Bone marrow lesions, subchondral bone cysts and...

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Bone marrow lesions, subchondral bone cysts and subchondral bone attrition are associated with histological synovitis in patients with

end-stage knee osteoarthritis: A cross-sectional study

Authors: Anwarjan Yusup1,2, Haruka Kaneko1, Lizu Liu1,3, Liang Ning2, Ryo Sadatsuki1, Shinnosuke Hada1, Koji Kamagata4, Mayuko Kinoshita1, Ippei Futami1, Yukio Shimura5, Masaru Tsuchiya5, Yoshitomo Saita1, Yuji Takazawa1, Hiroshi Ikeda1, Shigeki Aoki4, Kazuo Kaneko1,3 and Muneaki Ishijima1,3#

Affiliations: 1 Department of Medicine for Orthopaedics and Motor Organ, Juntendo University Graduate School of Medicine, Tokyo, Japan

2 Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan 3 Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan 4 Department of Radiology, Juntendo University Graduate School of Medicine, Tokyo, Japan 5Department of Orthopedics, Juntendo Tokyo Koto Geriatric Medical Center, Tokyo, Japan

E-mail addresses: AY; [email protected], HK; [email protected], LL; [email protected], LN; [email protected], RS; [email protected], SH, [email protected], KOK, [email protected], MK; [email protected], IF; [email protected], YS; [email protected], MT; [email protected], YS; [email protected], YT; [email protected], HI; [email protected], SA, [email protected], KAK; [email protected], MI; [email protected] # Corresponding author: Muneaki Ishijima, M.D., Ph.D. Associate Professor, Department of Medicine for Orthopaedics and Motor Organ Juntendo University Graduate School of Medicine 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan Tel; +81-3-3813-3111, Fax; +81-3-3813-3428 E-mail; [email protected]

http://www.juntendo.ac.jp/english/department/gra/medicine_motor_organ/index.html


mailto:[email protected]














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Abstract 1

Objective 2

The aim of this study was to examine the osteoarthritis (OA)-related structural changes 3

associated with histological synovitis in end-stage knee OA patients. 4

Methods 5

Forty end-stage knee OA patients (female: 88%, mean age: 71.8 y) were enrolled. All 6

participants underwent 3.0-Tesla MRI. The structural changes, such as cartilage morphology, 7

subchondral bone marrow lesion (BML), subchondral bone cyst (SBC), subchondral bone 8

attrition (SBA), osteophytes, meniscal lesion and synovitis, were scored using the 9

whole-organ MRI scoring (WORMS) method. Synovial samples were obtained from five 10

regions of interest of the knee joint during total joint replacement surgery. The associations 11

between the histological synovitis score (HSS) and WORMS or the synovial expression levels 12

of cyclooxygenase (COX)-2, interleukin (IL)-1β, IL-6 and transforming growth factor (TGF)–13

β were examined using Spearman’s correlation coefficient. 14

Results 15

Among the seven OA-related structural changes, the BML, SBC, SBA and synovitis were 16

significantly associated with the HSS (r = 0.33, 0.35, 0.48 and 0.36, respectively), while other 17

morphological changes were not. Although synovial COX-2, IL-1β or IL-6 expression levels 18

were not associated with the HSS, the synovial TGF-β expression levels were associated with 19

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the HSS. 20

Conclusion 21

The presence of BML, SBC and SBA was associated with histological synovitis in end-stage 22

knee OA patients. 23

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4

Introduction 25

There are no disease-modifying osteoarthritis (OA) drugs available for treating knee OA at 26

present, and symptom-modifying therapy is the only available treatment for knee OA [1-3]. 27

Despite the importance of the symptoms of the disease, much remains unknown regarding the 28

nature, causes and natural history of OA symptoms. 29

Pain is the most prominent and disabling symptom of knee OA [4, 5]. Because 30

OA-associated joint damage may be associated with clinical problems, the joint damage 31

associated with the pain and the pathogenesis of pain must be investigated [6]. However, the 32

severity of joint disease is only weakly related to the clinical findings according to classic 33

radiographic techniques [2]. 34

Although OA was considered to be a non-inflammatory condition, the role of synovitis in 35

OA has attracted particular attention [7, 8]. It was recently reported that synovial 36

inflammation could play an important role in the pathophysiology of OA [9-13]. Synovitis in 37

OA may be a secondary phenomenon related to the cartilage alterations induced by the release 38

of degenerative compounds from the extracellular matrix of articular cartilage in response to 39

the presence of microcrystals in the synovial fluid and in the synovium [11, 14]. However, 40

most of the previous studies focused on synovitis in OA were conducted on patients with 41

early- to advanced- stage knee OA. 42

We previously revealed that the symptoms of patients with end-stage knee OA who required 43

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total knee arthroplasty (TKA) showed a significant correlation with the severity of synovitis 44

in the affected knee joint [15]. On the other hand, no joint structural changes evaluated by 45

classic radiography were associated with the pain and symptoms of these patients. In addition, 46

it has remained unclear whether synovitis is also related to cartilage alterations or other 47

features in patients with end-stage knee OA, where the articular cartilage has been nearly lost. 48

We also previously reported that the cytokine profiles of the synovium in patients with 49

end-stage knee OA were different from those in patients with early-stage knee OA [13]. 50

The interest in developing other treatments for OA has stimulated the search for more 51

sensitive indicators of OA for use in conjunction with the traditional radiographic outcomes. 52

Magnetic resonance imaging (MRI) measurements, in addition to biomarkers, have sufficient 53

sensitivity to detect OA-related structural changes [16, 17]. MRI is currently being optimized 54

for OA imaging and is more sensitive than radiographic techniques to detect bone and soft 55

tissue changes, which are features of OA [18]. MRI can also provide a wealth of information 56

on the pathology of knee OA, its natural history and the structure-pain relationships, which is 57

not obtainable using radiography [19]. The semi-quantitative whole-organ MRI scoring 58

(WORMS) method offers an initial instrument for performing multi-feature assessments of 59

the knee using conventional MRI [20]. 60

The aim of our present study was to investigate whether the MRI-detected structural changes 61

of the knee joint were associated with histological synovitis in patients with end-stage knee 62

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OA who underwent TKA. 63

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Patient and methods 65

Subjects 66

Forty patients who fulfilled the American College of Rheumatology criteria for knee OA 67

[21] and who received TKA were enrolled in this study. This study was approved by the 68

institutional ethical review committee of our university. Written informed consent was 69

obtained from all participating patients. 70

71

Clinical manifestations 72

The clinical manifestations were evaluated using the Japanese Knee Osteoarthritis Measure 73

(JKOM) score [22] and the pain was evaluated using the visual analog scale (VAS, 0–100). 74

The JKOM is a patient-based, self-answered evaluation score that includes four subcategories: 75

pain and stiffness, activities of daily living, social activities, and general health conditions 76

with 100 points as the maximum score. The JKOM score is higher in patients with more pain 77

and physical disabilities, and this evaluation modality is considered to have sufficient 78

reliability and validity for studies of the clinical outcomes of Japanese people with knee OA. 79

80

Radiographic evaluation of knee OA 81

The standing, extended and anteroposterior and lateral view radiographs and the 82

posteroanterior weight-bearing radiograph made with the knee in 45° of flexion 83

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(Rosenberg radiograph) were taken at the admission for the operation [23, 24]. In addition to 84

the evaluation of the Kellgren and Lawrence (K/L) grade [25] and the femorotibial angle 85

(FTA), the joint space width (JSW) was determined at the center point of the medial 86

femorotibial compartment on a radiograph. All radiographs were quantified independently by 87

two readers (AY, LL and RS) who were blinded to the baseline characteristics of the patients. 88

89

MRI-based evaluation of knee OA 90

All patients showed a K/L grade 4 [25] and were also examined with the MAGNETOM Verio 91

MR 3.0-Tesla MRI system (Siemens Medical Solutions, Erlangen, Germany) according to the 92

previously reported method [17]. The knee was scored using the WORMS method [20]. 93

Specifically, three regions (anterior, central and posterior) of the medial and lateral femoral 94

condyles and tibial plateaus, and two regions (medial and lateral) of the patella were each 95

scored separately for the cartilage morphology, bone marrow lesion (BML), subchondral bone 96

cyst (SBC), subchondral bone attrition (SBA) and osteophytes. Each region of a compartment 97

surface received its own score, following the method reported previously [17, 20]. At each 98

region, the cartilage morphology was given a score of 0-6. The BML and SBC were given a 99

score of 0-3. The SBA was scored 0-3. Osteophytes were scored 0-7. The anterior horn, 100

posterior horn, and body of the medial and lateral meniscus were each graded 0-4. A 101

cumulative grade for each meniscus was also determined using a score of 0-6. No intravenous 102

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contrast was injected in this study, which thus precluded us from differentiating synovial 103

thickening and joint effusion. Thickening and effusion were therefore graded collectively as 104

per the WORMS protocol from with a score of 0-3 for synovitis [20]. 105

The intra-observer reproducibility (AY) of the MRI evaluation of OA was measured at 106

separate times for twenty patients [inter-class correlation coefficient (ICC): 0.81 (95 % CI: 107

0.79 - 0.84)]. AY and RS independently conducted the MRI evaluation. To confirm their 108

accuracy for the MRI evaluation, the musculoskeletal radiologist (KOK) also independently 109

conducted the MRI evaluation. The inter-observer reproducibility was measured between 110

these three observers (AY, RS and KOK) who conducted 20 examinations [ICC between AY 111

and RS: 0.71 (95 % CI: 0.68 - 0.75), ICC between AY and KOK: 0.72 (95 % CI: 0.68 - 0.75) 112

and ICC between RS and KOK: 0.69 (95 % CI: 0.61 - 0.75)]. 113

114

Histological examination: 115

Sample preparation 116

Synovial tissue samples were obtained from the patients at the time of the operation from 117

five regions of interest (ROIs) [26]. They included three in the suprapatellar recess [lateral 118

recess (ROI 1), medial recess (ROI 2)], and just above the trochlear groove (ROI 5), and one 119

each in the lateral and medial distal femoral gutters (ROIs 3 and 4, respectively). The synovial 120

tissue samples were fixed in 10% neutral buffered formalin, and subsequently processed by 121

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standard histological techniques, followed by mounting in paraffin blocks for sectioning. The 122

5-µm paraffin sections were stained with hematoxylin and eosin for a microscopic analysis 123

[13, 15]. The staining procedures were performed consecutively at one time for all the 124

sections. Ten sections were randomly selected from 30 sections per sample from one ROI. For 125

one section, five examination fields (EFs) which included synovial articular surfaces were 126

randomly selected using a special eye-piece with a 10×10-grid frame. Six inflammatory 127

parameters described below were studied in each of the EFs under 200x magnification [26]. 128

129

The histological parameters 130

The six histological parameters were: (1) the thickness of the synovial lining layer, (2) 131

subsynovial infiltration by lymphocytes and plasma cells, (3) surface fibrin deposition, (4) 132

blood vessel vasodilation and blood vessel proliferation, (5) fibrosis, and (6) perivascular 133

edema. The parameters were graded as follows: 0, none; 1, mild; 2, moderate; and 3, severe. 134

Grade 0 corresponded to normal synovial tissue, and grade 3 corresponded to the most severe 135

pattern observed in the OA samples. 136

The histological examiner (AY) was blinded to all data. The mean of each of the 137

parameters for five EFs was used to represent the section. The procedures were undertaken 138

for 10 sections for each parameter, and the mean of each of these 10 sections was used to 139

represent each ROI. The procedures were repeated for the five ROI specimens. The mean of 140

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each parameter from the five ROIs was considered to represent the histological parameters of 141

the patients. The average of the six histological parameters was calculated to give a mean total 142

histological synovitis score (HSS) for the patient. 143

144

Immunohistochemical staining 145

Similar to chondrocytes, the synovial cells of OA patients produce inflammatory cytokines, 146

such as interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, which in turn decrease 147

anabolic collagen synthesis and increase catabolic mediators, such as matrix 148

metalloproteinase (MMP)-1 and MMP-13, via their subsequent intracellular signaling through 149

nuclear factor kappa B (NF-κB) and cyclooxygenase (COX)-2 [27]. Therefore, among these 150

molecules, IL-1β, COX-2 and IL-6 expression levels in the synovium were examined in the 151

present study. We also examined the synovial expression levels of transforming growth factor 152

(TGF)-β, which is also known to be expressed in the synovium in knee OA [7]. The 5-µm 153

paraffin sections (the same samples used for HE staining) were stained for TGF-β (TB21, 154

AbD Serotec, Kidlington; 1:5,000 dilution) [28], COX-2 (33/COX-2, BD Biosciences, 155

Franklin Lakes, USA; 1:50 dilution) [10], IL-1β (MAB601; R&D Systems, Wiesbaden, 156

Germany; 1:20 dilution) [28] and IL-6 (MAB2061; R&D Systems, Wiesbaden, Germany; 157

1:300 dilution) [29]. A semi-quantitative analysis of the stained sections was conducted, as 158

previously reported [13, 30]. The number of positively-stained cells was estimated in ten 159

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high-powered fields (400x) chosen at random. In each high-powered field, three histological 160

findings of the synovium, including the vasculature, synovial sublining layer and the synovial 161

lining layer, were scored separately according to the scoring system. Each section was scored 162

on a scale from 0-3 to reflect the degree of specific staining as follows: 0 represented 0-5% 163

positive staining, 1 represented 6-29%, 2 indicated 30-59% and 3 indicated ≥60% staining. 164

The cumulative staining scores were calculated by summing the mean score of these four 165

parameters for each case. 166

The intra-observer reproducibility (AY) of the histological scores was measured at separate 167

times for ten sections [ICC: 0.97 (95% CI: 0.94 - 0.98)]. The inter-observer reproducibility 168

was measured by two observers [AY and LL for HE, AY and LN for immunohistochemistry] 169

who conducted 10 examinations ([ICC: 0.94 (95% CI: 0.89 - 0.97)] and [ICC: 0.93 (95% CI: 170

0.86 - 0.96)], respectively). 171

172

Statistical analysis 173

Spearman’s correlation coefficient was used to investigate the correlation of either the 174

MRI-detected OA-related joint structural changes or the inflammatory cytokines and growth 175

factor with histological synovitis in the patients. A p-value < 0.05 was considered to be 176

statistically significant. The SPSS 19.0 software program (SPSS Institute, Chicago, IL, USA) 177

was used for the statistical analysis. 178

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179

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Results 180

Patient characteristics 181

The characteristics of the patients in the present study are shown in Table 1. All patients 182

had medial type knee OA with a K/L grade of 4 for the radiographic OA severity, and most of 183

the patients were female (88%). The HSSs of the patients were significantly associated with 184

the symptoms evaluated by the JKOM score (r = 0.345, p = 0.03), consistent with the findings 185

of a previous study [15]. 186

187

The MRI-detected joint structural changes associated with synovitis in the patients 188

Among the OA joint changes evaluated by the WORMS analysis, the BML score, SBC 189

score, SBA score and synovitis scores were associated with the HSSs of the patients (Figure 190

1), while other joint structural changes, such as the cartilage morphology score, osteophyte 191

score and meniscal pathology scores, were not (Table 2). 192

193

Associations between synovitis and the synovial expression levels of inflammatory 194

mediators and growth factors in the patients 195

No associations were observed between the synovial IL-1β expression levels and the HSSs 196

of the patients (Table 3). Similarly, neither synovial COX-2 expression levels nor synovial 197

IL-6 expression levels were associated with the HSSs of the patients (Table 3). Although the 198

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TGF-β expression in the synovial lining and sublining layers were not associated with the 199

HSSs of the patients, the TGF-β expression in the vasculature of the synovium were 200

associated with the HSSs of the patients (Table 3). 201

202

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Discussion 203

We previously reported that synovitis in the knee joint was associated with the symptoms in 204

patients with end-stage knee OA who received TKA [15]. However, the OA-related structural 205

changes associated with synovitis have remained unclear. In the present study, we examined 206

the OA-related structural changes using MRI to determine which changes were associated 207

with histological synovitis in patients with end-stage knee OA who underwent TKA. We 208

found that the presence of subchondral pathologies, such as BML, SBC and SBA, in addition 209

to MRI-detected synovitis, was significantly associated with the presence of histological 210

synovitis in patients with end-stage knee OA. The inflammatory mediators known to be 211

involved in the pathophysiology of OA [7], such as COX-2, IL-1β and IL-6, were not 212

associated with the histological synovitis in patients with end-stage knee OA. On the other 213

hand, the synovial expression of TGF-β, which is a growth factor known to be involved in the 214

pathophysiology of OA [31], was associated with histological synovitis in patients with 215

end-stage knee OA. Our study demonstrated the associations between BML, SBC and SBA, 216

synovial TGF-β expression and histological synovitis in patients with end-stage knee OA, 217

which were not previously well established in the literature. 218

219

Because synovitis in knee OA occurs locally in areas of cartilage loss [11], the medial type 220

of knee OA shows medial local synovitis, which is associated with cartilage degradation. In 221

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the medial type of knee OA, the number of anti-type II collagen-positive fragments, which is 222

one of the causes of synovitis in the medial compartment of the knee, was higher than that 223

found in the lateral compartment [32]. In the present study, the presence of subchondral 224

pathologies, such as BML, SBC and SBA, was associated with synovitis. These data suggest 225

that synovitis is present not only in early-stage but also end-stage knee OA and is possibly 226

induced by not only articular cartilage destruction but also, at least in part, due to the 227

subchondral pathologies. 228

229

We previously reported that the factors associated with the pain severity in patients with 230

knee OA varied with the radiographic disease severity [33]. The serum levels of IL-6, which 231

is related to synovitis, were mainly associated with the pain severity in early-stage knee OA, 232

while the anatomical axis angle, which represents the detrimental mechanical loading across 233

the joint, was mainly associated with that in advanced- to end-stage knee OA. 234

As the expression of COX-2, IL-1β and IL-6 in synovial tissues is thought to be activated by 235

degenerated articular cartilage, the expression of these inflammatory mediators would be 236

expected to be enhanced in the synovial tissues dependent on the severity of the disease. 237

However, the expression levels of these cytokines in patients with end-stage knee OA were 238

decreased in comparison to those in patients with early- to advanced-stage knee OA in 239

previous studies [12, 13]. In contrast, the expression levels of TGF-β in the synovium were 240

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increased depending on the severity of the disease in patients with the medial type of knee OA 241

[13]. 242

243

BMLs are suggested to be one of the pathological features related to detrimental mechanical 244

loading across the joint [18, 34-36]. Prevalent and incident SBA is strongly associated with 245

BMLs in the same subregion [37]. BML has also been revealed to be associated with the 246

progression of OA [18, 34, 36, 38]. The enlargement of BML was associated with the 247

progression of the disease [34]. The malalignment of the lower limbs was associated with 248

both the incident risk and the enlargement of BML in the more loaded compartments of the 249

knee joint [35]. As all patients in the present study showed the medial type of knee OA, 250

BMLs were observed in the medial compartments of the knee joint in all patients who showed 251

varus lower-limb alignment (FTA: 184.9º on average). Although COX-2, IL-1β and IL-6 may 252

be produced by and/or related to the cartilage destruction in knee OA, limited articular 253

cartilage remained and the subchondral bone showed eburnation, especially in the medial 254

compartment of the knee joint of patients with end-stage medial type of knee OA in the 255

present study. Consistent with this phenomenon, the HSSs were associated with the 256

subchondral pathologies, such as BML, SBC and SBA, and the TGF-β expression levels in 257

the vasculature of the synovium in the patients, suggesting the presence of a relationship 258

between histological synovitis and subchondral pathologies, and presumably synovial TGF-β 259

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expression in patients with end-stage knee OA. 260

However, there are still many unsolved questions remaining, such as how to explain the 261

relationship between synovial TGF-β and subchondral pathologies, such as BML, SBC and 262

SBA, whether TGF-β is released when subchondral pathologies develop in subchondral 263

lesions, and if so, how TGF-β in subchondral lesions is transferred to the joint, i.e., directly or 264

indirectly (such as via the blood flow), or, if not, how BMLs in subchondral lesions induce 265

TGF-β expression in the synovium. In addition, whether TGF-β expressed in the synovium in 266

patients with end-stage knee OA is activated remains unclear. However, TGF-β is the present 267

studies suggest that TGF-β is involved in the association between synovitis and the 268

subchondral pathologies in patients with end-stage knee OA, although further investigation is 269

required. 270

271

There were several limitations associated with the current study. As the present study is 272

cross-sectional, the causal relationship between the MRI-detected OA-related structural 273

changes and histological synovitis is still obscure. In this context, the results obtained in this 274

study may be understood to be indirect evidence. The MRI-based WORMS assessment was 275

performed by non-expert readers with limited experience in the semi-quantitative MRI 276

analysis of knee OA features. To overcome this limitation, we calculated the inter-observer 277

reproducibility for the MRI evaluation between the observers and the musculoskeletal 278

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radiologist, as described in the Method section. 279

280

In conclusion, the presence of BML, SBC and SBA, but not other MRI-detected structural 281

changes, was associated with local histological synovitis in end-stage knee OA patients who 282

received TKA. 283

284

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Acknowledgement 285

The authors wish to thank Dr. H. Kurosawa for giving us a chance to conduct this study. The 286

authors would also like to thank Dr. K. Hayashi for his helpful comments and suggestions in a 287

statistical analysis and Dr. T. Sueyoshi for technical assistance. This study was funded in part 288

by a High Technology Research Center Grant from the Ministry of Education, Culture, Sports, 289

Science and Technology, Japan (to MI and KAK). 290

291

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Contributions 292

AY, HK and MI conceived and designed the study. HK, RS, SH, KOK, MK, IF, YS, MT, YS, 293

YT, HI and MI collected and registered patients data. AY, HK, LL, LN, RS, SH, MK, YS, MT, 294

SA, KAK and MI had the major role in analysis and interpretation of the data, and contributed 295

to drafting the report. KAK also supervised the statistical analysis. All authors have read and 296

approved the final manuscript. 297

298

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Role of the funding source 299

This study was funded in part by a High Technology Research Center Grant from the Ministry 300

of Education, Culture, Sports, Science and Technology, Japan (to MI and KAK). 301

302

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Competing interests 303

All authors declare that they have no competing interests. 304

305

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References 306

1. Felson DT. Clinical practice. Osteoarthritis of the knee. N Engl J Med 2006; 354: 307

841-848. 308

2. Dieppe PA, Lohmander LS. Pathogenesis and management of pain in osteoarthritis. 309

Lancet 2005; 365: 965-973. 310

3. Ishijima M, Kaneko H, Kaneko K. The evolving role of biomarkers for osteoarthritis. 311

Therapeutic Advances in Musculoskeletal Disease 2014; 6: 144-153. 312

4. Felson DT. The sources of pain in knee osteoarthritis. Curr Opin Rheumatol 2005; 17: 313

624-628. 314

5. Ishijima M, Watari T, Naito K, Kaneko H, Futami I, Yoshimura-Ishida K, et al. 315

Relationships between biomarkers of cartilage, bone, synovial metabolism and knee 316

pain provide insights into the origins of pain in early knee osteoarthritis. Arthritis Res 317

Ther 2011; 13: R22. 318

6. Carr AJ, Robertsson O, Graves S, Price AJ, Arden NK, Judge A, et al. Knee 319

replacement. Lancet 2012; 379: 1331-1340. 320

7. Goldring MB, Goldring SR. Osteoarthritis. J Cell Physiol 2007; 213: 626-634. 321

8. Scanzello CR, Goldring SR. The role of synovitis in osteoarthritis pathogenesis. Bone 322

2012; 51: 249-257. 323

9. Fernandez-Madrid F, Karvonen RL, Teitge RA, Miller PR, An T, Negendank WG. 324

26

Synovial thickening detected by MR imaging in osteoarthritis of the knee confirmed by 325

biopsy as synovitis. Magn Reson Imaging 1995; 13: 177-183. 326

10. Crofford LJ. COX-2 in synovial tissues. Osteoarthritis Cartilage 1999; 7: 406-408. 327

11. Ayral X, Pickering EH, Woodworth TG, Mackillop N, Dougados M. Synovitis: a 328

potential predictive factor of structural progression of medial tibiofemoral knee 329

osteoarthritis -- results of a 1 year longitudinal arthroscopic study in 422 patients. 330

Osteoarthritis Cartilage 2005; 13: 361-367. 331

12. Benito MJ, Veale DJ, FitzGerald O, van den Berg WB, Bresnihan B. Synovial tissue 332

inflammation in early and late osteoarthritis. Ann Rheum Dis. 2005; 64: 1263-1267. 333

13. Ning L, Ishijima M, Kaneko H, Kurihara H, Arikawa-Hirasawa E, Kubota M, et al. 334

Correlations between both the expression levels of inflammatory mediators and growth 335

factor in medial perimeniscal synovial tissue and the severity of medial knee 336

osteoarthritis. Int Orthop 2011; 35: 831-838. 337

14. Scanzello CR, McKeon B, Swaim BH, DiCarlo E, Asomugha EU, Kanda V, et al. 338

Synovial inflammation in patients undergoing arthroscopic meniscectomy: molecular 339

characterization and relationship to symptoms. Arthritis Rheum 2011; 63: 391-400. 340

15. Liu L, Ishijima M, Futami I, Kaneko H, Kubota M, Kawasaki T, et al. Correlation 341

between synovitis detected on enhanced-magnetic resonance imaging and a histological 342

analysis with a patient-oriented outcome measure for Japanese patients with end-stage 343

27

knee osteoarthritis receiving joint replacement surgery. Clin Rheumatol 2010; 29: 344

1185-1190. 345

16. Menashe L, Hirko K, Losina E, Kloppenburg M, Zhang W, Li L, et al. The diagnostic 346

performance of MRI in osteoarthritis: a systematic review and meta-analysis. 347


17. Hada S, Kaneko H, Sadatsuki R, Liu L, Futami I, Kinoshita M, et al. The degeneration 349

and destruction of femoral articular cartilage shows a greater degree of deterioration 350

than that of the tibial and patellar articular cartilage in early stage knee osteoarthritis: a 351

cross-sectional study. Osteoarthritis Cartilage 2014; 22: 1583-1589. 352

18. Felson DT, Niu J, Guermazi A, Roemer F, Aliabadi P, Clancy M, et al. Correlation of 353

the development of knee pain with enlarging bone marrow lesions on magnetic 354

resonance imaging. Arthritis Rheum. 2007; 56: 2986-2992. 355

19. Wenham CY, Conaghan PG. Imaging the painful osteoarthritic knee joint: what have 356

we learned? Nat Clin Pract Rheumatol 2009; 5: 149-158. 357

20. Peterfy CG, Guermazi A, Zaim S, Tirman PF, Miaux Y, White D, et al. Whole-Organ 358

Magnetic Resonance Imaging Score (WORMS) of the knee in osteoarthritis. 359


21. Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, et al. Development of 361

criteria for the classification and reporting of osteoarthritis. Classification of 362

28

osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the 363

American Rheumatism Association. Arthritis Rheum 1986; 29: 1039-1049. 364

22. Akai M, Doi T, Fujino K, Iwaya T, Kurosawa H, Nasu T. An outcome measure for 365

Japanese people with knee osteoarthritis. J Rheumatol 2005; 32: 1524-1532. 366

23. Buckland-Wright JC, Macfarlane DG, Williams SA, Ward RJ. Accuracy and precision 367

of joint space width measurements in standard and macroradiographs of osteoarthritic 368

knees. Ann Rheum Dis 1995; 54: 872-880. 369

24. Ravaud P, Auleley GR, Chastang C, Rousselin B, Paolozzi L, Amor B, et al. Knee joint 370

space width measurement: an experimental study of the influence of radiographic 371

procedure and joint positioning. Br J Rheumatol 1996; 35: 761-766. 372

25. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis 373

1957; 16: 494-502. 374

26. Loeuille D, Chary-Valckenaere I, Champigneulle J, Rat AC, Toussaint F, 375

Pinzano-Watrin A, et al. Macroscopic and microscopic features of synovial membrane 376

inflammation in the osteoarthritic knee: correlating magnetic resonance imaging 377

findings with disease severity. Arthritis Rheum 2005; 52: 3492-3501. 378

27. de Lange-Brokaar BJ, Ioan-Facsinay A, Yusuf E, Visser AW, Kroon HM, Andersen SN, 379

et al. Degree of synovitis on MRI by comprehensive whole knee semi-quantitative 380

scoring method correlates with histologic and macroscopic features of synovial tissue 381

29

inflammation in knee osteoarthritis. Osteoarthritis Cartilage 2014; 22: 1606-1613. 382

28. Mussener A, Funa K, Kleinau S, Klareskog L. Dynamic expression of transforming 383

growth factor-betas (TGF-beta) and their type I and type II receptors in the synovial 384

tissue of arthritic rats. Clin Exp Immunol 1997; 107: 112-119. 385

29. Fiocco U, Oliviero F, Sfriso P, Calabrese F, Lunardi F, Scagliori E, et al. Synovial 386

biomarkers in psoriatic arthritis. J Rheumatol Suppl 2012; 89: 61-64. 387

30. Soden M, Rooney M, Cullen A, Whelan A, Feighery C, Bresnihan B. 388

Immunohistological features in the synovium obtained from clinically uninvolved knee 389

joints of patients with rheumatoid arthritis. Br J Rheumatol 1989; 28: 287-292. 390

31. van der Kraan PM, van den Berg WB. Osteophytes: relevance and biology. 391


32. Saito I, Koshino T, Nakashima K, Uesugi M, Saito T. Increased cellular infiltrate in 393

inflammatory synovia of osteoarthritic knees. Osteoarthritis Cartilage 2002; 10: 394

156-162. 395

33. Shimura Y, Kurosawa H, Sugawara Y, Tsuchiya M, Sawa M, Kaneko H, et al. The 396

factors associated with pain severity in patients with knee osteoarthritis vary according 397

to the radiographic disease severity: a cross-sectional study. Osteoarthritis Cartilage 398

2013; 21: 1179-1184. 399

34. Kubota M, Ishijima M, Kurosawa H, Liu L, Ikeda H, Osawa A, et al. A longitudinal 400

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study of the relationship between the status of bone marrow abnormalities and 401

progression of knee osteoarthritis. J Orthop Sci 2010; 15: 641-646. 402

35. Hayashi D, Englund M, Roemer FW, Niu J, Sharma L, Felson DT, et al. Knee 403

malalignment is associated with an increased risk for incident and enlarging bone 404

marrow lesions in the more loaded compartments: the MOST study. Osteoarthritis 405

Cartilage 2012; 20: 1227-1233. 406

36. Felson DT, Parkes MJ, Marjanovic EJ, Callaghan M, Gait A, Cootes T, et al. Bone 407

marrow lesions in knee osteoarthritis change in 6-12 weeks. Osteoarthritis Cartilage 408

2012; 20: 1514-1518. 409

37. Roemer FW, Neogi T, Nevitt MC, Felson DT, Zhu Y, Zhang Y, et al. Subchondral bone 410

marrow lesions are highly associated with, and predict subchondral bone attrition 411

longitudinally: the MOST study. Osteoarthritis Cartilage 2010; 18: 47-53. 412

38. Felson DT, McLaughlin S, Goggins J, LaValley MP, Gale ME, Totterman S, et al. Bone 413

marrow edema and its relation to progression of knee osteoarthritis. Ann Intern Med 414

2003; 139: 330-336. 415

416

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Tables 417

Table 1 418

The characteristics of the patients in this study 419

Subject (n) 40

Age (y) 71.8 (6.9)

Gender (F / M) 35 / 5

JKOM score (Range; 0 - 100) 49.2 (20.0)

Pain VAS score (0 - 100) 61.2 (26.9)

FTA (º) 185.0 (5.6)

WORMS (0 - 332) 145.0 (27.0)

Cartilage morphology (0 - 84) 61.1 (8.6)

BML (0 - 45) 16.1 (9.3)

SBC (0 - 45) 2.9 (3.0)

SBA (0 - 42) 4.3 (3.2)

Osteophyte (0 - 98) 48.0 (13.7)

Menisci Medial (0 – 6) 5.5 (0.5)

Lateral (0 – 6) 3.8 (1.0)

Synovitis (Range; 0 – 3) 2.0 (0.9)

HSS (0 – 15) 5.5 (0.8)

The data indicates the means (SD). JKOM: Japanese knee osteoarthritis measure, VAS: visual 420

analog scale, FTA: femoro-tibial angle (lateral FTA; 185 degrees indicate 5 degrees of 421

anatomical varus), WORMS: whole-organ magnetic resonance imaging score, BML: bone 422

marrow lesion, SBC: subchondral bone cyst, SBA: subchondral bone attrition, HSS: 423

histological synovitis score. 424

425

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Table 2 426

Correlation between the total HSS and the WORMS in patients with end-stage knee OA 427

receiving TKA 428

HSS

r p

Cartilage morphology -0.006 0.97

BML 0.325 0.04*

SBC 0.350 0.03*

SBA 0.482 <0.01*

Osteophyte -0.100 0.54

Menisci Medial 0.155 0.34

Lateral 0.266 0.10

Synovitis 0.358 0.02*

HSS: histological synovitis score, WORMS: whole-organ magnetic resonance imaging score, 429

BML: bone marrow lesion, SBC: subchondral bone cyst, SBA: subchondral bone attrition. * 430

indicates p<0.05. 431

432

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Table 3 433

Correlation between the total HSSs and the inflammatory cytokines and growth factor in 434

patients with end-stage knee OA receiving TKA 435

HSS

r p

IL-1β Lining layer

Sublining layer

0.223

0.277

0.19

0.10

COX-2

Lining layer

Sublining layer

Vasculature

0.018

0.080

0.231

0.92

0.67

0.22

IL-6

Lining layer

Sublining layer

Vasculature

0.043

0.211

0.122

0.81

0.24

0.50

TGF-β

Lining layer

Sublining layer

Vasculature

0.073

0.151

0.394

0.70

0.43

0.03*

HSS: histological synovitis score, IL-1β; interleukin-1β, COX-2; cyclo-oxygenase (COX)-2, 436

TNF-α; tumor necrosis factor-α, TGF-β; transforming growth factor, *p<0.05 437

438

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Figure 1. Association between the HSS and the BML score (A), SBC score (B) and SBA 439

score (C) in patients with end-stage knee OA receiving TKA 440

The sagittal T2-weighted MR image (D, E and F) and the histological sections (G, H and I) of 441

the three representative cases (J, K and L, respectively) those showed the presence of BML, 442

SBC and SBA. J: Cartilage loss: grade 6 in MFc (arrow with head) and MTc, grade 5 in MFa 443

and MTa, grade 4 in MFp and MTp, BML: grade 3 in MTa, grade 2 in MFc (arrow head), 444

SBC: grade 1 in MFc (thin arrow), SBA: grade 1 in MTc (thick arrow), osteophyte: grade 7 in 445

MFa (open arrow head), grade 5 in MFp, MTa and MTp, meniscus: grade 4 in the medial 446

meniscus (open arrow). K: Cartilage loss: grade 6 in MFa, MFc, MTa and MTc, grade 5 in 447

MFp (arrow with head) and MTp, BML: grade 3 in MFa, MFc (arrow head), MTa and MTc, 448

grade 2 in MTp, SBC: grade 1 in MFa and MFc (thin arrow), SBA: grade 2 in MTc (thick 449

arrow), osteophyte: grade 7 in MFa (open arrow head) and MFp, grade 6 in MTa, grade 5 in 450

MTp, meniscus: grade 3 in the medial meniscus (open arrow), effusion: grade 1 (star). L: 451

Cartilage loss: grade 6 in MFc (arrow with head), MFp and MTc, grade 4 in MFa and MTa, 452

BML: grade 3 in MFa, MFc (arrow head), MFp, MTa, MTc and MTp, SBC: grade 3 in MFc 453

(thin arrow), grade 2 in MFp, SBA: grade 3 in MFc and MTc (thick arrow), osteophyte: grade 454

4 in MTa (open arrow head) and MTp, grade 2 in MFa, meniscus: grade 3 in the medial 455

meniscus (open arrow), effusion: grade 3 (star). BML: bone marrow lesion, SBC: subchondral 456

bone cyst, SBA: subchondral bone attrition, HSS: histological synovitis score, TKA: total 457

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knee arthroplasty, MF: medial femoral plateau, MT: medial tibial plateau, a: anterior, c: 458

central, p: posterior. 459

Figure 1

50µm

HSS

BML score

J

K

L

HSS

0

4

5

6

7

0 10 20 30 40

A

SBC score

J K

L H

SS

0

4

5

6

7

0 2.5 5 7.5 10 12.5

B

SBA score

0

4

5

6

7

0 2.5 5 7.5 10 12.5

J K

L

C

G H I 50µm 50µm

D E F

J K L

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