Increased serum and synovial levels of midkine are associated with radiological progression in primary knee osteoarthritis patients

The Egyptian Rheumatologist 41 (2019) 189–195

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Original Article

Increased serum and synovial levels of midkine are associated with radiological progression in primary knee osteoarthritis patients Waleed A. Hassan a,⇑, Amira I. Mansour b a b

Rheumatology, Rehabilitation and Physical Medicine Department, Benha University, Kalyoubia, Egypt Clinical and Chemical Pathology Department, Benha University, Kalyoubia, Egypt

a r t i c l e

i n f o

Article history: Received 31 October 2018 Accepted 5 November 2018 Available online 15 November 2018 Keywords: Midkine Radiological progression Osteoarthritis Musculoskeletal ultrasound

a b s t r a c t Background: Midkine is a heparin-binding growth factor that is believed to have functional antagonism, although it helps in tissue repair, it can also enhance inflammatory reactions resulting in more tissue injury. Aim of the work: This study aimed to determine serum and synovial fluid (SF) levels of midkine in patients with primary knee osteoarthritis (KOA) and to correlate these levels with patients’ clinical and functional parameters as well as radiological progression of KOA. Patients and methods: Midkine was measured in the serum and 23 SF samples from 52KOA patients as well as in the serum from 20 healthy controls. In the patients, The Western Ontario McMaster scale (WOMAC) was recorded to assess functional status. Graded plain radiographs using Thomas score, and musculoskeletal ultrasound examination (MSUS) of both knees were performed at baseline and after 2 years to assess radiological progression. Results: The patients mean age was 51.5 ± 10.6 years and disease duration was 5.4 ± 4.7 years. Serum levels were significantly increased in KOA patients (80.8 ± 31.8 pg/mL) compared to the controls (65.6 ± 14.8 pg/mL). Patients with elevated serum and SF midkine had twofold increased risk of radiological progression with MSUS (RR2.4 and 2.6 respectively). However, there was no increased risk of radiological progression detected with plain radiography. Conclusion: Osteoarthritis patients have significantly elevated serum and synovial levels of midkine that were correlated with functional status assessed with WOMAC index and obviously associated with radiological progression on MSUS suggesting that it could be a useful marker to reflect OA severity and implies a possible role in the disease pathogenesis. Ó 2018 Egyptian Society of Rheumatic Diseases. Publishing services provided by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction Osteoarthritis (OA) is the most common joint disease worldwide. It is mainly characterized by articular cartilage degeneration, joint capsule hypertrophy, remodeling of subchondral bone, formation of osteophytes, laxity of surrounding ligaments, and synovial inflammation [1]. It usually manifests after the age of forty and is commonly diagnosed clinically. Key symptoms and signs include mechanical pain, stiffness especially after inactivity; crepitus and synovial effusion may also be present [2]. OA is slowly progressive with an intermittent worsening pattern rather than a linear continuous deterioration [3]. Yet, its pathophysiology is multifactorial and the exact molecular mechanisms that contribute

Peer review under responsibility of Egyptian Society of Rheumatic Diseases. ⇑ Corresponding author at: Rheumatology, Rehabilitation and Physical Medicine, Benha University, Postal code 13516, Kalyoubia, Egypt. E-mail address: [email protected] (W.A. Hassan).

are not fully understood and there is no definite treatment that inhibits cartilage degeneration or prevents progression [4]. There is increasing interest about the role of inflammation in the pathogenesis of OA [2]. Inflammatory mediators produced by the synovium, subchondral bone and articular cartilage such as growth factors, cytokines, reactive oxygen species and lipid derivatives release matrix metalloproteinases (MMP) and results in progressive cartilage degeneration [5]. Many studies on Egyptian patients with primary knee OA have (KOA) been conducted in order to detect novel biomarkers related to the disease pathogenesis or severity [6–10]. Midkine is a13-Kd protein that acts as a heparin-binding growth factor that has a vital role in mesoderm remodeling as in adipocyte survival and chondrogenesis as it is expressed in the growth plate of the epiphysis during fetal life [11]. In adult life, it is induced with inflammatory conditions and there is an increased midkine expression in damaged tissues [12]. Binding of midkine to its functional receptor can activate many intracellular signaling

https://doi.org/10.1016/j.ejr.2018.11.001 1110-1164/Ó 2018 Egyptian Society of Rheumatic Diseases. Publishing services provided by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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pathways that can promote proliferation, growth, survival or has anti-apoptotic function [13]. Plain X-ray, the traditional imaging modality used for OA assessment is helpful in evaluation of sclerosis, osteophytes and joint space narrowing [14]. But it has many limitations as it cannot visualize hyaline cartilage, soft tissue structures surrounding the joint or menisci [15]. Musculoskeletal ultrasound (MSUS) is an imaging modality that can assess inflammation as well as structural damage in OA with a potentially increasing role in its assessment [16]. Inflammation of the synovium is demonstrated with synovial hypertrophy, effusion and positive Doppler signal while structural damage is demonstrated with osteophytes formation and cartilage lesions [17]. It has many advantages as being noninvasive, accessible, cheap and relatively safe with no ionizing radiation and it can be used for early detection of OA and monitor its progression especially in the knee as it has wide acoustic window [10]. The potential role of midkine in the pathophysiology OA has been reported in experimental models [18]. This study aimed to determine serum and synovial fluid (SF) levels of midkine in patients with primary KOA and to correlate these levels with patients’ clinical and functional parameters as well as radiological progression of KOA over 2 years follow up period. 2. Patients and methods Sixty patients, fulfilling the clinical and radiological American College of Rheumatology (ACR) classification criteria of primary KOA [19] were selected from the Rheumatology and Rehabilitation Department of Banha University Hospitals. 20 age and sex matched apparently healthy individuals, who had no symptoms, clinical or radiological findings suggesting KOA, were also included as a control group. Patients’ assessment included history taking and physical examination, pain assessment using numerical rating scale of pain (NRSP) [20]. Patients were asked to complete Western Ontario and McMaster Universities (WOMAC) composite index to assess pain, stiffness and function [21]. Body mass index (BMI) was assessed. Patients were followed up for 2 years and at the end of the study there were 8 drop-outs that were excluded. Only 52 patients were longitudinally followed at the allocated time. Patients were excluded if they had secondary KOA, coexisting hip and knee OA or were expose to conditions that influence midkine concentration as systemic steroids or local steroid injection in the knee during the past 3 months, diabetes mellitus, recent infection, stroke, liver diseases and malignancy. The local ethics committee approved this study and a written informed consent was obtained from all participants before being enrolled in this study. Plain x-ray knees (anteroposterior weight-bearing, lateral and skyline views) were taken at baseline and after 2 years and assessed by Kellgren and Lawrence (K/L) grading scale [22] (used at baseline to classify OA; grade II or less is considered as early and grade III or IV is considered late OA) and by Thomas score [23] (used at baseline and after 2 years to assess radiographic progression). Medial, lateral and patellofemoral compartments were evaluated by Thomas score for degree of joint space narrowing, subchondral sclerosis, formation of osteophytes and subchondral bone cysts. Each item is scored from 0 to 3 and then the grade of each compartment is calculated by the summation of the scores of the 4 items on right and left sides. The total score is calculated by summation of the 3 compartments scores. 2.1. Musculoskeletal ultrasound Grayscale assessment of the femoral articular cartilage was done using Logiq e scanner (General Electric Medical Systems, Wisconsin, USA) equipped with a linear high-frequency transducer

(8–13 MHz). MSUS knees was performed according to the OA grading scale of Saarakkala et al. [24] with the knee fully flexed and the subject lying supine. The transducer was placed transversely just above the patella for evaluation and measurement of the hyaline cartilage in medial and lateral femoral condyle as well as in intercondylar (sulcus) area. The following grades were given: Grade 0: normal with anechoic band and hyperechoic sharp cartilage interfaces. Grade 1: mild degenerative changes with decreased sharpness of the cartilage interfaces and/or increased echogenicity of the cartilage. Grade 2A: moderate degenerative changes with <50% decrease in cartilage thickness, in addition to the degenerative changes found in grade 1. Grade 2B: decreased cartilage thickness >50% and <100%. Grade 3: advanced degeneration with loss of the full cartilage thickness. The medial and lateral aspects were scanned to detect osteophytes and effusion. 2.2. Measurement of midkine serum and SF levels Fasting venous samples were collected and centrifuged at the base of the study from KOA patients and controls. 23 SF samples were aspirated and centrifuged from the affected knees. Both serum and SF samples were stored at 80 °C until analysis. Midkine was measured by enzyme linked immunosorbant assay (ELISA) technique according to the manufacturer’s instructions (Human Midkine ELISA Kit Cat.No: MBS730516. My biosource, San Diego, California, USA). 2.3. Statistical analysis Data were presented as mean ± standard deviation (SD), median (range) or frequency and percentage. Chi-square test (v2) and Fisher’s Exact Test (FET) were used to compare frequencies and Student t-test was used to detect mean differences between two groups regarding quantitative data. Mann-Whitney test was used to detect mean differences between two groups regarding nonparametric data. Pearson correlation coefficient was used. The Risk Ratio (RR) was estimated for radiological progression among OA patients with increased and normal serum and SF midkine levels. Receiver Operating Curve (ROC) analysis was carried out to evaluate the diagnostic performance of serum and SF midkine levels for OA progression. The best cut-off point and the related sensitivity and specificity and Area under the Curve (AUC) were calculated. Significance was accepted at p < 0.05. The statistical tests were performed using Statistical Package of Social Sciences (SPSS) version 19.0. 3. Results The 52 KOA patients that completed the follow up study had a mean age of 51.5 ± 10.6 years, 40 of them (76.92%) were females and the 20 controls were sex (15 of them, 75%, were females) and age (52.6 ± 8.3 years) matched. The mean disease duration in KOA patients was 5.4 ± 4.7 years. 43 patients (82.69%) were receiving acetaminophen, whereas 39 patients (75%) were receiving nonsteroidal anti-inflammatory drugs (NSAIDs) and 36 patients (69.23%) were receiving chondroprotectives as glucosamine sulfate, chondroitin sulfate and collagen. Plain x-ray and MSUS of the knees at baseline and after 2 years are presented in Fig. 1. Serum midkine levels were significantly increased in KOA patients (80.79 ± 31.8 pg/mL) compared to controls (65.6 ± 14.76 pg/mL) (p = 0.045). Midkine SF level (216.31 ± 94.93 pg/mL) was significant increased compared to the serum levels (p < 0.001). The SF midkine levels were significantly increased in early OA patients (median, 235 pg/mL; 90–400 pg/mL) compared to serum levels in late OA (188.5 pg/mL; 51–

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Fig. 1. Radiological progression of a 54-year-old female with knee osteoarthritis patient with elevated serum and synovial fluid midkine levels at baseline (1A) and 2 years follow up (1B) on anteroposterior weight bearing plain radiographs of the right knee. Measurements of femoral hyaline cartilage at baseline (1C) and 2 years follow up (1D) of the same patient with musculoskeletal ultrasound are presented; 1: at medial femoral condyle; 2: at lateral femoral; 3: at sulcus area. There is increase in the Thomas score and decrease in the femoral cartilage thickness at the follow up evaluation.

320 pg/mL), (p = 0.03). There was no significant difference in serum midkine between early and late KOA patients (87 pg/mL, 34– 145 pg/mL and 83 pg/mL, 25–140 pg/mL respectively), (p = 0.81) (Fig. 2). Elevated midkine serum level, (>mean + 2SD in controls; 95.12 pg/ml) was found in 16 KOA patients (30.77%), while normal midkine serum level was found in 36 (69.23%). Clinical findings of knee assessment at baseline and 2 years follow up in KOA patients with elevated and normal midkine serum levels are shown in Table 1. Comparisons between KOA patients with normal and elevated midkine serum and SF levels as regard radiological progression using plain radiography and MSUS evaluation at baseline and after 2 years are presented in Table 2. There was no increased risk of radiological progression with plain radiography after 2 years between KOA with elevated and normal serum and SF midkine levels (age, sex and BMI adjusted RR 1.3 and 1.54, 95% CI respectively). There was twofold increased risk of radiological progression with MSUS after 2 years between KOA with elevated and normal serum and SF midkine levels (age, sex and BMI adjusted RR 2.3 and 2.6, 95% CI respectively). Regarding plain radiography, the ROC curve showed at a cutoff of 67 pg/ml (AUC 0.59 95% CI) serum midkine levels showed a sensitivity of 75% and specificity of 48.7% for radiological progression. While the best cutoff of SF midkine at 94 pg/ml (AUC 0.65 95% CI) showed a sensitivity of 77.8% and specificity of 61.5%. (Fig. 3). Regarding MSUS at a cutoff of 91 pg/ml (AUC 0. 683 95% CI) the serum midkine levels showed a sensitivity of 60% and specificity of 81.2% for radiological progression. While the best cutoff of SF

at 94.8 pg/ml (AUC 0.754 95% CI) showed a sensitivity of 71.4% and specificity of 75% (Fig. 4). Serum and SF midkine concentrations showed a significant negative correlation with baseline medial condyle cartilage thickness (r = 0.44 and 0.52 respectively, p = 0.046 and 0.032 respectively) and they showed a significant positive correlation WOMAC index (r = 0.48 and 0.58 respectively, p = 0.043 and 0.005 respectively). Also, Serum midkine concentrations showed a significant positive correlation with its SF concentrations (r = 0.68, p = 0.002). There was no other significant correlation between serum or SF midkine concentrations and other disease parameters. 4. Discussion Osteoarthritis is frequently considered to be a result of wear and tear process. The finding that chondrocytes interact with many cytokines and can produce MMP was the first proof of the role of inflammation in the pathophysiology of OA [25]. Also, it is found that, the type and the origin of these cytokines can vary according to OA phenotype [26]. The pathological changes that occur in joints share common characteristics that affect the entire joint structure leading to joint pain, stiffness and physical disability [27]. The expression of midkine, a heparin-binding growth factors, is increased in damaged tissues and is believed to have functional antagonism; as it helps in tissue repair and survival while, on the other hand it can enhance inflammatory reactions resulting in more tissue injury [28]. Muramatsu et al. [29] found midkine serum levels in 68 normal human subjects to be low or

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Fig. 2. Distribution of midkine serum (A) and synovial fluid (B) among early and late knee osteoarthritis patients.

Table 1 Clinical findings in knee osteoarthritis patients at baseline evaluation and after 2 years in relation to high and normal serum midkine levels at baseline and after 2 years. mean ± SD (range) or n (% of knees)

Effusion Stiffness (min) NRSP WOMAC Crepitus

Serum midkine in KOA patients (n = 52) Baseline

After 2 years

High (n = 16)

Normal (n = 36)

p

High (n = 16)

Normal (n = 36)

p

11 (34.4) 10 ± 7.5 4.69 ± 2.4 39.9 ± 15.8 12 (37.5)

12 (16.7) 9.2 ± 6.4 4.13 ± 2.1 38.2 ± 14.4 34 (47.2)

0.08 0.42 0.4 0.64 0.48

8 (25) 13.1 ± 6.6 5 ± 2.1 42.1 ± 15.6 19 (59.4)

7 (9.7) 11.3 ± 6.1 4.44 ± 1.7 39.4 ± 14.3 37 (51.4)

0.08 0.33 0.06 0.59 0.59

KOA: knee osteoarthritis; NRSP: numerical rating scale of pain; WOMAC: Western Ontario McMaster scale. Bold values are significant at p < 0.05.

undetectable and Kadomatsu et al. [30] found it to be mainly expressed during midgestation stage of embryogenesis, while its expression is low in most of normal mature tissues. In the present study, 28.8% of the OA patients had elevated baseline serum midkine levels. The SF levels also showed a significant increase compared to their serum levels. This can be explained as Takada et al. [31] who found elevated midkine SF concentrations due to its increased expression in endothelial lining of synovial blood vessels and synoviocytes in OA patients with inflammatory synovitis. Kaspiris et al. [32] found it to be highly expressed in chondrocytes and osteocytes of subchondral bone in OA patients and Pufe et al. [33] suggested that pleiotrophin SF level can be used as a marker for OA progression. In this work, OA patients with elevated midkine serum and SF levels had an increased risk of radiological progression when evaluated using MSUS. On the other hand, Xu et al. [34] found administration of recombinant human midkine to mice models with OA to decrease the disease related allodynia, improve movement activity and prevents cartilage degradation and related this to recovery of cartilage preventing vascular invasion. Also, Zhang et al. [35] revealed that recombinant human midkine can stimulate articular chondrocytes proliferation. This discrepancy can be

attributed to the controversial role of midkine in OA pathogenesis as midkine can be beneficial and enhance repair process through promoting increase in the hyaline cartilage thickness and stimulation of cultured chondrocytes proliferation [18,33]. On the other hand, midkine can cause more damage to injured tissues through amplification of inflammation via recruitment of inflammatory cells [36], stimulation of chemokine synthesis and regulatory T cells suppression [37]. In the current study, midkine SF concentration was significantly higher in early compared with late KOA patients. This can be explained by the significant involvement of the synovial membrane in early OA [38] as a result of the released cartilage fragment that can induce foreign body inflammatory synovitis and even synovial hyperplasia and villous formation [39] with release of inflammatory cytokines that result in more cartilage degeneration [40]. This vicious circle leads to loss of cartilage homeostasis with eventually joint failure [5]. A variation in radiological progression between KOA patients with elevated and normal midkine level that was more obvious when evaluation was done using MSUS compared with plain radiography. This may be due to the ability of MSUS to visualize articular cartilage directly at a higher sensitivity in recognition of

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Table 2 Comparison between knee osteoarthritis patients with normal and elevated midkine serum and synovial fluid levels as regard radiological progression using plain radiography and musculoskeletal ultrasound evaluation at baseline and after 2 years. Variable mean ± SD or n(%)

Midkine level (pg/ml) in primary KOA patients Baseline

After 2 years

p

Baseline

After 2 years

p

Serum midkine (n = 52) High (n = 16) Thomas score

MC LC PFC total Radiological Progression

MSUS Cartil. Thick (mm)

MCondyle LCondyle Sulcus Radiological Progression

Normal (n = 36)

5.5 ± 2.7 5.7 ± 2.5 2.6 ± 1.5 2.7 ± 1.5 1.3 ± 1.1 1.4 ± 1.1 9.3 ± 4.3 9.8 ± 4.3 11 (34.4) * P (RR; 95% CI) 0.3 (1.37; 0.7–2.6) 24.2 ± 3.9 23.6 ± 4.1 25.6 ± 2.6 25.4 ± 2.7 25.7 ± 2.6 25.6 ± 2.6 21 (65.6) P* (RR; 95% CI) 0.0002 (2.4; 1.5–3.7)

0.004 0.08 0.04 0.0003

6.5 ± 2.6 2.6 ± 1.6 1.5 ± 1.03 9.9 ± 4.1 18 (25)

6.6 ± 2.5 2.7 ± 1.6 1.5 ± 1.02 10.2 ± 4.1

0.013 0.08 0.16 0.06

0.002 0.06 0.08

24.03 ± 2.2 25.4 ± 1.7 25.6 ± 1.7 20 (27.8)

23.8 ± 2.2 25.3 ± 1.7 25.5 ± 1.7

0.007 0.06 0.1

Synovial fluid midkine (n = 23) High (n = 13) Thomas score

MC LC PFC total Radiological Progression

MSUS Cartil. Thick (mm)

MCondyle LCondyle Sulcus Radiological Progression

Normal (n = 10)

4.6 ± 1.9 5 ± 1.9 2.1 ± 0.5 2.2 ± 0.7 1.3 ± 0.6 1.4 ± 0.7 8 ± 2.9 8.6 ± 3.04 6 (46.2) P* (RR; 95% CI) 0.49 (1.54; 0.5–4.7) 22.3 ± 2.8 20.1 ± 2.02 25.1 ± 2.9 24.6 ± 3.01 25.4 ± 3.1 25.3 ± 3.1 10 (76.9) P *(RR; 95% CI) 0.06 (2.56; 0.95–6.92)

0.02 0.17 0.34 0.025

5.2 ± 2.4 2.5 ± 1.5 1.7 ± 1.2 9.4 ± 3.9 3 (30)

5.3 ± 2.2 2.6 ± 1.5 1.9 ± 0.99 9.8 ± 3.8

0.34 0.34 0.17 0.1

<0.001 0.027 0.34

23.6 ± 2.8 25.3 ± 0.8 25.1 ± 1.1 3 (30)

23.2 ± 3.1 25.2 ± 0.9 25 ± 1.3

0.1 0.34 0.59

KOA: knee osteoarthritis, MSUS: musculoskeletal ultrasound, MC: medial compartment, LC: lateral compartment, PFC: patellofemoral compartment, SF: synovial fluid, RR: relative risk, *: P is less than 0.05 if the RR is significantly different from 1, High medkine level was based upon serum or synovial fluid concentrations > 95.12 pg/ml. Bold values are significant at p < 0.05.

Fig. 3. Receiver operating characteristic (ROC) curve assessing the validity of the midkine serum and synovial fluid levels in prediction of osteoarthritis radiological progression using plain radiography. (A) Serum midkine Area under the curve (AUC) was 0.59 95%CI. (B) Synovial fluid (SF): AUC 0.65 95%CI.

degenerative changes at earlier changes [41]. In this work, serum and SF midkine concentrations significantly correlated with the WOMAC index. The Knee articular cartilage changes using MSUS correlated significantly with WOMAC index [42] and arthroscopic findings in KOA patients [24].

There are some limitations to this study including the relative low number of enrolled KOA patients and the relative short follow-up period duration. Larger scale longitudinal studies are needed to describe the exact role of midkine in the pathophysiology and radiological progression of OA and to investigate if

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Fig. 4. Receiver operating characteristic (ROC) curve assessing the validity of the midkine serum and synovial fluid levels in prediction of osteoarthritis radiological progression using musculoskeletal ultrasound. (A) Serum midkine: Area under the curve (AUC) was 0.68 at 95%CI. (B) Synovial fluid (SF): AUC was 0.75.

recombinant human midkine or midkine antagonists could be used as a treatment option in OA patients. In conclusion, Osteoarthritis patients have significantly elevated serum and synovial level of midkine that correlated with the functional status assessed with WOMAC index and was obviously associated with radiological progression on MSUS, suggesting that it could be a useful marker to reflect OA severity and implies a possible role in the pathogenesis of the disease.

Conflict of interest Authors declare that they have no conflict of interest.

Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References [1] Favero M, Ramonda R, Goldring MB, Goldring SR, Punzi L. Early knee osteoarthritis. RMD Open 2015;1(Suppl 1):e000062. [2] Berenbaum F, Eymard F, Houard X. Osteoarthritis, inflammation and obesity. Curr Opin Rheumatol 2013;25(1):114–8. [3] Kirwan JR, Elson CJ. Is the progression of osteoarthritis phasic? Evidence and implications. J Rheumatol 2000;27:834. [4] Krasnokutsky S, Samuels J, Abramson SB. Osteoarthritis in 2007. Bull NYU Hosp Jt Dis 2007;65(3):222–8. [5] Berenbaum F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage 2013;21(1):16–21. [6] Mohammed MA, Rady SAK, Mohammed RA, Fadda SMH. Relation of plasma fibroblast growth factor-23 (FGF-23) to radiographic severity in primary knee osteoarthritis patients. Egypt Rheumatol 2018;40(4):261–4. [7] El-Najjar AR, Ezzeldin N, Khalil SS, El-Gerby KM, Alazizi NM, Ibraheem HA. Vascular endothelial growth factor and colour Doppler ultrasonography in knee osteoarthritis: relation to pain and physical function. Egypt Rheumatol 2019;41(2):139–43. [8] El-Fetiany AE, Kassem EM, El-Barbary AM, Gaber RA. Zyton HA Evaluation of plasma basic fibroblast growth factor (bFGF) in primary knee osteoarthritis patients. Egypt Rheumatol 2017;39(1):33–7. [9] Mohammed FI, Abd El-Azeem MI, KamalElDin AM. Plasma and synovial fluid osteopontin levels in patients with knee osteoarthritis: relation to radiological grade. Egypt Rheumatol 2012;34(3):131–6. [10] El-Brashy AS, El-Tanawy RM, Hassan WA, Shaban HM, Bhnasawy MMI. Potential role of vitamin K in radiological progression of early knee osteoarthritis patients. Egypt Rheumatol 2016;38(3):217–23.

[11] Ohta S, Muramatsu H, Senda T, Zou K, Iwata H, Muramatsu T. Midkine is expressed during repair of bone fracture and promotes chondrogenesis. J BoneMinerRes 1999;14(7):1132–44. [12] Shindo E, Nanki T, Kusunoki N, Shikano K, Kawazoe M, Sato H, et al. The growth factor midkine may play a pathophysiological role in rheumatoid arthritis. Mod Rheumatol 2017;27(1):54–9. [13] Muramatsu T. Midkine, a heparin binding cytokine with a multiple roles in development, repair and disease. ProcSer B PhysBiol Sci 2010;86(4):410–25. [14] Hirvasniemi J, Thevenot J, Immonen V, Liikavainio T, Pulkkinen P, Jämsä T, et al. Quantification of differences in bone texture from plain radiographs in knees with and without osteoarthritis. Osteoarthritis Cartilage 2014;22 (10):1724–31. [15] Hunter DJ, Conaghan PG. Imaging outcomes and their role in determining outcomes in osteoarthritis and rheumatoid arthritis. CurrOpinRheumatol 2006;18:157–62. [16] Möller I, Bong D, Naredo E, Filippucci E, Carrasco I, Moragues C, et al. Ultrasound in the study and monitoring of osteoarthritis. Osteoarthritis Cartilage 2008;16(Suppl 3):S4–7. [17] Iagnocco A. Imaging the joint in osteoarthritis: a place for ultrasound? Best Pract Res Clin Rheumatol 2010;24(1):27–38. [18] Xu C, Zhu S, Wu M, Zhao Y, Han W, Yu Y. The therapeutic effect of rhMK on osteoarthritis in mice, induced by destabilization of the medial meniscus. Biol Pharm Bull 2014;37(11):1803–10. [19] Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee.Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum 1986;29:1039–49. [20] Ferraz MB, Quaresma MR, Aquino LR, Atra E, Tugwell P, Goldsmith H. Reliability of pain scales in the assessment of literate and illiterate patients with rheumatoid arthritis. J Rheumatol 1990;17(8):1022–4. [21] Guermazi M, Poiraudeau S, Yahia M, Mezganni M, Fermanian J, Habib Elleuch M, et al. Translation, adaptation and validation of the Western Ontario and McMaster Universities osteoarthritis index (WOMAC) for an Arab population: the Sfax modified WOMAC. Osteoarthritis Cartilage 2004;12(6):459–68. [22] Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis 1957;16:494–502. [23] Thomas RH, Resnick D, Alazraki NP, Daniel D, Greenfield R. Compartmental evaluation of osteoarthritis of the knee. A comparative study of available diagnostic modalities. Radiology 1975;116(3):585–94. [24] Saarakkala S, Waris P, Waris V, Tarkiainen I, Karvanen E, Aarnio J, et al. Diagnostic performance of knee ultrasonography for detecting degenerative changes of articular cartilage. Osteoarthritis Cartilage 2012;20:376–81. [25] Goldring MB, Otero M. Inflammation in osteoarthritis. Curr Opin Rheumatol 2011;23(5):471e8. [26] Bijlsma JW, Berenbaum F, Lafeber FP. Osteoarthritis: an update with relevance for clinical practice. Lancet 2011;377(9783):2115–26. 18. [27] Darwish AF, Abdel-Ghany HS, El-Sherbini YM. Diagnostic and prognostic value of some biochemical markers in early knee osteoarthritis. Egypt Rheumatol 2012;34(1):1–8. [28] Muramatsu T. Midkine and pleiotrophin: two related proteins involved in development, survival, inflammation and tumorigenesis. J Biochem 2002;132 (3):359–71. [29] Muramatsu H, Song X, Koide N, Hada H, Tsuji T, Kadomatsu K, et al. Enzymelinked immunoassay for midkine, and its application to evaluation of midkine

W.A. Hassan, A.I. Mansour / The Egyptian Rheumatologist 41 (2019) 189–195

[30]

[31]

[32]

[33]

[34]

[35]

levels in developing mouse brain and sera from patients with hepatocellular carcinomas. J Biochem 1996;119:1171–5. Kadomatsu K, Huang RP, Suganuma T, Murata F, Muramatsu T. A retinoic acid responsive gene MK found in the teratocarcinoma system is expressed in spatially and temporally controlled manner during mouse embryogenesis. J. Cell Biol. 1990;110:607–16. Takada T, Toriyama K, Muramatsu H, Song XJ, Torii S, Muramatsu T. Midkine, a retinoic acid-inducible heparin-binding cytokine in inflammatory responses: chemotactic activity to neutrophils and association with inflammatory synovitis. J Biochem 1997;122:453–8. Kaspiris A, Mikelis C, Heroult M, Khaldi L, Grivas TB, Kouvaras I, et al. Expression of the growth factor pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta in the serum, cartilage and subchondral bone of patients with osteoarthritis. Joint Bone Spine 2013;80:407–13. Pufe T, Bartscher M, Petersen W, Tillmann B, Mentlein R. Pleiotrophin, an embryonic differentiation and growth factor, is expressed in osteoarthritis. Osteoarthritis Cartilage 2003;11:260–4. Xu C, Zhang Z, Wu M, Zhu S, Gao J, Zhang J, et al. Recombinant human midkine stimulates proliferation and decreases dedifferentiation of auricular chondrocytes in vitro. Exp Biol Med (Maywood) 2011;236:1254–62. Zhang ZH, Li HX, Qi YP, Du LJ, Zhu SY, Wu MY, et al. Recombinant human midkine stimulates proliferation of articular chondrocytes. Cell Prolif 2010;43:184–94.

195

[36] Sato W, Kadomatsu K, Yuzawa Y, Muramatsu H, Hotta N, Matsuo S, et al. Midkine is involved in neutrophil infiltration into the tubulointerstitium in ischemic renal injury. J Immunol 2001;167:3463–9. [37] Wang J, Takeuchi H, Sonobe Y, Jin S, Mizuno T, Miyakawa S, et al. Inhibition of midkine alleviates experimental autoimmune encephalomyelitis through the expansion of regulatory T cell population. Proc Natl Acad Sci USA 2008;105:3915–20. [38] Guermazi A, Roemer FW, Hayashi D, Crema MD, Niu J, Zhang Y, et al. Assessment of synovitis with contrast-enhanced MRI using a whole-joint semiquantitative scoring system in people with, or at high risk of knee osteoarthritis: the MOST study. Ann Rheum Dis 2011;70(5):805–11. [39] Myers SL, Flusser D, Brandt KD, Heck DA. Prevalence of cartilage shards in synovium and their association with synovitis in patients with early and endstage osteoarthritis. J Rheumatol 1992;19(8):1247–51. [40] Krasnokutsky S, Belitskaya-Levy I, Bencardino J, Samuels J, Attur M, Regatte R, et al. Quantitative MRI evidence of synovial proliferation is associated with radiographic severity of knee osteoarthritis. Arthritis Rheum 2011;63 (10):2983–9. [41] Naredo E, Acebes C, Möller I, Canillas F, de Agustín JJ, de Miguel E, et al. Ultrasound validity in the measurement of knee cartilage thickness. Ann Rheum Dis 2009;68:1322–7. [42] Razek AA, El-Basyouni SR. Ultrasound of knee osteoarthritis: interobserver agreement and correlation with Western Ontario and McMaster Universities Osteoarthritis. Clin Rheumatol 2016;35:997–1001.