was to characterize IFP
tissue in obese OA patients and to compare its features
with thigh subcutaneous AT to determine whether the
IFP contributes to local inflammation in knee OA via
production of specific cytokines.
Methods. IFP and subcutaneous AT samples were
obtained from 11 obese women (body mass index >30
kg/m2) with knee femorotibial OA. Gene expression was
measured by real-time quantitative polymerase chain
reaction. Cytokine concentrations in plasma and in
conditioned media of cultured AT explants were deter-
mined by enzyme-linked immunosorbent assay or by
Luminex xMAP technology.
Results. In IFP tissue versus subcutaneous AT,
there was a decrease in the expression of genes for key
enzymes implicated in adipocyte lipid metabolism,
whereas the expression levels of genes for AT markers
remained similar. A 2-fold increase in the expression of
the gene for interleukin-6 (IL-6), a 2-fold increase in the
release of IL-6, and a 3.6-fold increase in the release of
soluble IL-6 receptor (sIL-6R) were observed in IFP
samples, compared with subcutaneous AT, but the rates
of secretion of other cytokines in IFP samples were
similar to the rates in subcutaneous AT. In addition,
leptin secretion was decreased by 40%, whereas adi-
ponectin secretion was increased by 70%, in IFP sam-
ples versus subcutaneous AT.
Conclusion. Our results indicate that the IFP
cytokine profile typically found in OA patients could
play a role in paracrine inflammation via the local
production of IL-6/sIL-6R and that such a profile might
contribute to damage in adjacent cartilage.
Obesity is a potent risk factor in the development
and progression of knee osteoarthritis (OA) (1). While
mechanical stress obviously contributes to this patho-
logic outcome in obese patients, the relationship be-
tween obesity and OA remains complex, since mechan-
ical stress alone cannot explain the link between obesity
and pathology in non–weight-bearing joints, such as
hand OA (1). Thus, other pathophysiologic functions of
the adipose tissue (AT) in obese patients could also be
involved. It has been well-established that AT releases
cytokines that may act in an autocrine, paracrine, or
endocrine manner (2). More specifically, among the
many biologically active proteins secreted by AT,
interleukin-6 (IL-6), tumor necrosis factor ? (TNF?),
and IL-1? are known to be involved in inflammation (3).
Adipokines are largely found in the synovial fluid
of patients with OA and rheumatoid arthritis (4). It has
been suggested that these adipokines might originate in
the infrapatellar fat pad (IFP), also known as Hoffa’s fat
pad. Hoffa’s fat pad is located between the lower surface
of the patella and the trochlear surface of the femur, in
an intracapsular but extrasynovial location, and was
initially thought to have a mainly biomechanical function
(5). The presence of several cytokines in the IFP has
been noted in a few previous studies (6,7). However,
these studies were performed in heterogeneous patient
1Emilie Distel, Thomas Cadoudal, PhD, Sylvie Durant, PhD,
Chantal Benelli, PhD: INSERM UMR-S 747, Universite ´ Paris Des-
cartes, Paris, France;
MD, PhD: Ho ˆpital Henri Mondor, Cre ´teil, France.
Ms Distel and Dr. Cadoudal contributed equally to this work.
Drs. Chevalier and Benelli contributed equally to this work.
Address correspondence and reprint requests to Chantal
Benelli, PhD, INSERM UMR-S 747, Centre Universitaire des Saints-
Pe `res, 45 Rue des Saints-Pe `res, F-75006 Paris, France. E-mail: chantal.
Submitted for publication April 1, 2009; accepted in revised
form July 11, 2009.
2Alexandre Poignard, MD, Xavier Chevalier,
groups with differences in inflammation levels and met-
abolic status. Furthermore, these studies provided no
evidence that this particular AT was different from other
“classic” ATs, such as subcutaneous AT, although it has
been well-established that AT has specific characteristics
according to its localization.
The aim of the present study was to characterize
IFP tissue from obese OA patients and to compare its
features with samples of thigh subcutaneous AT taken
from the same individuals, in order to determine
whether the IFP contributes to local inflammation in
knee OA via the production of specific cytokines.
PATIENTS AND METHODS
Samples and laboratory methods. We obtained IFP
tissue and thigh subcutaneous AT from 11 obese women (body
mass index [BMI] ?30 kg/m2) with knee femorotibial OA
(grade IV, according to the Kellgren/Lawrence scale ) who
were undergoing total knee replacement surgery. None of the
patients had known metabolic or malignant diseases, and none
were taking medications known to alter adipocyte metabolism.
Both IFP tissue and thigh subcutaneous AT were carefully
dissected in order to obtain AT explants. In IFP samples,
special care was taken to remove the synovial membrane. For
experiments with messenger RNA (mRNA), AT explants were
frozen in liquid nitrogen, whereas, for experiments with cyto-
kines, AT explants were incubated for 3 hours in Krebs
medium with 1% bovine serum albumin. Real-time quantita-
tive polymerase chain reaction was used to analyze mRNA.
Cytokine concentrations in plasma and in conditioned media
of cultured AT explants were determined by enzyme-linked
immunosorbent assay (ELISA), according to the manufactur-
er’s protocols for the Human Adiponectin/Acrp30 Quantikine
ELISA kit and the Human sIL-6R Quantikine ELISA kit
(R&D Systems, Abingdon, UK); other cytokines were mea-
sured using Plateforme Technologique Phe ´notypage du Petit
Animal et Microdosage (Ho ˆpital Saint Antoine, Paris, France).
The study was approved by the Institutional Ethics Committee
of Ho ˆpital Henri Mondor.
Statistical analysis. Pairwise comparisons were made
using the nonparametric Mann-Whitney U test, and analyses
were performed using StatView A (SAS Institute, Cary, NC).
Results are presented as the mean ? SEM. P values less than
0.05 were considered significant.
Characteristics of the patients included in this
study are shown in Table 1. The 11 women were all
obese (BMI ?30 kg/m2), and all had low-grade inflam-
mation (C-reactive protein ?10 mg/liter). However, all
patients had a high level of IL-6 in plasma.
First, in both IFP tissue and subcutaneous AT, we
determined expression levels of genes for key enzymes
that are involved, in one of the following ways, in
adipocyte lipid metabolism: lipid uptake (fatty acid
transport CD36 [FAT/CD36]), intracellular fatty acid
trafficking (fatty acid binding protein 4/aP2 [FABP-4/
aP2]), nuclear receptor (peroxisome proliferator–
activated receptor ? [PPAR?]), lipolysis (adipocyte tri-
glyceride lipase [ATGL], lipoprotein lipase [LPL], and
hormone sensitive lipase [HSL]), fatty acid reesterifica-
Figure 1. Expression pattern of genes for key enzymes involved in
lipid metabolism, in subcutaneous adipose tissue (SCAT) and infrapa-
tellar fat pad (IFP) explants. Total RNA was extracted from 300 mg of
subcutaneous AT and IFP explants from 11 obese patients with
osteoarthritis. Complementary DNA (1.25 ?g) was analyzed using
real-time quantitative polymerase chain reaction. Values were normal-
ized to RPL13 ribosomal RNA and expressed as a percentage of the
gene value obtained in subcutaneous AT (control). Values are the
mean and SEM. ??? ? P ? 0.001 versus control. FABP-4 ? fatty acid
binding protein 4; PEPCK-C ? cytosolic phosphoenolpyruvate car-
boxykinase; FAT/CD36 ? fatty acid transport CD36; ATGL ?
adipocyte triglyceride lipase; LPL ? lipoprotein lipase; HSL ? hor-
mone sensitive lipase; PPARg ? peroxisome proliferator–activated
receptor ?; CPT-1 ? carnityl palmitoyltransferase 1.
Characteristics of the 11 OA patients*
74.6 ? 1.93
31.6 ? 1.44
5.4 ? 0.60
4.39 ? 0.83
11.66 ? 1.49
2.93 ? 0.55
6.2 ? 0.68
7.22 ? 1.89
22.82 ? 1.78
* Values are the mean ? SEM. OA ? osteoarthritis; BMI ? body
mass index; CRP ? C-reactive protein; IL-6 ? interleukin-6; sIL-6R ?
soluble IL-6 receptor.
INFRAPATELLAR FAT PAD AND IL-6/sIL-6R IN KNEE OA3375
tion (cytosolic phosphoenolpyruvate carboxykinase
[PEPCK-C]), or ?-oxidation (carnityl palmitoyltrans-
ferase 1 [CPT-1]) (Figure 1). Expression of genes for
ATGL, LPL, HSL, FAT/CD36, and PPAR? was strik-
ingly decreased in IFP tissue compared with subcutane-
ous AT, whereas differences in expression of genes for
CPT-1, FABP-4/aP2, and PEPCK-C, also considered to
be AT markers, were not significant.
We then investigated the patterns of expression
and secretion of various cytokines in both IFP tissue and
subcutaneous AT. Expression of the genes for major
proinflammatory cytokines (TNF?, IL-1?, IL-6, IL-8,
and macrophage chemotactic protein 1 [MCP-1]) was
observed in both IFP and subcutaneous AT explants
(Figure 2A). A nearly 2-fold increase in IL-6 gene
expression was observed in IFP samples versus subcuta-
neous AT, with no significant differences in the expres-
sion of the other cytokines. In addition, the rate of IL-6
release was ?2-fold higher in IFP tissue than in subcu-
taneous AT; for the other cytokines (TNF?, IL-8, and
MCP-1), the differences in the rates of release were not
significant (Figure 2B). Concomitantly, the release of
soluble IL-6 receptor (sIL-6R) in IFP samples was
3.6-fold higher than in subcutaneous AT.
Obesity has also been linked to a modulation of
AT secretion of adipokines, such as adiponectin, leptin,
and resistin (2). Notably, these adipokines are known to
be present in the synovial fluid of OA patients (4).
Expression of the gene for adiponectin was not signifi-
cantly different in IFP tissue compared with subcutane-
ous AT; however, there was a significant decrease in
expression of the gene for leptin (Figure 2A). While
resistin secretion was undetectable in both IFP and
subcutaneous AT explants, leptin secretion in IFP was
decreased by 40% of that observed in subcutaneous AT,
and adiponectin secretion in IFP was increased by 70%
of that observed in subcutaneous AT (Figure 2B).
Our results clearly demonstrate that IFP tissue
from obese patients, compared with subcutaneous AT
from the same individuals, exhibits an original pattern of
expression and secretion of cytokines. Rates of IL-6
expression and secretion were increased in IFP tissue
compared with rates in subcutaneous AT, whereas the
rates of expression and secretion of other cytokines
known to be involved in the pathogenesis of OA (e.g.,
TNF?, IL-8, etc.) remained similar between IFP tissue
and subcutaneous AT. It is now accepted that cytokines
can act through endocrine, paracrine, or autocrine
mechanisms. Long-term high levels of IL-6 within AT
Figure 2. Expression pattern and secretion of adipokines and proinflammatory cytokines, in subcutaneous adipose tissue (SCAT) and infrapatellar
fat pad (IFP) explants. A, Adipokine and cytokine gene expression. Total RNA was extracted from 300 mg of subcutaneous AT and IFP explants
from 11 obese patients with osteoarthritis. Complementary DNA (1.25 ?g) was analyzed using real-time quantitative polymerase chain reaction.
Values were normalized to RPL13 ribosomal RNA and are expressed as the mean and SEM percentage of the gene value obtained in subcutaneous
AT (control). ? ? P ? 0.01 versus control; ?? ? P ? 0.001 versus control. B, Adipokine and cytokine secretion. Subcutaneous AT explants (300 mg)
were incubated for 3 hours in Krebs medium containing 1% bovine serum albumin. Cytokine levels were measured in incubation medium. Leptin
and interleukin-6 (IL-6) levels were determined using Luminex technology; adiponectin and soluble IL-6 receptor (IL-6sR) levels were determined
using enzyme-linked immunosorbent assay. Values are the mean and SEM. ? ? P ? 0.01; ?? ? P ? 0.001. TNF? ? tumor necrosis factor ?;
MCP-1 ? macrophage chemotactic protein 1.
3376DISTEL ET AL
are concomitant with altered expression of lipolytic Download full-text
genes or proteins (7). The high concentration of IL-6
that we observed in IFP samples might explain the
reduction in the expression of genes for proteins in-
volved in adipocyte lipid metabolism (2).
In addition to its autocrine effect, IL-6 from the
IFP could have paracrine effects on articular cartilage
mediated by sIL-6R, which is also increased in the IFP.
In fact, to be fully active, IL-6 must bind to its receptor,
which can be either membrane-bound or soluble. As
chondrocytes express low levels of the IL-6 membrane-
bound receptor, the presence of sIL-6R is required to
obtain the full effect of IL-6 (9).
Obesity is associated with AT macrophage infil-
tration, which can be different depending on the location
of the AT. Macrophages secrete proinflammatory cyto-
kines such as IL-6, resulting in a so-called “low-grade
inflammatory state” (2). In the current study, subcuta-
neous AT and IFP tissue similarly express macrophage
markers (CD14, CD68; data not shown), suggesting that
IL-6 overexpression and production by the IFP in knee
OA are probably not related to a general phenotype in
obesity but rather to a specific characteristic of the IFP.
The overproduction of IL-6/sIL-6R in the IFP is
associated with a decrease in local leptin secretion and
an increase in adiponectin secretion in IFP tissue. The
results of previous studies have suggested that, in con-
trast to its protective role against obesity, adiponectin in
skeletal joints might be proinflammatory and involved in
matrix degradation (10). Moreover, it has been shown
that adiponectin may strongly induce IL-6 secretion in a
cultured chondrogenic cell line (10), amplifying the
The decrease of locally produced leptin by the
IFP is unexpected in light of the increase of circulating
leptin and IL-6 previously observed in obese patients
(11) and the proposed proinflammatory role of leptin in
the regulation of cartilage metabolism (12,13). Further
research will be needed to clarify this finding.
In conclusion, our results show a different meta-
bolic pattern in IFP tissue than in subcutaneous AT and
strongly suggest that the specific cytokine profile found
in the IFP tissue of obese OA patients may contribute to
paracrine inflammation and progressive cartilage dam-
age, via the local production of IL-6/sIL-6R and adi-
ponectin. It would be of interest to know whether the
same metabolic profile is found in OA patients who are
We thank Dr. Maı ¨te ´ Corvol, Dr. Claude Forest, and
Professor Robert Barouki for their participation in helpful
discussions, and Nade `ge Brunel (Plateforme Technologique
Phe ´notypage du Petit Animal et Microdosages, Ho ˆpital Saint-
Antoine, Paris, France) for technical assistance with cytokine
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. Dr. Benelli had full access to all of the
data in the study and takes responsibility for the integrity of the data
and the accuracy of the data analysis.
Study conception and design. Chevalier, Benelli.
Acquisition of data. Distel, Cadoudal, Durant, Poignard, Chevalier.
Analysis and interpretation of data. Distel, Cadoudal, Durant, Benelli.
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