Subchondral cyst development and MMP

Orthopaedics & Traumatology: Surgery & Research (2013) 99, 523—529
Available online at
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ORIGINAL ARTICLE
Subchondral cyst development and MMP-1
expression during progression of osteoarthritis:
An immunohistochemical study
A. Kaspiris a,∗, L. Khaldi b, T.B. Grivas c, E. Vasiliadis a, I. Kouvaras a,
S. Dagkas a, E. Chronopoulos d, E. Papadimitriou e
a
Department of Trauma and Orthopaedics, Thriasio General Hospital of Attica — NHS, G. Gennimata avenue, Magoula,
19600 Athens, Greece
b
Department of Osteopathology, Laboratory for Research of the Musculoskeletal System, School of Medicine, University of
Athens, Attica, Greece
c
Department of Trauma and Orthopaedics, Tzanio General Hospital of Piraeus — NHS, Piraeus, 18536 Attica, Greece
d
Department of Orthopaedics, Laboratory for Research of the Musculoskeletal System, School of Medicine, University of Athens,
Attica, Greece
e
Laboratory of Molecular Pharmacology, School of Health Sciences, University of Patras, Patras, Greece
Accepted: 21 March 2013
KEYWORDS
Osteoarthritis;
Subchondral bone
cysts;
MMP-1;
Immunohistochemistry
∗
Summary
Background: Subchondral bone cyst (SBC) formation is often identified in patients with
osteoarthritis. Furthermore, several studies have shown that expression of matrix metalloproteinases (MMPs) is elevated in patients with OA.
Objectives: The aim of our study is to correlate the presence of SBCs and MMP-1 expression
with the osteochondral alterations during OA progression.
Methods: We studied the cartilage and subchondral bone of 15 patients who had undergone
total knee or hip replacement due to primary OA. As controls, we used the femoral heads of
three patients without macroscopic OA changes. We evaluated three specimens per patient.
Results: Specimens were divided in four groups based on the Mankin histological severity score.
Using immunohistochemistry, we noted SBCs at the site of greatest disease severity. Specifically,
these were present more frequently in group III (Mankin score: 6—7) and IV (Mankin: ≥ 8), compared with group I (Mankin: 1—3) and II (Mankin: 4—5). Mild OA stages (Mankin: 1—6) were
characterized by degeneration and thinning of the cartilage, followed by increased osteoblast
and osteoclast activity of the subjacent bone and the subsequent appearance of SBCs. Simultaneously, we observed expression of MMP-1 in groups I and II in the cartilage and III and IV in
Corresponding author. Tel.: +30 213 2028248; fax: +30 261 0623049.
E-mail address: [email protected] (A. Kaspiris).
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http://dx.doi.org/10.1016/j.otsr.2013.03.019
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A. Kaspiris et al.
both the cartilage and the subchondral bone. Moreover, osteoblast-like cells in the lining of the
SBCs showed an increased expression of MMP-1 in stages III and IV.
Conclusion: Our study provides immunohistological evidence that SBCs accumulate in advanced
OA and contain activated cells, which express MMP-1, suggesting that they may thus participate
in the osteochondral changes of OA.
Level of evidence: Level III; prospective comparative study.
© 2013 Elsevier Masson SAS. All rights reserved.
Introduction
Osteoarthritis (OA) is the major cause of disability in the
adult population. Although in the past it was considered as
a primary disorder of articular cartilage, it is now generally considered as a disease of the whole joint, including
the calcified cartilage, subchondral cortical and trabecular
bone, joint capsular tissues and the synovium [1]. Not only
the structural support, but also the biological cross-talk
between bone and cartilage, make subchondral bone and
cartilage become a closely functional unit that cannot be
separated [2]. A characteristic of bone adaptation associated with OA is the presence of subchondral bone cysts (SBC)
[3] that are present in about 50% of subjects with knee OA
[4,5].
Subchondral bone cysts (SBCs), ‘‘pseudocysts’’ or
‘‘geodes’’ [6—8], were first identified by Ondrouch [9] and
Landells [10] in the load-bearing regions of the femur,
patella, and shoulder of arthritic patients, although the
exact cause is not well known [8]. Currently, there are
two main theories: the ‘‘Bone Contusion Theory’’ where
bony microcontusions below the joint surface, associated
with increased intra-articular pressure lead to extension of
synovial fluid into the subchondral bone through tiny gaps
in the articular surface, and the ‘‘Synovial Breach Theory’’ where a breach in the subchondral plate caused by
a diminished local cartilage leads to a rapid inflammation
response and the proliferation of myxomatous tissue within
the bone marrow [6,8,9,11]. Subchondral cystic lesions
appear as well-delimited areas of fluid signal on magnetic
resonance imaging (MRI), corresponding to radiolucencies
encompassed with sclerotic margins on standard radiographs
[12,13]. They are currently gaining increasing attention for
their potential etiologic role in the development and progression of OA. Moreover, their presence is associated with
increased cartilage loss and risk of knee joint replacement
[14].
The matrix metalloproteinases (MMPs) are a family of
23 proteolytic enzymes that share several structural and
functional characteristics with different substrate specificities. MMPs degrade proteins of the extracellular matrix and
they have been considered the main enzymes responsible
for degradation of collagens in OA cartilage [15]. MMP-1
is an interstitial collagenase that is capable of degrading
interstitial collagens (types I, II and III) and is thought to be
a multifunctional molecule with important roles in diverse
physiologic processes maintaining osteochondral integrity
[16,17].
In this study, we correlated SBCs presence and MMP-1
expression in different OA stages by using histological and
immunohistological measurements, in order: to shed light on
SBCs role during the progression of OA and to explore their
correlation with MMP-1 expression at the whole cartilagesubchondral bone functional unit.
Our hypothesis was that SBCs might be associated with
increased MMP-1 expression.
Patients and methods
Overall, 15 patients aged 60—89 years diagnosed with idiopathic OA of the hip or of the knee in accordance with the
criteria of the American College of Rheumatology [18,19]
were included and compared to three controls aged 68—83
years (Table 1). Exclusion criteria were as follows: secondary
arthritis, haemochromatosis, hip fractures, inflammatory or
autoimmune diseases, malignancies, intra-articular administration of steroids. Eight patients suffered of knee OA and
seven of hip OA. OA severity was estimated based on pain,
functionality, and clinical data using the Harris score for
hip OA [20] and the index of severity (ISK) for knee OA
[21]. Radiographically, assessment of OA was based on the
Ahlback classification for the knee OA [22] and the Kellgren
& Lawrence for hip OA [23]. The same orthopaedic surgeon
specialized in OA evaluated all X-rays. Controls consisted
of three femoral heads [24—27], which were harvested in
patients undergoing hip hemiarthroplasty following fracture
of the femoral neck. All control patients had no known history of bone or joint disease and their cartilage was free of
OA lesions (grade 0), according to the Collins scale modified
by Muehleman et al. [28].
Ethical approval and informed consent were received,
according to the 1964 Helsinki Declaration.
Histology and immunohistochemistry
We evaluated three specimens per patient, and per control.
Histology
The specimens were fixed in 10% buffered formalin for
24—36 h, decalcified in neutral ethylene-diamine-tetraacetic acid (EDTA) for 6—8 weeks at room temperature,
and embedded in paraffin blocks. Three-micrometer thick
histological sections were obtained and stained with Haematoxylin/Eosin. The quantitative histological evaluation of
the specimens was based on a modified form of the Mankin
scale [29,30]. Normal cartilage was graded as 0, while the
scale went up proportionally to the severity of the OA
changes. In addition, the status of chondrocytes and the subchondral area were similarly graded. The total score of all
parameters characterized the severity of the OA changes in
Subchondral cyst development and MMP-1 expression: An immunohistochemical study
Table 1
525
Characteristics of the study population.
Characteristics
OA Patients (n = 15)
Controls (n = 03)
Sexa
Mean age (years)b
Mean height (cm)b
Mean weight (kg)b
14 females, 1 male
72.4 ± 8.29 (Min: 63, Max: 89)
164.4 ± 5.355 (Min: 156, Max: 173)
85.5 ± 15.16 (Min: 65, Max: 110)
2 females, 1 male
72.3 ± 6.66 (Min: 65, Max: 78)
172.67 ± 2.52 (Min: 170, Max: 175)
77.10 ± 7.94 (Min: 68, Max: 83)
a
b
Expressed as number of individuals.
Expressed as mean ± standard deviation.
every histological section. Four groups of OA were formed:
Group I was constituted of sections with Mankin score 1—3,
group II with Mankin score 4—5 and group III and IV with
Mankin score 6—7 and greater or equal to 8, respectively.
The sums of scores of all sections in each group were statistically analysed and compared with immunohistochemical
staining for MMP-1 in the same sections.
Immunohistochemistry
The slices were deparaffinised in xylene and degraded
alcohols, immersed in distilled water. The endogenous peroxidase was blocked with 3% H2 O2 for 30 min in a dark
chamber at room temperature. Sections were then washed
in distilled water and three times with TBS, incubated for
1 hour at room temperature with anti-MMP 1/8 (H-300)
(Santa Cruz sc-30069) diluted 1:50 in antibody diluents
(DAKO REAL S2022), incubated for 45 min at room temperature with peroxidase-labelled anti-mouse/rabbit IgG
(En-vision Kit, DAKO Detection System, Peroxidase/DAB+,
Rabbit/Mouse K5007), washed three times with TBS, and
stained for 10 minutes in a dark chamber at room temperature with 3-amino-9-ethylcarbazole/H2 O2 , washed in
distilled and counterstained with haematoxylin.
Statistical analysis
Kruskal-Wallis test was used for comparing the histological
and immunohistochemical evaluation results of the sections
between the groups of patients with OA results. Differences
were considered significant when P-values were inferior to
0.05.
Results
Subchondral bone cysts and Mankin score in OA
Histological findings were identical for all the noncommunicating cysts, which contained necrotic bone
fragments with dead denuclearized cells. The cavities were
surrounded by a layer of fibrous connective tissue containing adipocytes and osteoblasts. Overall, the frequency of
SBCs was significantly greater in groups III and IV (Fig. 1A).
Specifically, their frequency in patients with knee OA was
higher in the group III (Fig. 1B). Their frequency in patients
with hip OA (Fig. 1C) was remarkably increased in group IV
(P = 0.028).
Figure 1 A. Overall results from the immunohistochemical analysis processed statistically. B. Results from the
immunohistochemical analysis of the knee OA patients.
C. Immunohistochemical findings in patients with Hip OA.
526
Figure 2 Cartilage and subchondral bone without OA changes
in a control negative for MMP-1.
Expression of MMP-1 in OA tissues
Cartilage and subchondral bone matrix and cells, as well as
the cystic lesions of OA patients were stained positively for
MMP-1, while it was undetectable in controls (Fig. 2). MMP-1
expression was observed in the sections of the second, third
A. Kaspiris et al.
and fourth group and its staining rose significantly with the
severity of OA changes. Additionally, the frequency of MMP1 expression in the cartilage and in the subchondral bone
was increased in groups III and IV compared with the groups
I and II in both patients with knee (P = 0.03 and P = 0.002,
respectively) and hip OA (P = 0.0019 and P = 0.0014, respectively).
MMP-1 was detected in the matrix during the aggregation
of chondrocytes (Fig. 3A) and in the fibrocartilage (Figs. 3B
and C), pannus (Fig. 3D) or fissures (Fig. 4A). In the subchondral bone, MMP-1 was detected around the osteoblast-like
cells (Fig. 4B) and in the bone-lining cells (Fig. 4B). The
presence of osteoblast-like cells was accompanied by the
simultaneous presence of osteoclasts, mainly in group III.
However, expression of MMP-1 in the osteoclasts around the
cysts was not observed (Fig. 4C). In group IV there was an
increased number of apoptotic osteocytes positive for MMP-1
(Fig. 4D).
The wall osteoblasts of SBCs in groups III and IV also
expressed MMP-1 (Figs. 5 and 6A and B), whereas MMP-1
expression was not detectable in groups I and II (Fig. 6C).
Discussion
To the best of our knowledge, this is the first study that
examines the relationship between the presence of SBC and
Figure 3 A. Cartilage matrix (black arrows) with positive expression for MMP-1 in a patient with a Mankin score of 5 and chondrocytes in aggregations (red arrows). B. Fibrocartilage (black arrows) and cartilage matrix (red arrows) positive for MMP-1 in a patient
with a Mankin score of 7. C. A large number of subchondral cysts (black arrows) with overlying fibrocartilage tissue (red arrows) in
a patient with a Mankin score of 6. D. MMP-1 expression in cartilage with pannus (black arrows) and chondrocytes in aggregation
(red arrows), from a slice with a Mankin score of 7.
Subchondral cyst development and MMP-1 expression: An immunohistochemical study
527
Figure 4 A. Presence of subchondral cysts presenting osteoblastic expression of MMP-1 in overlying cartilage with crevices (black
arrows). We note fibrous tissue (red arrows) in the cyst wall. From a slice with a Mankin score of 7. B. Intense MMP-1 expression
in the walls of subchondral cysts and the subchondral bone by osteoblast-like cells (black arrows) and lining cells (red arrows) in a
slice with a Mankin score of 8. C. Subchondral bone cyst showing mild expression of MMP-1, from mural osteoblast-like cells (black
arrows). Adjacent, we observed MMP-1 expression by subchondral osteoblast-like cells and an aggregation of multinuclear cells
(osteoclasts, red arrows) from a slice with a Mankin score of 5. D. Expression of MMP-1 in fibrocartilage tissue, in osteoblast-like
cells (black arrows) and in apoptotic osteocytes (red arrows) around a SBC (Mankin score 8).
MMP-1 expression. Despite the small number of patients
in the control group the results reached significance. It is
important to note that our observations mostly derived from
female patients, reflecting an epidemiological proportion of
OA in our region.
The frequency of SBC was related to the severity of
the degenerative changes and they were found to develop
at the site of greatest disease severity, which is consistent with other studies in humans [31] and in animal
models, such as the rat anterior cruciate ligament transection model [3]. It also looks in agreement with the theory
of Ondrouch, according to which SBCs appearance is preceded by joint narrowing that would induce subchondral
bone micro-fracture in response to repeated overloading.
SBCs were found to coexist with increased cell number
of osteoblasts and osteoclasts. Additionally, defects filled
by fibrocartilage were observed around the cysts (Fig. 4A),
which were also surrounded by large numbers of apoptotic osteocytes. This suggests incomplete healing following
repeated microtrauma, leading to further deterioration and
finally to focal osteonecrosis [3].
Another important finding is the concurrent secretion of
MMP-1 in the subchondral bone-lining cells in Mankin stages
6 or more (Fig. 6D). Although the heterogeneity of their
osteoblastic phenotype has been well established, bonelining cells constitute a subpopulation of the osteoblastic
family, which responds to abnormal mechanical loading.
Before osteoclastic attachment and resorption, bone-lining
Figure 5 We note MMP-1 expression in osteocytes (black
arrows), in cartilage tissue with pannus (red arrows) and mild
expression in areas of cystic processes in the cartilage and subchondral bone (Mankin 6).
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A. Kaspiris et al.
Figure 6 A. Bone cyst with lining osteoblast-like cells that express MMP-1 (black arrows). In an adjacent area we note bone-lining
cells (red arrows) with mild expression of MMP-1 (Mankin score 7). B. MMP-1 expression by osteoblast-like cells (black arrows) in the
lining of a SBC from a slice with a Mankin score of 5. C. We note osteoblast-like cells in the lining of a SBC with low expression of
MMP-1 (black arrows) in Mankin score 5. D. MMP-1 expression by osteoblast- like (black arrows) and bone-lining cells (red arrows)
in a patient with Mankin score 9.
cells digest non-mineralized collagen protruding from the
bone surface, action that would be activated by MMPs [32].
The SBC osteoblast-like cells showed an increased expression of MMP-1 in Mankin stages greater than 6, which would
account for degradation of non-mineralized collagen type
I, exposing binding sites on the surface of the bone. This
has been shown to be a prerequisite for osteoclast stimulation and attachment to the bone [33—36]. Our data are in
agreement with the study of Sasaki et al. showing that stromal lining cells and osteoblasts would express MMP-1, upon
mechanical stimulation, thus preparing recruitment sites for
osteoclasts [37]. Furthermore, the presence study showed
the coexistence of SBCs with apoptotic osteocytes expressing MMP-1, in late stages of OA. The relationship of MMP-1
with cell apoptosis has been suggested by recent reports
providing evidence for the role of MMP-1 in targeting nonmatrix substrates, such as cell bound cytokines, enzymes
and cell surface receptors [38].
These findings have clinical significance and show that
SBCs, as well as MMP-1, may be directly involved in the
progress of the disease. It has been reported that the presence of SBCs increases the risk of joint replacement [14]
and revision arthroplasty [39]. In fact, increased expression of MMP-1 is implicated in the aseptic loosening of joint
replacement implants [40].
Conclusion
In conclusion, MMP-1 expression by osteoblasts, the lining cells of the subchondral bone and SBCs in advanced
OA stages, may contribute to the pathological tissue
remodelling and the osteochondral changes in OA. Hence,
targeting MMP-1 may provide an important therapeutic
alternative for OA that affect not only the cartilage but the
subchondral bone, as well.
Disclosure of interest
The authors declare that they have no conflicts of interest
concerning this article.
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