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Preponderance of Sensory Versus Sympathetic Nerve Fibers

and Increased Cellularity in the Infrapatellar Fat Pad in

Anterior Knee Pain Patients after Primary Arthroplasty
Birgit Lehner,2 Franz X. Koeck,1 Silvia Capellino,2 Thomas E.O. Schubert,3 Raphael Hofbauer,1 Rainer H. Straub2
Department of Orthopedic Surgery, University Hospital Regensburg, Regensburg, Germany
Laboratory of Exp. Rheumatology and Neuroendocrino-Immunology, Department of Internal Medicine I,
University Hospital Regensburg, 93042 Regensburg, Germany
Department of Pathology, University Hospital Regensburg, Regensburg, Germany

Received 17 January 2007; accepted 4 July 2007

Published online 27 September 2007 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jor.20498

ABSTRACT: Sensory nerve fibers transmit pain perception and secrete pro-inflammatory substance
P (SP). Sympathetic nerve fibers secrete anti-inflammatory norepinephrine and endogenous opioids,
which inhibit pain perception in a bidirectional crosstalk with sensory fibers. In patients with
anterior knee pain after primary arthroplasty of the knee (AKP), this study investigated in parallel
the innervation of the infrapatellar fat pad by sensory and sympathetic nerve fibers. A total of 32
patients with osteoarthritis (OA) of the knee (n ¼ 10), AKP after primary knee joint replacement
(n ¼ 7), and OA of the hip (n ¼ 15) were included. Sensory nerve fibers were semiquantitatively
detected by immunohistochemistry against SP, and sympathetic nerve fibers were stained with an
antibody against tyrosine hydroxylase. Cellular density of the tissue was investigated by counting
cell nuclei. The density of sympathetic nerve fibers in the fat tissue was similar in knee OA as
compared to AKP. In the fat tissue, density of sensory substance P–positive nerve fibers was higher
in AKP than in knee OA, which was not observed in the fibrosis capsule of the fat pad. The
preponderance of sensory over sympathetic nerve fibers was accompanied by an increased cellular
density in fat tissue in patients with AKP compared to knee OA. A positive correlation existed
between cellularity and sensory nerve fiber density in fat tissue. This study revealed a
preponderance of sensory over sympathetic innervation in the infrapatellar fat pad in AKP after
primary arthroplasty of the knee, which possibly leads to aggravation and continuation of AKP and
local inflammation. ß 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.
J Orthop Res 26:342–350, 2008
Keywords: anterior knee pain; sympathetic nerve fibers; sensory nerve fibers;
substance P; osteoarthritis

INTRODUCTION It has been demonstrated that neuronal dys-

function with reduced coordination of motor units
The vast majority of cases of anterior knee pain between the medial and lateral vastus muscles play
(AKP) are caused by trauma superimposed on a role in AKP.3 Knee joint position sense is reduced
predisposing anatomical malalignment.1 In approxi- in AKP,4 and saline injection into the infrapatellar
mately 5% of patients with AKP,1 the pain is fat pad caused AKP in healthy subjects.5 Peripa-
referred from a source outside the knee, for tellar soft tissues are in close contact with the
example, the infrapatellar fat pad (Hoffa’s fat patellofemoral joint and are perfectly innervated.6
pad2). These extra-articular reasons for AKP can The occurrence and distribution of sensory sub-
include aspects of the nervous system, which is stance P (SP)–positive nerve fibers inside the
subject of this present study. infrapatellar fat pad suggest a nociceptive function
in AKP.7 Witonski and colleagues found high
Birgit Lehner and Franz X. Koeck contributed equally to
numbers of SP-positive nerve fibers in patients
this work. with chronic AKP in the infrapatellar fat pad.8 One
Correspondence to: Rainer H. Straub (Telephone: 49-941- study demonstrated that patients with AKP benefit
944-7120; Fax: 49-941-944-7121;
E-mail: rainer.straub@klinik.uni-regensburg.de)
from electroacupuncture treatment, which indi-
ß 2007 Orthopaedic Research Society. Published by Wiley Periodicals,
cates that central pain inhibition by afferent
Inc. stimulation is a plausible explanation.9 In 1998,



Scott Dye performed arthroscopy of his own knee versus sympathetic nerve fibers is balanced at
without intra-articular anesthesia and reported 1:1.25 Taken together, the presence of sympathetic
the infrapatellar fat pad to be a highly sensitive nerve fibers leading to high concentrations of
structure.10 sympathetic neurotransmitters can inhibit pro-
The main neuropeptide of sensory afferents in inflammatory effects of SP, which might be also
the infrapatellar fat pad is SP, which is a pro- relevant in AKP. However, the parallel investiga-
inflammatory neuropeptide. For example, SP stimu- tion of sensory and sympathetic nerve fibers has
lates interleukin(IL)-1,11 tumor necrosis factor never been reported.
(TNF),11 prostaglandin E2,12 NF-kB,13 and super- In patients with AKP after primary arthroplasty
oxide anion production14 from various cell types. Its of the knee and in patients with osteoarthritis of the
pro-inflammatory role in acute arthritis has been knee, it was the aim of this comparative study to
demonstrated earlier.15 In addition, SP has a investigate the density of sensory and sympathetic
strong effect on fibroblast activation and extrac- nerve fibers in the infrapatellar fat pad and the
ellular matrix production leading to increased surrounding connective tissue capsule. We com-
fibrogenesis.16–20 We recently demonstrated pared the density of these fibers with the synovial
sprouting of SP-positive nerve fibers in two dis- tissue of patients with osteoarthritis of the hip
eases with exaggerated fibrogenesis, Achilles ten- undergoing replacement surgery. In addition, we
dinosis and Dupuytren’s contracture.21,22 Thus, SP studied the density of cells in the infrapatellar fat
might be an important factor for the aggravation pad and the surrounding connective tissue capsule
and continuation of AKP. because presence of sensory SP-positive nerve
In contrast to SP, neurotransmitters of the sym- fibers is often linked to connective tissue disease
pathetic nerve endings can have anti-inflammatory with increased fibrogenesis.21,22
effects at high neurotransmitter concentrations.
Norepinephrine binds preferentially a-adrenoceptors SUBJECTS AND METHODS
(at high physiological concentrations it also Subjects
binds b-adrenoceptors). Adenosine preferentially
A total of 32 patients with osteoarthritis (OA) of the knee
binds adenosine 1 (A1) receptors (at high physio-
(n ¼ 10), AKP after primary arthroplasty of the knee
logical concentrations it also binds adenosine (n ¼ 7), and OA of the hip (n ¼ 15) were included.
2 (A2) receptors; reviewed in Ref.23). Ligation of b- The characteristics of patients are given in Table 1.
adrenoceptors or A2 adenosine receptors increase We included a group of hip OA patients in order to get a
intracellular cAMP levels and ligation of a2- more complete picture of synovial innervation and
adrenoceptors or A1 adenosine receptors decrease cellular density independent of the anatomical location.
intracellular cAMP levels (reviewed in Ref. 23). We did not include other patients without arthroplasty
Generally, an elevated sympathetic tone due to of the knee or hip (e.g., younger people undergoing
increased firing rates at sympathetic nerves results endoscopy), because the material needed has a size of
in increased levels of norepinephrine and adeno- approximately 5 cm2, which can only be obtained during
sine (after conversion from ATP) in the vicinity of replacement surgery. The three groups were not differ-
ent in age, sex, systemic inflammation measured by the
the nerve terminal. This leads to an increase of
erythrocyte sedimentation rate, and weight (Table 1).
intracellular cAMP in multiple peripheral target Patients with OA of the hip were taller as compared to
cells. Elevation of cAMP by these mechanisms has AKP patients (Table 1). The patient groups did not differ
been repeatedly demonstrated to induce many in the WOMAC score, the Besette–Hunter score, the
anti-inflammatory effects on target immune mech- femur axis, the patella tilt and shift, and the patella
anisms such as secretion of TNF or interferon g height index (Table 1). As expected, patients with OA as
(reviewed in Ref. 23). Thus, presence of sympa- compared to AKP had a stronger aberration of the lower
thetic nerves at a high fiber density would yield a limb mechanical axis (Table 1). All three groups had a
high enough anti-inflammatory concentration of similar percentage of patients treated with nonsteroidal
norepinephrine and adenosine (reviewed in Ref. anti-inflammatory drugs (NSAIDs; Table 1). In AKP
23). In addition, sympathetic nerve terminals bear patients, between index surgery and revision (approx-
imately 2 years, see Table 1), postoperative/intermittent
vesicles with endogenous opioids that are able to
physiotherapy and NSAIDs were the sole treatment
inhibit release of the pro-inflammatory SP from options.
afferent sensory nerve fibers.24 In a highly inflam- Patients with knee OA underwent primary total knee
matory disease such as rheumatoid arthritis, the joint replacement surgery, patients with AKP had a
preponderance of SP-positive nerve fibers over revision of the infrapatellar fat pad with partial resection
sympathetic nerve fibers is approximately 8:1, and surgical denervation (after primary arthroplasty of
whereas in healthy tissue, density of sensory the knee) due to AKP, and patients with hip OA



Table 1. Characteristics of Patients

Osteoarthritis Anterior Knee Pain after Osteoarthritis

Characteristic of the Knee Primary Arthroplasty of the Hip
n 10 7 15
Age (years) 68.6  2.2 66.9  3.4 67.3  2.6
Sex (F/M), n (%) 6/4 (60/40) 6/1 (86/14) 8/7 (53/47)
Duration since primary arthroplasty (years) n.a. 2.0  0.6 [0.8–4.8] n.a.
Erythrocyte sedimentation rate, 1st h 9.4  3.2 16.7  9.5 10.8  2.2
Weight (kg) 92  6 80  8 81  5
Height (cm) 165  2.5 162  4.9 171  2.0*
WOMAC score (points) 84.4  10.1 74.3  2.7 n.d.
Besette–Hunter score (points) 50.8  9.4 50.4  5.6 n.d.
Deviation of lower limb mechanical axis (8) 6.7  1.2** 1.2  0.9 n.d.
Femur axis (8) 7.9  0.4 8.6  0.5 n.d.
Patella tilt (8) 3.5  1.1 7.9  2.2 n.d.
Patella shift (mm) 2.8  0.7 3.5  2.0 n.d.
Patella height index 0.95  0.05 1.01  0.07 n.d.
Treated with NSAID, n (%) 4 (40) 2 (29) 2 (13)

Abbreviations: n.a., not applicable; n.d., not determined; NSAID, nonsteroidal anti-inflammatory drugs.
Data are given as means  SEM, percentages in parentheses, and ranges in brackets.
*p < 0.05 and **p < 0.01 for the comparison versus anterior knee pain.

underwent total hip arthroplasty. All patients were conjugated secondary antibody (catalog no. A-11010
informed about the purpose of the study and gave written against mouse IgG; catalog no. A-121010 against rabbit
consent. The study was approved by the Ethical Com- IgG; Molecular Probes, Leiden, The Netherlands) was
mittee of the University of Regensburg. used to achieve immunofluorescent staining of sympa-
thetic and sensory SP-positive nerve fibers (Fig. 1A,C).
Tissue Preparation and Histology The numbers of THþ sympathetic and SPþ sensory nerve
fibers per square millimeter were determined by averag-
Tissue samples were obtained immediately after open- ing the number of stained nerve fibers (typical bead chain
ing the infrapatellar fat pad (OA of the knee, AKP) or the structure with at least four separated vesicles along the
hip joint capsule (OA of the hip). The preparation of the axon, minimum length 50 mm, determined by a micro-
tissue for histology was as described.25 Fat tissue, fat meter eyepiece) in 17 randomly selected high power fields
capsule tissue, and synovial tissue were used for of view (400). We controlled the positive nerve fiber
histology. Samples intended for the determination of staining by incubating the tissue with polyclonal control
cell density and detection of nerve fibers were fixed for antibodies that always yielded a negative result.
18 h in phosphate-buffered saline (PBS) containing 3.7%
formaldehyde and then incubated in PBS with 20%
sucrose for 18 h. Thereafter, tissue was embedded in Presentation of Data and Statistical Analysis
Tissue Tek (Tissue Tek, Sakura Finetek, Zoeterwoude, Mean values are given  SEM. Group medians were
The Netherlands) and quick-frozen. All tissue samples compared by the nonparametric Mann–Whitney test,
were stored at 808C. correlations were calculated by Spearman rank correla-
Histological evaluation has been described in an tion analysis (SPSS/PC, ver. 12.0, SPSS Inc., Chicago,
earlier study.26 Briefly, the frozen tissue samples were IL). Frequencies in two different groups were compared
cut into 6- to 8-mm-thick sections and cell density was by the w-squared test using Yates continuity correction
evaluated using a standard hematoxylin and eosin (HE) or Fisher’s Exact test if possible. p < 0.05 was the level of
staining. Cellular density in the tissue was determined significance.
by counting stained cells in 17 randomly selected high
power fields (400) and expressed per mm2. The deter-
mination of synovial innervation has been described RESULTS
previously.8 Briefly, 6 to 8 cryosections (5–9 mm thick) of Nerve Fiber Density and Cellular Density in the
the formaldehyde/sucrose–fixed tissue samples were Fibrosis Capsule of the Infrapatellar Fat Pad
used for immunohistochemistry with a primary antibody
against tyrosine hydroxylase (THþ, the key enzyme for In the fibrosis capsule of the infrapatellar fat pad,
NE production in sympathetic nerve endings; catalog no. nerve fiber density of sympathetic nerves did not
AB152, Chemicon, Temecula, CA) and against substance differ between AKP after primary arthroplasty
P (SPþ, the key neurotransmitter of SPþ sensory nerve and knee OA, and it was also similar in synovial
fibers; catalog no. AB1566, Chemicon). An Alexa 546 tissue of patients with hip OA (Fig. 1B). With



Figure 1. Sympathetic and sensory innervation in the infrapatellar fat pad. (A) Staining of
tyrosine hydroxylase in the fat pad (sympathetic nerve fiber). The typical bead chain–like structure
is detectable at a magnification of 400 (arrows). (B) Staining of substance P–positive sensory nerve
fibers in the fat pad. Original magnification, 400. A similar bead chain–like structure is visible
(arrows). (C, D) Tissue density of sympathetic tyrosine hydroxylase–positive (C) and sensory
substance P–positive (D) nerve fibers in the fibrosis capsule of the infrapatellar fat pad in knee
osteoarthritis (OA) and anterior knee pain (AKP), and, in addition, in synovial tissue in hip OA.
Density is given in nerve fibers/mm2.



respect to density of SP-positive nerve fibers, fat was similar in knee OA as compared to AKP after
pad capsule innervation was not different in primary arthroplasty (Fig. 3A). However, density
knee OA versus AKP after primary arthroplasty of sensory substance P-positive nerve fibers was
(Fig. 1D). Sensory innervation tended to be higher higher in AKP after primary arthroplasty than in
in the synovium of hip OA patients as compared to knee OA (Fig. 3B). This was accompanied by an
the fibrosis capsule of the infrapatellar fad pad in increased cellular density in fat tissue in patients
knee OA and AKP after primary arthroplasty with AKP after primary arthroplasty compared to
(Fig. 1D). knee OA (Fig. 3C).
In addition, we studied the cellular density in the In order to study the direct interrelation
fibrosis capsule and found an increased cellular between cellular density and substance P-positive
density in patients with AKP after primary nerve fiber density in fat tissue, a correlation
arthroplasty as compared to knee OA (fibrosis analysis was carried out (Fig. 4). It is obvious that
capsule) and hip OA (synovial tissue; Fig. 2). a positive correlation existed between cellularity
and nerve fiber density in fat tissue (Fig. 4).
Nerve Fiber Density and Cellular Density in
Fat Tissue of the Infrapatellar Fat Pad
These elements were studied in patients with knee
OA and AKP after primary arthroplasty because a This study in patients with AKP after primary
similar fat pad does not exist at the hip joint. In the arthroplasty demonstrates that sensory innerva-
fat tissue, the density of sympathetic nerve fibers tion of the infrapatellar fat tissue was increased as

Figure 2. Cellular density in the fibrosis capsule of the infrapatellar fat pad [in knee osteoarthritis
(OA) and anterior knee pain (AKP)] and in the synovium of hip OA. Cellular density is given in



Figure 3. Nerve fiber density (A, B)and cellular density (C) in fat tissue of the infrapatellar fat pad
in patients with knee osteoarthritis (OA) and anterior knee pain (AKP). The results for sympathetic
tyrosine hydroxylase (A) and sensory substance P–positive nerve fibers (B) are given. The density is
given as nerve fiber/mm2 (in A, B) or cells/mm2 (in C), respectively.

compared to the same tissue of patients with knee onine enkephalin and leucine enkephalin are
OA. The elevated density of sensory nerve fibers released from sympathetic nerve terminals, and
was positively related to an increased cellular these opioids block release of substance P from
density in fat tissue. This was not accompanied by sensory nerve fibers in the bidirectional cross-
a change in sympathetic innervation, which has talk.24 This local analgesic effect of sympathetically
not been investigated so far in AKP. However, a released opioids has been demonstrated in inflam-
similar finding was reported in traumatic patellar matory lesions.39 In normal connective tissue, a
tendinopathy.27 We know that the rate of AKP due balance between density of sympathetic and sen-
to pain outside the knee is only approximately sory nerve fibers exists, which has been demon-
5%,2 which is a relatively rare cause of a very strated in the synovial tissue in patients with knee
common clinical entity. Nevertheless, our data trauma and in the ruptured Achilles tendon of
might help to explain a piece of pathophysiology of athletes.22,25 This study confirmed this particular
AKP under these particular conditions. balance in the fibrosis capsule of the infrapatellar
The sympathetic nervous system confers direct fat pad in patients with AKP and knee OA and in
anti-inflammatory and pro-apoptotic effects when the synovial tissue of hip OA. Others have
concentrations of neurotransmitters are in the demonstrated that an experimentally induced loss
range of 106 to 105 M via the b-adrenergic of sympathetic innervation increases sensory path-
receptor on target cells.28–37 High concentrations ways relevant for pain perception.27,40–42 Interest-
of norepinephrine can appear in the vicinity of ingly and vice versa, sensory denervation increased
sympathetic nerve terminals.38 In addition to sympathetic innervation.43 We hypothesize that a
norepinephrine, endogenous opioids such as methi- balance of sympathetic and sensory nerve fibers is



stimulus for the sprouting response of these nerve

fibers. This was accompanied by an elevated
cellular density within fat tissue, which supports
the proproliferative role of this neuropeptide. A
very similar preponderance of substance P positive
over sympathetic nerve fibers was observed in
rheumatoid arthritis, Achilles tendinosis, and
Dupuytren’s contracture.21,22,44 These rheumatic
diseases and AKP are accompanied by increased
pain, and it is conceivable that a higher density of
sensory over sympathetic nerve fibers is respon-
sible for increased pain. Our study was not able to
demonstrate the hen or the egg in the pathophysio-
logic sequence of AKP; however, the following
scenario is plausible.
A traumatic event can trigger a local inflamma-
tory repair process with infiltrating leukocytes and
activation of local cells (adipocytes, fibroblasts,
myocytes, endothelial cells, etc.). Under inflamma-
tory conditions, infiltrating macrophages can
secrete factors, which repel sympathetic nerve
fibers (e.g., semaphorin 3C)45 and which stimulate
sprouting of sensory nerve fibers (nerve growth
factor, brain-derived neurotrophic factor).25,46
Sprouting of sensory nerve fibers in the infrapa-
tellar fat pad in AKP has been confirmed in this
study and in others.7,8 In the presence of sensory
nerve fiber sprouting and sympathetic nerve
repulsion (or growth inhibition), a preponderance
of sensory over sympathetic nerve fibers evolves
(see above).
Substance P from sensory nerve fibers is known
Figure 4. Interrelation between cellular and nerve fiber
density in fat tissue of the infrapatellar fat pad. Filled symbols
to stimulate IL-111 and TNF secretion11,12 and
stand for patients with knee osteoarthritis and open symbols consequently other painful factors such as prosta-
represent patients with anterior knee pain. The linear regres- glandins and bradykinin.12,47 Thus, neuronally
sion line, the Spearman rank correlation coefficient, and its p- released substance P is per se a pro-inflammatory
value are given. and painful stimulus, which contributes to pain
sensitization. In contrast, because norepinephrine
and sympathetic endogenous opioids at physiolog-
ically high concentrations inhibit secretion of TNF
important to maintain normal pain perception and and other pro-inflammatory factors (reviewed in
tissue homeostasis including control of inflamma- Ref. 23), norepinephrine and endogenous opioids
tion. most probably counteract the pro-inflammatory
Substance P is a pro-inflammatory neuropeptide effects of substance P when neurotransmitter
of sensory nerve fibers and it can stimulate cyto- concentrations are high enough. Thus, the balance
kine release and fibrogenesis under different con- of the two systems is an important factor in pain
ditions.11–14,16–20 A preponderance of substance and inflammation control. After knee arthroplasty,
P over sympathetic neurotransmitters would be a sensory hyperinnervation might be a long-standing
pro-inflammatory signal leading to increased pain. phenomenon leading to a reduction of pain thresh-
This study demonstrated such a preponderance of olds because the normally present sympathetic
sensory over sympathetic nerve fibers in the fat inhibition of inflammatory pathways is reduced. In
tissue of the infrapatellar fat pad in AKP. Because addition, elevated concentrations of substance P
all our patients with AKP had primary arthro- might lead to smoldering mild inflammation, which
plasty 2 years earlier, sensory hyperinnervation leads to continuation of AKP after primary arthro-
might be related to prior surgery, which could be a plasty. Under these conditions, triggering factors



such as small traumatic events might trigger or 13. Lieb K, Fiebich BL, Berger M, et al. 1997. The neuro-
aggravate AKP after primary arthroplasty. peptide substance P activates transcription factor NF-
In conclusion, the preponderance of sensory over kappa B and kappa B-dependent gene expression in
human astrocytoma cells. J Immunol 159:4952–4958.
sympathetic innervation in the infrapatellar fat 14. Tanabe T, Otani H, Mishima K, et al. 1996. Mechanisms of
pad in AKP after primary arthroplasty compared to oxyradical production in substance P stimulated rheuma-
OA is probably an unfavorable factor, which toid synovial cells. Rheumatol Int 16:159–167.
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substance P contributes to the severity of experimental
AKP in this group. It is presently not known
arthritis. Science 226:547–549.
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