Rom J Morphol Embryol 2015, 56(1):169173 [625902]

Rom J Morphol Embryol 2015, 56(1):169–173
ISSN (print) 1220–0522 ISSN (on-line) 2066–8279 OORRIIGGIINNAALL PPAAPPEERR
Synovial inflammation in patients with different stages of
knee osteoarthritis
RĂZVAN ENE1), RUXANDRA DIANA SINESCU2), PATRICIA ENE3), MONICA MIHAELA CÎRSTOIU4),
FLORIN CĂTĂLIN CÎRSTOIU1)
1)Department of Orthopedics and Traumatology, Emer gency University Hospital, Bucharest, Romania
2)Department of Plastic and Reconstructive Surgery, E lias Emergency University Ho spital, Bucharest, Romania
3)Department of ENT, Emergency Univer sity Hospital, Bucharest, Romania
4)Department of Obstetrics and Gynecology, Emer gency University Hospit al, Bucharest, Romania
Abstract
The synovium is an intra-articular mesenchymal tissue and essential for the normal joint function. It is involved in many patho logical
characteristic processes and sometimes specific for this distinctive tissue. In this study, we refer to synovial proliferative disorders
according to the stage of osteoarthritis (OA) disease. Forty-three patients with knee OA were treated in the Department of Orth opedics and
Traumatology, Emergency University Hospital of Bucharest, Romania, in the last two years. In all cases, we used at least five c riteria for
the knee OA: knee pain, knee joint tenderness, no palpable warmth over the knee, stiffness, erythrocyte sedimentation rate and C-reactive
protein levels. In all the cases the synovial tissue was selected by the orthopedic surgeon. X-ray examination was taken in eve ry case of
the affected joint. Patients who were considered to have early OA underwent arthroscopic synovial biopsy of the symptomatic joi nt.
Synovial tissue samples from patients with late OA were obtained at the time of knee joint arthroplasty. Microscopic examinatio n in early
osteoarthritis revealed for more than half of patients with synovial biopsy through arthroscopic technique having synovitis les ions with
mononuclear infiltrates, diffuse fibrosis, thickening of the lining layer, macrophages appearance and neoformation vessels also . The
synovitis seen in advanced OA knees tends to be diffuse and is not mandatory localized to areas of chondral defects, although a n
association has been reported between chondral defects and associated synovitis in the knee medial tibio-femoral compartment. T he
overexpression of mediators of inflammation and the increased mononuclear cell infiltration were seen in early OA, compared wit h late OA.
Keywords : synovitis, osteoarthritis, mediators of inflammation, cell infiltration.
 Introduction
Knee osteoarthritis (OA) is the most common form
of arthritis, and is the single most important cause of
disability in older adults and sometimes even in young
patients. First, the synovium and also the bone and
cartilage are involved in pathological processes that lead
to progressive joint degeneration [1, 2].
There is a multifactorial etiology of OA that might
include both systemic and lo cal biomechanical factors.
Systemic factors include age, sex, estrogen levels, racial
and genetic susceptibility, bone density, and many
nutritional factors. The occurrence of synovitis after
trauma to the knee joint may result in progressive patello-
femoral chondropathy [3, 4].
The synovial membrane in osteoarthritis (OA) shows
a more or less ‘normal’ ap pearance with no increase in
the thickness of the intimal cell layer or significant cellular
reaction.
While synovitis is common in advanced osteoarthritis
(OA), its prevalence and severity in patients with early
or mild OA are uncertain [5–7].
Although osteoarthritis (OA) is commonly described as
a non-inflammatory joint disease, synovial inflammation is
increasingly recognized as co ntributing to the symptoms
and progression of OA. Synovial histological changes
include synovial hypertrophy and hyperplasia with a big number of lining cells often accompanied by infiltration
with lymphocytes [8].
Starting from other studies [9, 10] of the quality of
the synovium, in our study we aimed to evaluate the synovial inflammation degree by macroscopic, X-ray examination and histological findings in patients with early or late knee OA.
 Materials and Methods
Samples of synovial tissue were obtained from 43
patients with knee OA that were treated in the Department of Orthopedic and Traumatology, Emergency University
Hospital of Bucharest, Romani a, in the last two years.
Gender ratio was 33 females and 10 males with the age between 49 and 76-year-old.
Patients with anterior knee pain for at least one year,
who were considered to have early OA, underwent to X-ray examination and arthroscopic synovial biopsy of the
symptomatic joint. The three articular compartments of
the knee joint were explored. Synovial tissue samples from patients with late OA were obtained at the time of
knee joint arthroplasty.
In all cases, we used at least five clinical and
laboratory criteria for the knee OA diagnosis: knee pain,
knee joint tenderness, no palpable warmth over the knee,
stiffness, erythrocyte sedimentation rate and C reactive protein levels.
R J M E
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Răzvan Ene et al.
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In all the cases, the synovial tissue was selected by
the orthopedic surgeon, after the patients previously
signed an informed consent. E fforts were made to ensure
that tissue was selected from areas demonstrating gross
synovial hypertrophy. If hypertrophy was not apparent,
tissue samples were randomly selected.
All histological sections were examined without
knowledge of the clinical details of the case, including
the diagnosis.
Tissue fragments were placed in 10% buffered formalin
taking care that the volume of the formalin solution
exceeds 10 times the volume of the sample. Then, the
tissue was embedded in paraffin using the standard
technique. The paraffin blocks were sectioned using
the microtome to 5 μm thick sections, which were then
stained using the classic Hematoxylin and Eosin (HE)
technique.
HE-stained sections were evaluated for the presence
of intimal cell hyperplasia, increased vascularity, fibrin
deposition, diffuse lymphocytic infiltrate, perivascular
lymphocytes, lymphoid follicles, plasma cells, diffuse fibrosis and perivascular fibrosis. There were processed in the laboratory also synovial
fluid samples taken at surgery time.
 Results
Microscopic changes in early osteoarthritis
Histological study of synovial tissue revealed more
than half of patients w ith synovial biopsy through
arthroscopic technique having synovitic lesions. With,
thickening of the lining layer, proliferation of the lining
cells, mononuclear infiltration especially with macro-
phages. The presence of small blood capillaries with
turgescent endothelium shows the neo-formation aspect
and highlights the proliferation process of synovitis
(Figures 1 and 2).
Different degrees of fibrosis were present in the
synovial connective tissue (Figure 3).
Knee’s articular cartilage has no perichondrium, thus
we found cartilage structural alterations in all patients, synovial changes being presen t especially in areas of
chondral defects (Figure 4).

Figure 1 – Synovial with an alte red structure, by the
presence of a chronic mode rate inflammatory and
numerous neoformation vesse ls (HE staining, ×200). Figure 2 – Area of synovial membrane, strongly infiltra-
ted with macrophage and ly mphocyte cells (HE staining,
×200).

Figure 3 – Intensely thickened synovial by abundant
deposit of hyaline and collagen fibers (HE staining, ×100). Figure 4 – Fibrin deposit, areas of necrosis and degene-
rated cartilage (HE staining, ×100).

At this stage of osteoarthritis, most patients accused
anterior knee pain while going up and down the stairs,
symptoms that also appears when the level of physical activity increases, without any deformities of the knee
or biomechanical axis deviation.
In the early stage of OA, the X-ray findings are

Synovial inflammation in patients with different stages of knee osteoarthritis
171
minimal or absent, due to the minimal changes of
cartilage, thus for no changes of the subchondral bone.
Microscopic changes in late osteoarthritis
There was noticed an extensive synovitis in patients
who underwent total knee replacement. Synovial inflam-
mation was not confined to patients with extensive radiographic joint damage or advanced stage disease.
The synovitis seen in advanced OA knees tends to
be diffuse and it is not mandatory localized to areas of chondral defects, although an association has been reported
between chondral defects and associated synovitis in the
knee medial tibio-femoral co mpartment. Histologically,
the increase of collagen fibers, the presence of lymphoid
cell infiltrates can be finding, near the increase of neo-
formation vessels (Figures 5 and 6).
Patients in advanced stages of OA have pain all
around the knee more pronounced on the medial side
and sometimes this pain wakes them up at night. They
accuse different degrees of knee stiffness with creaks or crunches as they move. It can be seen that the knees
look swollen because of th e osteophytes around the
sides of the joint or caused by extra fluid in the joint.
Imagistic in late osteoarthritis
In this stage of OA, the following radiographic changes
can be identified: narrowing of the joint space, osteo-
phytes, subchondral sclerosis, appearance of subchondral
cysts and subluxation of the joint particularly in advanced
OA (Figure 7). X-ray findings of this stage of OA show not only the degenerative aspect, of the articular surface,
but also the proliferative aspect. The advanced fibrosis
of the synovitis, which also involves the joint capsule of the medial tibio-femoral compartment and the presence
of osteophytes, explains the proliferative aspect of OA
and also helps to subluxation of the knee joint.
Magnetic resonance imaging (MRI) shows joint
effusion, meniscal disruption subchondral signal changes,
and synovitis, which appears in advanced OA (Figure 8).

Figure 5 – Synovial membrane with numerous hyper-
trophied cells and disordered placement collagen fibers,
present in the late stages of the disease (HE staining,
×200). Figure 6 – Microscopic aspect of non-specific chronic
synovitis, with numerous co ngested blood vessels and
collagen deposits (HE staining, ×200).

Figure 7 – X-ray showing late OA with chronic synovitis
and calcification. Figure 8 – MRI of a late knee OA.

 Discussion
OA is considered not only a degenerative, but also a
proliferative disease, due to the chronic inflammatory
response to the cartilage da mage of the joint surface.
Regarding the old publications in osteoarthritis appeared to be a relatively normal synovium, accompanied by
areas of fibrosis, hyper-vascularization and fragments of
cartilage. Otherwise, recent studies demonstrates both
obvious changes of the synovial membrane and synovial
fluid in osteoarthritis disease that varies depending on
the severity of the condition [11–13].

Răzvan Ene et al.
172
Our study corresponds with other research papers
and demonstrates the early histological modifications
of the synovium, like mononuclear cells, macrophages
infiltration, accumulated colla gen fibers and neoformatted
vessels, in the beginning phase of OA. Radiological
aspects in this phase of OA is normal or with minimal
modification. Any small damage of the cartilage surface induces an inflammatory response by the overexpression
of pro-inflammatory mediators, like IL-1, TNF α (tumor
necrosis factor alpha), and VEGF [14].
The observation of the synovial tissue from patients
with early OA demonstrated more features of inflammation
than late OA. OA synovial tissues have also been shown to produce vascular endothelial growth factor and other
angiogenic factors that promote neovascularisation of
subchondral bone [15]. These neoformatted vessels are more fragile and their damage leads to hemorrhage
contributes to the increase of the inflammatory response.
Interleukin-1 receptor antagonist is frequently detected
in the synovial membrane of normal patients, but both
TNFα and IL-1 are rarely detected [16, 17]. Proliferation
of new blood vessels, and increased expression of several critical molecules, including cytokines, angiogenic factors,
adhesion molecules, and inducible COX are characteristic
of chronic synovitis in inflammatory arthritis. Even the early stage of OA is distinguished by a high level of
production of inflammatory cytokines IL-1, IL-6, TNF α,
infiltration of mononuclear cells, thickening of the synovial lining layer and fibrosis. The explanation for the apparent
difference is unclear, but may be related to differences
in patient and tissue selection, or to the quantification techniques that were employed. Involvement of synovitis
in the pathophysiology of osteoarthritis inflammation is
evident but may not be alwa ys the primary mechanism
that generates it [18, 19].
The overexpression of mediators of inflammation
and the increased mononuclear cell infiltration is seen in
early OA, compared with late OA. Isolated fibroblast-like
synoviocytes were functionally similar in both, early and
late OA, consistent with microenvironmental differences in the synovial tissue during different phases of OA.
These aspects are very important in the treatment of
patients with early OA [20].
All these mechanisms lead to recurrent inflammatory
response, cartilage damage aggravation. This vicious circle
of pathophysiology leads to clinical, radiological and histological aspect of the OA and the better knowledge
of the pathology opens new opportunities in the treatment.
 Conclusions
The extent of the synovial inflammatory lesions is
important for the clinical outcome of the patient. Our
study revealed that early osteoarthritis is accompanied by a localized synovial inflammation in areas of chondral
defects, while late osteoarticular knee inflammation
determines diffuse chronic s ynovitis. This diffuse fibrotic
process involve closer joint structures, the appearance of
new vessels explains also the proliferative aspect of the
disease. Early X-ray examination shows the normal aspect of the joint or minimal modification of OA, like
subchondral sclerosis. In ad vanced stages of OA, the diffuse fibrotic process in synovial tissue may involve
the joint capsule, which explains the limitation of the
joint mobility and the subluxation of the joint.
Conflict of interests
The authors declare that they have no conflict of
interests.
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Corresponding author
Răzvan Ene, MD, PhD, Department of Orthopedics and Traumatology, Emergency University Hospital, 169
Independen ței Avenue, 050098 Bucharest, Romania; Phon e +40740–082 338, e-mail: razvan77ene@yahoo.com

Received: October 23, 2014
Accepted: February 5, 2015