|Year : 2016 | Volume
| Issue : 2 | Page : 133-141
Adiponectin in patients with knee osteoarthritis
Ahmed S El-Dein Farag MD 1, Shereen A Machaly2, Wahid A Sultan2, Nermin Y Soliman3, Mohamed F Al-Harrass4, Atif E El-Ghaweet2
1 Physical Medicine, Rheumatology & Rehabilitation Department, Students Hospital, Mansoura University, Mansoura, Egypt
2 Physical Medicine, Rheumatology and Rehabilitation Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
3 Radiodiagnosis Department, Faculty of Medicine, Mansoura, Egypt
4 Clinical Pathology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
|Date of Submission||27-Apr-2016|
|Date of Acceptance||30-Apr-2016|
|Date of Web Publication||1-Mar-2017|
Ahmed S El-Dein Farag
Department of Rheumatology and Rehabilitation, Faculty of Medicine, Mansoura University, Mansoura, 35516
Source of Support: None, Conflict of Interest: None
Investigations suggest that adipokines may play an important role in pathogenesis and cartilage damage in osteoarthritis (OA). Whether adiponectin (ADN) has proinflammatory or anti-inflammatory actions in OA remain controversial.
The aim of this study was to measure the serum level of ADN in patients with knee osteoarthritis (KOA) and to evaluate the relationship between its level and clinical and radiological picture of OA.
Patients and methods
The study included 56 patients with primary symptomatic KOA and 30 matched controls. Parameters of obesity and serum ADN, leptin (LEP), and matrix metalloproteinase (MMP)-3 were measured in all participants. Clinical features of KOA severity and activity were evaluated in the patients. Extent of knee joint damage due to OA was evaluated by means of plain radiograph and MRI. The volume of the infrapatellar fat pad was measured using MRI.
KOA patients had high serum ADN, LEP, and MMP-3 compared with controls and they were higher in female KOA patients than in male KOA patients. Serum ADN, LEP, and MMP-3 were significantly correlated with parameters of obesity and with each other. The serum ADN level was significantly correlated with tenderness, visual analogue scale pain, OA activity, OA severity, and also with Western Ontario and McMaster Universities Osteoarthritis Index score. Serum LEP level was significantly correlated with OA severity. Serum level of MMP-3 was significantly correlated with the tenderness score. Higher ADN serum levels were associated with increased Kellgren–Lawrence grade, increased Noyes MRI grade, increased OA severity MRI grade, and increased meniscal degeneration MRI grade. Serum levels of ADN, LEP, and MMP-3 were significantly correlated with the Hoffa fat pad volume.
ADN serum level was associated with radiological evidence of OA severity and was correlated with serum LEP and MMP-3 levels. These findings strongly suggest that ADN is involved in the pathogenesis of joint inflammation and cartilage destruction in OA and may be a target for disease-modifying drug development.
Keywords: adiponectin, leptin, matrix metalloproteinase-3, osteoarthritis
|How to cite this article:|
El-Dein Farag AS, Machaly SA, Sultan WA, Soliman NY, Al-Harrass MF, El-Ghaweet AE. Adiponectin in patients with knee osteoarthritis. Benha Med J 2016;33:133-41
|How to cite this URL:|
El-Dein Farag AS, Machaly SA, Sultan WA, Soliman NY, Al-Harrass MF, El-Ghaweet AE. Adiponectin in patients with knee osteoarthritis. Benha Med J [serial online] 2016 [cited 2021 Dec 5];33:133-41. Available from: http://www.bmfj.eg.net/text.asp?2016/33/2/133/201287
| Introduction|| |
Osteoarthritis (OA) is a heterogeneous and multifactorial disease characterized by chronic articular cartilage damage along with the involvement of bones, muscles, ligaments, and synovial membrane . Pathologically, this disease is typically illustrated by the loss of cartilage, subchondral bone sclerosis or cyst, and osteophyte formation. Until now, the exact etiopathogenetic mechanisms of OA is still not fully identified. However, several factors that seemingly increase the risk for OA had been identified. In this prospect, excess body weight emerges as a factor of major importance.
Obesity is considered as a major risk factor for the development and progression of OA through increasing the mechanical loads on joint tissues. However, the effect of excess body weight on joint cannot explain the link between obesity and hand OA . Furthermore, it was observed that the loss of body fat produced more favorable symptomatic relief compared with the reduction in body weight . This observation indicated that the link of obesity and OA may be the effect of molecules synthesized in the circulation by the adipose tissues, such as adipokines (ADK).
It had been reported that adiponectin (ADN) exerts the anti-inflammatory action as it reduces the production of proinflammatory mediators and induces the release of anti-inflammatory cytokines ,,. However, it was also reported that ADN has a wide variety of actions in pathological conditions involving inflammatory processes, including OA . Therefore, whether ADN had proinflammatory or anti-inflammatory actions remain the issue of debate, and the role of this molecule in joint diseases is still controversial. The aim of this study was to measure the serum level of ADN in patients with knee osteoarthritis (KOA) and to evaluate the relationship between its level and clinical and radiological picture of OA.
| Patients and methods|| |
Consecutive 80 patients with symptomatic primary KOA were invited to participate in this study. All patients met the EULAR 2010 criteria for diagnosis of primary KOA  and patients had to show radiological changes in studied knees on plain radiograph. All patients were recruited from the Outpatient Clinic of Physical Medicine, Department of Rheumatology and Rehabilitation, Mansoura University Hospital. At enrollment in the study, the aim of the study and procedures of the study were explained to all participants. All eligible participants provided written informed consent before participation in the study.
Patients with coronary heart disease, chronic renal failure, diabetes mellitus, hypertension, inflammatory rheumatic diseases, and pregnant women were excluded from the study. Patients with any knee condition other than primary OA were also excluded. From the 80 patients with primary KOA selected for the study, 14 patients were excluded according to the exclusion criteria and 10 patients did not provide written consent, leaving only 56 patients with primary KOA eligible and enrolled in the study. For each patient with bilateral KOA, the findings of the more symptomatic knee joint were recorded and analyzed. The study also included 30 controls with no radiological evidence for KOA.
Data were collected from the participants through structured history taking obtained during interview at enrollment into the study and thorough clinical examination. The medical records of the patients were also reviewed. Body weight, BMI, waist circumference, and waist–hip ratio (WHR) were all measured in the participants during examination.
Knee pain was assessed using the pain visual analogue scale tool. OA severity was evaluated using the Lequesne index of severity for OA. This is an 11-item questionnaire designed to evaluate three domains: (a) pain or discomfort, (b) maximum distance walked, and (c) activities of daily living. It is scored as the sum of all questions ranging from 0 to 24 . Disease activity was assessed using the Tegner Lysholm Knee Scoring Scale. The tool comprises eight items; the total score is the sum of all items ranging from 0 to 100 . Functional status was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire that assesses pain (five questions), knee stiffness (two questions), and difficulty in activities of daily living (17 questions). Each question is graded on a scale of 0–4 with total score ranging from 0 to 96 .
After 12 h fasting, 5 ml of venous blood samples was drawn from the antecubital vein between 8:00 and 9:00 a.m. on the same day of history taking and clinical examination. Blood samples were investigated for erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, serum uric acid, alanine transaminase, aspartate transaminase, serum creatinine, fasting blood glucose, and lipid profile.
Two millimeters from the same blood samples was used to determine serum ADN concentrations. The samples were immediately centrifuged at 4°C and were stored in a cooling refrigerator at −20°C for mass measurements. Serum ADN concentrations were estimated using the enzyme-linked immunosorbent assay (ELISA) (Quantikine ELISA Human Total ADN/Acrp30, PDRP300; R&D Systems Inc., Oxford, UK). Serum leptin (LEP) concentrations were estimated using the ELISA DRG LEP (Sandwich ELISA, EIA-2395; DRG International Inc., New Jersey, USA). Serum matrix metalloproteinase (MMP)-3 concentrations were estimated using the ELISA test (Quantikine ELISA Human Total MMP-3,750598.6; RnD Systems Inc.).
Plain radiographs were obtained in both anteroposterior and lateral semiflexed positions with the patients standing. Radiological findings were evaluated and graded by two clinicians according to the Kellgren–Lawrence (KL) radiological scale . MRI was performed using 1.5 T units (Philips Ingenia, Philips Healthcare cairo, Egypt). Severity of the OA of the affected knee joint was assessed according to the criteria proposed by Park et al. . Cartilage damage was classified according to the Noyes classification system . The extent of meniscal degeneration was graded according to Stoller  scoring system and joint effusion was graded according to the Hill et al. scoring system. Hoffa’s pad fat volume was assessed by measuring its height, width, and anteroposterior diameter. The infrapatellar fat pad (IFFP) volume was calculated according to the following formula: IFFP volume (cm3)=height×width×anteroposterior diameter×0.52.
Ultrasonographic examination of both carotid arteries was carried out to determine intimal thickness as a direct measure of atherosclerosis using Medison (model Sonoace X6; Medison Co. Ltd., Dubai Branch), power 100–120/200–240 V, 0.8/5 A, 50/60 Hz equipped with 7.5–11.5 MHz linear transducer. Abdominal ultrasonography was performed for all participants using Toshiba Xario 100 (Toshiba, MEDICAL TECHNOLOGY (Operations for Egypt) 16, El Khartoum street, Heliopolis, Cairo, Egypt) machine with a convex 2–5 Hz probe to measure the subcutaneous fat thickness just right to the umbilicus and to assess the presence of fatty liver. Electrocardiographic examination was performed for all participants to exclude cardiac diseases.
All statistical analyses were performed using SPSS (version 20.0 for Windows; SPSS Inc., Chicago, Illinois, USA). Continuous data were expressed as mean±SD, whereas categorical data were expressed in number and percentage. The differences between two groups or more were determined using independent sample Student’s t-test or one-way analysis of variance test, respectively, for variables with continuous data or the χ2-test for variables containing categorical data. The Pearson correlation test was used to determine the correlation between two variables containing continuous data. Statistical significance was set at P less than 0.05.
| Results|| |
The study population included 56 patients (41 female and 15 male) with primary KOA and 30 apparently healthy volunteers (21 female and nine male) who served as a control group. No significant difference was found between the patients and the control group as regards age, sex, and parameters of obesity ([Table 1]).
|Table 1 Comparison of the clinical and laboratory findings between knee osteoarthritis patients and controls|
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The average ADN serum level in KOA patients was 9.70±6.83 μg/ml compared with 6.81±1.86 μg/ml in controls. This difference was significant [95% confidence interval (CI), 0.31–5.47; P=0.028]. The average LEP serum level in the patient and the control group was 41.79±16.79 and 25.03±12.91 ng/ml, respectively. This difference was significant (95% CI, 9.75–23.76; P<0.001). The MMP-3 serum level in KOA patients and in controls was 2320.13±1170.8 and 1501.87±653.72 ng/ml, respectively. This difference was significant (95% CI, 143.78–1849.88; P=0.023) ([Table 1]).
As shown in [Table 2], ADN is significantly correlated with body weight (P=0.024), BMI (P=0.005), waist circumference (P=0.028), and WHR (P=0.003). Moreover, ADN was significantly correlated with tenderness score (P=0.032), activity score (P=0.047), severity score (P=0.035), and WOMAC score (P=0.043). Moreover, LEP was significantly correlated with body weight (P=0.002), BMI (P<0.001), waist circumference (P=0.004), WHR (P=0.039), and severity index (P=0.016). MMP-3 was significantly correlated with body weight (P=0.008), BMI (P=0.015), waist circumference (P=0.023), WHR (P<0.001), and tenderness score (P=0.013).
|Table 2 Correlation of adiponectin, leptin, and matrix metalloproteinase 3 with the clinical findings of osteoarthritis in patients with knee osteoarthritis|
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As shown in [Figure 1], serum ADN level was significantly correlated with serum LEP level (r=0.367, P=0.005). Serum ADN level was also significantly correlated with MMP-3 serum level (r=0.548, P<0.001) ([Figure 2]). Moreover, serum LEP level was significantly correlated with MMP-3 serum level (r=0.307, P=0.021) ([Figure 3]).
|Figure 1 Correlation between adiponectin and leptin in patients with osteoarthritis.|
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|Figure 2 Correlation between adiponectin and matrix metalloproteinase 3 in patients with osteoarthritis.|
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|Figure 3 Correlation between leptin and matrix metalloproteinase 3 in patients with osteoarthritis.|
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As shown in [Table 3], the increased KL grades in the plain radiograph is associated with increased ADN serum levels (P=0.013). On MRI, the increased ADN grades were associated with increased Noyes grade (P=0.008) ([Table 4]), MRI severity grade (P=0.004) ([Table 5]), and with meniscal degeneration grade (P=0.016) ([Table 6]); they showed no association with effusion grades ([Table 7]). Moreover, serum LEP and MMP-3 levels showed no association with the plain radiograph and the MRI findings.
|Table 3 The association between the adiponectin, leptin, and matrix metalloproteinase 3 serum levels and the Kellgren–Lawrence grades|
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|Table 4 The association between the adiponectin, leptin, and matrix metalloproteinase 3 serum levels and the MRI Noyes grade|
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|Table 5 The association between the adiponectin, leptin, and matrix metalloproteinase 3 serum levels and the MRI severity grade|
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|Table 6 The association between the adiponectin, leptin, and matrix metalloproteinase 3 serum levels and the meniscal degeneration grades on MRI examination|
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|Table 7 The association between the adiponectin, leptin, and matrix metalloproteinase 3 serum levels and the effusion grades on MRI examination|
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The Hoffa fat pad volume was significantly correlated with serum ADN level (P=0.014) ([Figure 4]), serum LEP level (P=0.047) ([Figure 5]), and serum MMP-3 level (P=0.019) ([Figure 6]).
|Figure 4 Correlation between adiponectin and Hoffa fat pad volume in patients with osteoarthritis.|
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|Figure 5 Correlation between leptin and Hoffa fat pad volume in patients with osteoarthritis.|
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|Figure 6 Correlation between matrix metalloproteinase 3 and Hoffa fat pad volume in patients with osteoarthritis.|
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| Discussion|| |
The major findings of the current study are as follows: (a) serum ADN is significantly higher in patients with primary KOA in comparison with controls; (b) serum ADN in patients with primary KOA is correlated with the pain, tenderness, and clinical indices of KOA severity and activity; and (c) serum ADN in patients with primary KOA is correlated with the radiological evidence of the KOA severity, the cartilage damage, and the meniscal disc degeneration.
In the present study, the patients with KOA had significantly higher plasma ADN, LEP, and MMP-3 levels in comparison with the controls. In agreement with our results, the investigations of De Boer et al.  and Laurberg et al.  showed higher ADN plasma concentrations in OA patients in comparison with the controls with significant differences. In contrast, Honsawek and Chayanupatkul  and Coskun et al.  reported higher serum concentrations of ADN in patients with OA in comparison with the control group but this difference did not reach the significant level. However, a study by Honsawek and Chayanupatkul  reported elevated serum ADN levels in KL grade 2 OA patients compared with controls, but decreased levels in KL grade 4 OA patients.
Higher serum LEP in patients with OA compared with controls had been previously reported by several studies ,,. In OA, LEP is secreted from osteophytes, synovial membrane, cartilaginous tissues, inflammatory cells, and the IFFP ,,, which at least partially explains the elevated serum concentration of this marker in patients with OA. Evidence is increasing that LEP plays a proinflammatory role in the pathophysiological pathways of OA ,. Levels of MMPs at both the gene as well as at the protein level are enhanced by LEP and ADN .
The results of the current study had shown that serum ADN, but not LEP or MMP-3, was significantly higher in female KOA patients compared with male KOA patients. Two previous studies evaluated the effect of sex on serum ADK concentrations in patients with OA. One study demonstrated a statistically significant difference in serum LEP levels between female and male patients, but the study did not specify which sex had the highest levels; the same study showed that ADN levels were similar between male and female populations . The other study reported higher serum ADN and LEP levels in female patients compared with male patients with KOA . These differences could not be completely explained by anthropometric differences of body fat distribution between sexes ,,.
In our study, in primary KOA patients, serum ADN was significantly correlated with BMI, waist circumference, and WHR. These findings are in agreement with those of Coskun et al. . Interestingly, in the study by Coskun et al. , the BMI was found to be inversely correlated with ADN in controls. This finding suggests that arthritis itself plays a role in the increase in ADN levels. In contrast, several studies found no correlation between ADN serum level and BMI in patients with OA ,. However, in the study by Hao et al.  serum ADN level was significantly correlated with WHR in patients with OA, a finding that may suggest that plasma level of ADN is related to the amount of visceral adipose tissue rather than obesity. In contrast, an inverse correlation between serum ADN levels and BMI, and in particular the visceral adipose tissue, had also been observed ,. The study of De Boer et al.  enrolled only end-stage KOA patients. It is also possible that the plasma ADN level is affected by systemic factors, including hormonal, nutritional, or pharmacologic factors, and it is also possible that ADN is released by other tissues besides the white adipose tissue, which may account for this discrepancy . Another possible explanation is that, in patients with arthritis, the inflammatory process itself within the joint tissues rather than BMI is a major determinant for the ADN values in these patients .
In the present study, serum ADN was significantly correlated with the clinical parameters of OA severity and activity. In agreement with our findings, Fioravanti et al.  found that serum ADN levels were significantly associated with pain, tenderness score, and all WOMAC subscores and total score. Coskun et al.  reported a weak direct relationship between ADN level and WOMAC score. However, Massengale et al.  failed to find any correlation between ADN concentrations and WOMAC score.
In the present study, ADN serum level had shown a direct correlation with pain and tenderness and MMP-3 showed a direct correlation with tenderness but not with pain, whereas LEP showed no correlation with pain or with tenderness. Coskun et al.  reported a weak association between pain and ADN concentrations in patients with OA. Gandhi et al.  found that synovial fluid ADN levels and pain were positively correlated in patients with OA. In contrast, Massengale et al.  found no correlation between serum ADN and pain in patients with OA. Pain in OA develops as a result of multiple mechanisms in which various causes may have a role. Pain in KOA arises from irritation of nerve endings as a result of inflammation of the synovial membrane and pressure on joint ligaments or joint capsule by osteophytes . Therefore, degree of pain may not be directly correlated to a single biological marker or mechanism in OA.
The exact process that involves ADN in the pathogenesis of OA still remains unknown. However, the results of the current study revealed a positive significant correlation between the serum level of ADN and the serum level of MMP-3. Several studies are in agreement with our results. Koskinen et al.  found that the serum ADN levels correlated significantly with the levels of MMP-3 and COMP. Kang et al.  found that the higher ADN is significantly associated with higher MMP-3 level as well as nitric oxide, MMP-1, and MMP-13. Cultured cartilaginous tissue obtained from cases with primary KOA in the presence of ADN displayed elevated MMP levels, including MMP-3. These findings suggest that ADN may induce the production of nitric oxide synthase, and MMPs, including MMP-3 .
Conversely, in the study by Chen et al. , ADN did not increase the expression levels of MMP-3 and MMP-13 mRNA. In contrast, there is evidence that ADN plays a protective role against cartilage degeneration by elevating the levels of tissue inhibitor of metalloproteinase (TIMP)-2 and by suppressing the MMP-13 .
The conflicting findings considering the influence of ADN on MMP enzymes can be attributed to the experimental conditions. Chen et al.  worked on chondrocytes from the KOA tissues with KL grades 1 and 2 and also included chondrocytes from the nonlesional areas, whereas Kang et al.  isolated chondrocytes from KOA patients of KL grade 3 or 4. The OA chondrocyte behavior and phenotypes are affected by the surrounding matrix state; moreover, chondrocytes from lesional areas had different behavior than those from nonlesional areas , and hence this can be attributed to the difference in ADN-induced responses in each study. In the current study, 64.3% of our patients had KL grade higher than 2.
Another possibility for the controversial results is the different structure of the ADN isoforms that come from different tissue source from which ADN is synthesized. The various biological actions mediated by ADN is believed to be isoform dependent. High molecular weight (HMW) isoform had predominantly proinflammatory action ,, whereas the low molecular weight isoform had anti-inflammatory actions ,. The most profuse ADN isoforms are the hexamers and HMW forms, followed by trimers . The reagents utilized in most studies, including ours, determine these two isoforms. Interestingly, hexamers and HMW isoforms are the most abundant in the human OA cartilaginous tissue and synovial fluid .
In the present study, serum ADN level is positively correlated with radiological severity of the OA graded using the KL scale in plain radiography, positively correlated with OA severity grading in MRI examination, and with articular cartilage damage using Noyes grading in MRI examination. However, the results of the present study showed that serum LEP and MMP-3 levels did not show a significant correlation with the radiological severity of the OA graded using the KL scale or MRI findings. Consistent with our results, Coskun et al.  reported that radiological KOA severity in plain radiograph graded using the KL scale was positively correlated with ADN serum levels. Koskinen et al.  reported that serum ADN levels as well as ADN quantities produced by cultured chondrocytes from OA cartilaginous tissues were higher in KOA patients who had more severe radiographic grading (grades 3 and 4) than in patients with less severe disease (grades 1–3). They concluded that ADN is associated with cartilage degeneration in OA. Our results were also supported by the studies of Giles et al.  and Olcyzk-Wrochna et al.  in which higher serum levels of ADN were associated with more advanced stages of OA.
In contrast, Honsawek and Chayanupatkul  found that ADN serum levels (and also in the synovial fluid) was inversely correlated with the KOA severity measured according to the KL grading scale. The vast majority of patients in that study were female, which may at least partially explain the dissimilarities between their results and ours.
Yusuf et al.  had shown that higher levels of serum ADN reduced the risk for hand OA radiological progression in a six-year follow-up period. Staikos et al.  found no correlation between serum ADN levels and the radiologic OA severity. A cross-sectional study that enrolled 205 patients with KOA found that plasma ADN concentrations were significantly associated with reduced radiographic OA severity, whereas LEP was associated with increased knee articular cartilage volume at the patellar and medial tibial sites suggesting a protective role of these ADK . The disagreement between these studies and ours can be attributed to the different methodologies used to evaluate the serum ADN level, sex differences [the majority (91%) of the patients in that of Yusuf et al.  were female] and probably even by differences in the pathophysiological mechanisms involved in the hand and KOA.
Our results showed no association between LEP levels and radiological grading of KOA severity, cartilage damage, and meniscal disc degeneration. Yusuf  also found no association between LEP serum level and the radiological severity of OA. Previous studies on the role of LEP in cartilage were indecisive as catabolic , as well as protective  effects were obtained. Moreover, Nishimuta and Levenston  reported that meniscal tissues are more susceptible to ADK-derived catabolic effect compared with the cartilage tissues. However, this later study assayed the ex-vivo effect of ADN and LEP on bovine cartilage and meniscus explants.
Local factors in joints were also believed to play a role in the pathogenesis of OA. In particular, the knee joint encloses a relatively large adipose tissue, the IFFP, which may serve as a local source for inflammatory mediators . Our results had shown that ADN serum level and serum MMP-3 levels were significantly correlated with the IFFP volume. The serum LEP level is weakly correlated with the IFFP volume. In the study by De Boer et al. , the serum LEP, ADN, and MMP-3 levels were significantly correlated with the IFFP volume but relations were not very robust. Gandhi et al.  compared the serum and synovial fluid ADN levels between patients with end-stage shoulder OA and patients with end-stage KOA and found that serum and synovial fluid ADN levels were consistently higher in KOA patients as compared with shoulder OA patients. This result may add to the evidence of the role of the IFFP in the pathogenesis of KOA as shoulder joint lacks such fat pad.
| Conclusion|| |
ADN serum level was associated with radiologic evidence of OA severity and correlated with serum LEP and MMP-3 levels. These findings strongly suggest that ADN is involved in the pathogenesis of joint inflammation and cartilage destruction in OA and may be a target for disease-modifying drug development.
This work was supported by a grant from Academy of Scientific Research and Technology, Egypt, 2013.
Financial support and sponsorship
Academy of Scientific Research and Technology.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]