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Relation of plasma fibroblast growth factor-23 (FGF-23) to radiographic severity in primary knee osteoarthritis patients
The Egyptian Rheumatologist 40 (2018) 261–264
Contents lists available at ScienceDirect
The Egyptian Rheumatologist journal homepage: www.elsevier.com/locate/ejr
Original Article
Relation of plasma fibroblast growth factor-23 (FGF-23) to radiographic severity in primary knee osteoarthritis patients Mai A. Mohammed a, Shaimaa A.K. Rady b,⇑, Rabab A. Mohammed c, Samia M.H. Fadda d a
Beni-Suef Hospital, Ministry of Health, Beni-Suef, Egypt Rheumatology Department, Faculty of Medicine, Beni Suef University, Egypt c Clinical Pathology Department, Faculty of Medicine , Beni Suef University, Egypt d Rheumatology Department, Faculty of Medicine, Cairo University, Egypt b
a r t i c l e
i n f o
Article history: Received 13 January 2018 Accepted 20 January 2018 Available online 4 February 2018 Keywords: Fibroblast growth factor-23 Osteoarthritis KL score WOMAC score
a b s t r a c t Aim of the work: This study aimed to investigate the plasma level of fibroblast growth factor-23 (FGF-23) in patients with primary knee osteoarthritis (KOA) and to elaborate its relation with radiographic and symptomatic severity of OA. Patients and methods: 50 KOA patients were recruited from the Rheumatology and Rehabilitation Department, Beni-Suef University Hospital and 20 matched controls were also included. Plasma FGF23 level was estimated by ELISA. Severity of the disease was assessed clinically by Western Ontario and McMaster Universities Osteoarthritis (WOMAC) score and radiologically by Kellgren-Lawrence (KL) grading scale. Results: The mean age of the patients was 59.8 ± 8.02 years (51–75 years) and disease duration 3.8 ± 2.1 years (1–9 years); they were 8 males (16%) and 42 (84%) females with a body mass index of 34.04 ± 5.3 (23.6–48.4). FGF-23 level was higher in KOA patients (96.2 ± 148.9 pg/ml; 3.4–14814.6 pg/ml) than in control (18.3 ± 11.1 pg/ml; 5–38.4 pg/ml) (p = .023). There was no significant difference in FGF-23 between males and females. FGF-23 was significantly increased in patients who had effusion (p = .004) or bilateral involvement (p = .023). Plasma FGF-23 level significantly correlated with disease severity sores; WOMAC and KL (p = .009, p = .01 respectively) and also with the age (p = .016), disease duration (p = .006) and body mass idex (p = .008) Conclusions: FGF-23 might be a potential biomarker for diagnosing and evaluating the onset and development of KOA and significantly correlated with the symptomatic and radiographic severity of the disease. Controlling KOA progression by inhibitors of FGF23 may be an issue of interest in further studies. Ó 2018 Publishing services provided by Elsevier B.V. on behalf of Egyptian Society of Rheumatic Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
1. Introduction Osteoarthritis (OA) is the most common form of rheumatic disease, leading ultimately to chronic pain, restriction of joint mobility, disability and reduced quality of life (QoL) of the population over 65 years [1]. Clinical characteristics of OA show marked heterogeneity of clinical presentation including severe pain, joint stiffness, limited range of motion (ROM), swelling, crepitation and disability [2].
Peer review under responsibility of Egyptian Society of Rheumatic Diseases. ⇑ Corresponding author at: Rheumatology Department, Faculty of Medicine, Beni Suef University, Beni-Suef, Egypt. E-mail addresses: [email protected], [email protected] (S.A.K. Rady).
Although radiographs are practically used to assess the OA severity, it would be advantageous to have a biochemical parameter that could precisely reflect disease severity and OA progression [3]. Biomarkers of cartilage degeneration have been extensively investigated in other rheumatic diseases as rheumatoid arthritis (RA) and systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) [4–6]. Several biomarkers have been assessed in Egyptian patients with OA with a potential role in the disease pathogenesis [7–11]. Fibroblast growth factor-23 (FGF-23) is a novel member of the FGF family and is an important circulating phosphaturic factor in serum, which is essential in chondrocyte differentiation and mineral metabolism [12]. It has been actively involved in phosphate homeostasis and skeletogenesis, yet no role was found in another rheumatic disease as systemic sclerosis [13]. Zhou and colleagues
https://doi.org/10.1016/j.ejr.2018.01.007 1110-1164/Ó 2018 Publishing services provided by Elsevier B.V. on behalf of Egyptian Society of Rheumatic Diseases. 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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[14] found that FGF-23 was significantly higher in knee OA (KOA) patients. Furthermore, FGF-23 levels signficantly correlated with radiographic grading and symptomatic severity of KOA. In a previous study on Egyptian KOA patients studying FGF, it was found to be signficantly increased and plays a chief role in the disease pathogenesis [15]. The present study aimed at investigating the plasma level of FGF-23 in KOA patients and to evaluate its relation to radiographic severity according to the Kellgren-Lawrence (KL) grading scale. 2. Patients and methods The study was conducted on 50 primary KOA patients diagnosed according to clinical symptomatic criteria of the American College of Rheumatology (ACR) [16]. The patients included in the study were selected from the Rheumatology and Rehabilitation Department in Beni-Suef University Hospital. 20 healthy volunteers of matched age and sex with no clinical features of OA were included serving as a control group. Inclusion criteria included knee gelling <30 min., crepitus on active motion, bony tenderness or enlargement, no palpable warmth. Patients were excluded if KOA was secondary to an autoimmune disease, metabolic or crystal disease or post traumatic, with chronic kidney diseases. The study was approved by the local ethics committee of BeniSuef University, and informed consent was obtained from all patients according to the Declaration of Helsinki. All patients will be subjected to full history taking including demographic data and all established risk factors and detailed clinical examination. The symptomatic severity was evaluated according to the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) [17]. Routine laboratory investigations including lipid profile were performed and other investigastions needed to exclude secondary OA as C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor and serum uric acid. Level of fibroblast growth factor-23 (FGF-23) in plasma was assessed using enzyme-linked immunosorbent assay (ELISA) KITS BATCH NO.430074, Wuhan ElAab Science Co.,Ltd, Optics valley, China, normal range: 15.6–10 00 Pg/ml. Radiographic assessment of disease severity was considered by weight bearing anteroposterior views of the affected knee in standing position and the X-ray beam was centered on the joint according to the Kellgren-Lawrence (K-L) grading scale [18]. Statistical analysis: Analysis of data was done by IBM computer using SPSS (statistical program for social science) version 18. Description of quantitative variables were presented as mean, SD and range while qualitative variables as number and percentage. Unpaired t-test was used to compare quantitative variables and Pearson’s correlation was performed. P value < .05 was considered significant. 3. Results The study included 50 KOA patients with a mean age of 59.8 ± 8. 02 years (51–75 years) and disease duration 3.8 ± 2.1 years (1–9 years); they were 8 males (16%) and 42 (84%) females with a body mass index of 34.04 ± 5.3 (23.6–48.4). The 20 control were age (57. 2 ± 6.3 years) and sex (3 males and 17 females) and BMI (27.7 ± 4. 4; 19.8–31.6) matched (p = .3 and p = .29 respectively) while the BMI was lower (27.7 ± 4.4; 19.8–31.6)(p = .03). Serum triglycerides, cholesterol and very low density lipoprotein (VLDL) were higher in KOA patients than control (p = .008; p = .03 and p = .004 respectively) (Table 1). FGF-23 level was higher in KOA patients (96.2 ± 148.9 pg/ml; 3.4–14814.6 pg/ml) than in control (18.3 ± 11.1 pg/ml; 5–38.4 pg/ml) (p = .023). There was no
Table 1 Comparison between the knee osteoarthritis patients and the control regarding lipid profile. Parameter mean ± SD
KOA patients (n = 50)
Control (n = 20)
p
Triglycerides Cholesterol VLDL LDL HDL
187.9 ± 79.9 201.2 ± 67.9 37.6 ± 16.0 122.9 ± 72.3 41.2 ± 16.9
134.1 ± 43.8 161.8 ± 68.4 26.4 ± 8.9 96.8 ± 74.3 38.9 ± 15.1
0.006 0.03 0.004 0.18 0.6
KOA: knee osteoarthritis, VLDL: very low density lipoprotein, LDL: low density lipoprotein, HDL: high density lipoprotein. Bold values are significant at p < .05.
significant difference in FGF-23 between males and females. FGF23 was significantly increased in patients who had effusion (p = .004) or bilateral involvement (p = .023) (Table 2). Plasma FGF-23 level significantly correlated with disease severity sores; WOMAC and KL (p = .009, p = .01 respectively)(Fig. 1) and also with the age (p = .016), disease duration (p = .006) and body mass idex (p = .008) (Table 3). 4. Discussion Osteoarthritis (OA) is a degenerative joint disease causing pain and limitations in joint movement. At the tissue level, OA affects predominantly articular cartilage, although other tissues, such as bone, meniscus and synovium, are also involved. Indirectly, this may lead to social isolation, decrease in work ability and depression, i.e., decrease in the general QoL [19]. A central role for inflammatory pathways in processes relevant to OA, including regulation of the chondrocyte catabolic response, development of low grade synovitis, and modulation of pain responses continues to be supported [20]. A variety of the inflammatory mediators are produced by multiple joint tissues and cell types can promote inflammatory and catabolic responses in chondrocytes. Many of these mediators may be biomarkers of inflammatory activity but their clinical utility in early detection, diagnosis, or prognosis needs further assessment [21]. Fibroblast Growth Factor 23 drives matrix metalloproteinase expression and sustains differentiation of OA chondrocytes [22]. FGF-23 has been shown to be highly expressed in osteoarthritic chondrocytes and have low expression levels in normal chondrocytes [23]. In osteoarthritic chondrocytes, FGF-23 binds to FGFR1c with greater ability than in normal chondrocytes, confirming thus the enhanced activation of FGF23 signaling in OA. FGF23 signaling contributes to late hypertrophic events and impaired mineralization in osteoarthritic chondrocytes. This link between chondrocyte hypertrophy and matrix mineralization is well established in endochondral ossification at late stage OA, which is associated with FGF-23 overexpression [24]. These results demonstrate that endogenous FGF-23 is up-regulated during joint injury, which may be a risk factor for OA [14]. In the present study the role of FGF-23 in the progression and development of OA was investigated. There was a significant increase in the plasma FGF-23 levels in KOA patients. Also, a significant correlation was found with radiographic grading and symptomatic severity of KOA. Additionally, this observation indicated a significant elevation in the systemic levels of FGF-23 correlation with WOMAC scores in patients with KOA. These findings are in agreement with [14] a study reporting that serum level of FGF-23 was significantly higher in KOA patients and significantly correlated with WOMAC and KL score. These results indicated that the measurements of serum levels of FGF-23 might possibly serve as a biomarker for determining disease severity in KOA.
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Table 2 Fibroblast growth factor-23, clinical and radiographic severity scores in knee osteoarthritis patients according to unilateral vs bilateral involvement, the presence and absence of joint swelling and hand osteoarthritis. Clinical finding mean ± SD (p)
KOA patients (n = 50) FGF-23 (pg/ml)
Unilateral (n = 12) Bilateral (n = 38) Joint swelling (n = 39) No joint swelling (n = 11) Hand OA (n = 5) No hand OA (=45)
33.4 ± 22.6 116.1 ± 165.9 114.6 ± 163.8 31.3 ± 27.5 97.4 ± 153.5 82.5 ± 91.8
WOMAC 0.02 0.004 0.85
36.2 ± 17.9 42.9 ± 21.4 45.6 ± 21.5 29.1 ± 15.4 43.02 ± 21.8 29.5 ± 10.1
KL 0.69 0.02 0.2
2.3 ± 0.78 2.6 ± 0.82 2.7 ± 0.7 1.9 ± 0.8 2.6 ± 0.8 2 ± 0.8
0.87 0.002 0.15
FGF: fibroblast growth factor-23, KOA: knee osteoarthritis patients, BMI: body mass index, WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index, KL: Kellgren-Lawrence. Bold values are significant at p < .05.
Fig. 1. Correlation between the serum levels of fibroblast growth factor-23 (FGF-23) with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (left) and the Kellgren-Lawrence (K-L) radiological grading scale (right).
Table 3 Correlation between fibroblast growth factor-23 (FGF-23) with age, disease duration, body mass index, clinical and radiological severity scores in knee osteoarthritis patients. Parameters r (p)
FGF-23 in KOA patients (n = 50)
Age Disease duration BMI WOMAC-score KL-score
0.34 0.39 0.37 0.36 0.36
(0.016) (0.006) (0.008) (0.009) (0.01)
FGF: fibroblast growth factor-23, KOA: knee osteoarthritis patients, BMI: body mass index, WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index, KL: Kellgren-Lawrence. Bold values are significant at p < .05.
In another study on Egyptian patients with KOA, FGF levels were significantly increased and significantly correlated with the degree of radiographic severity evaluated by KL grading scale and cartilage degeneration evaluated by ultrasound. They concluded that FGF levels may be monitor the disease severity and could play an essential part in the pathophysiology of degenerative process in OA [15]. FGF-21 might be a potential biomarker for predicting radiographic bone loss of OA. Therapeutic interventions by blocking FGF signaling pathways to delay the degenerative process of OA warrants further investigations [25]. Despite the tremendous individual suffering and socioeconomic burden caused by OA, there are currently no effective diseasemodifying treatment options. This is in part because of our incomplete understanding of OA disease mechanism [26]. Anti-FGF antibody administration was associated with significantly
improved patient perception of their physical functioning and stiffness due to their disease as assessed by WOMAC [27]. Suppressing the FGF signaling may indicate a potential agent against OA [28]. As cartilage anabolism and prevention of cartilage degradation has been shown to result from growth factor signaling modulation as FGF making it a potential therapeutic target in OA aiming to improve overall joint health [26]. Statins were not found to inhibit the FGFR signaling in chondrocytes thus opposed to the previously described statin-mediated rescue of FGFR3-related chondrodysplasia [29]. However, there is a remarkable pathological role of FGF in OA development and an insufficient cartilage regeneration response [30]. Among this study’s limitations is the relatively small number of patietns and not taking into consideration the effect of medications received. A larger scale longitudinal study is recommended to confirm the present results. In conclusion, FGF-23 might be a potential biomarker for diagnosing and evaluating the onset and development of KOA and significantly correlated with the symptomatic and radiographic severity of the disease. Controlling KOA progression by inhibitors of FGF23 may be an issue of interest in further studies. Conflict of interest None. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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[16] Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken) 2012;64:465–74. [17] Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol 1988;15:1833–40. [18] Kellgren J, Lawrence J. X-ray severity of osteoarthritis of the knee. Ann Rheum Dis 1957;16:494–502. [19] Liukkonen MK, Mononen ME, Klets O, Arokoski JP, Saarakkala S, Korhonen RK. Simulation of subject-specific progression of knee osteoarthritis and comparison to experimental follow-up data: data from the osteoarthritis initiative. Sci Rep 2017;7(1):9177. [20] Chen D, Shen J, Zhao W, Wang T, Han L, Hamilton J, et al. Osteoarthritis: toward a comprehensive understanding of pathological mechanism. Bone Res 2017. epub ahead of print. [21] Attur M, Krasnokutsky-Samuels S, Samuels J, Abramson S. Prognostic biomarkers in osteoarthritis. Curr Opin Rheumatol 2015;25(1):136–44. [22] Bianchi A, Guibert M, Cailotto F, Gasser A, Presle N, Mainard D, et al. Fibroblast Growth Factor 23 drives MMP13 expression in human osteoarthritic chondrocytes in a Klotho-independent manner. Osteoarthritis Cartilage 2016;24(11):1961–9. [23] Orfanidou T, Iliopoulos D, Malizos KN, Tsezou A. Involvement of SOX-9 and FGF-23 inRUNX-2 regulation in osteoarthritic chondrocytes. J Cell Mol Med 2009;13:3186–94. [24] Orfanidou T, Malizos KN, Varitimidis S, Tsezou A. 1,25-Dihydroxyvitamin D(3) and extracellular inorganic phosphate activate mitogen-activated protein kinase pathway through fibroblast growth factor 23 contributing to hypertrophy and mineralization in osteoarthritic chondrocytes. Exp Biol Med (Maywood) 2012;237(3):241–53. [25] Li ZC, Xiao J, Wang G, Li MQ, Hu KZ, Ma T, et al. Fibroblast growth factor-21 concentration in serum and synovial fluid is associated with radiographic bone loss of knee osteoarthritis. Scand J Clin Lab Invest 2015;75(2):121–5. [26] Sun MM, Beier F, Pest MA. Recent developments in emerging therapeutic targets of osteoarthritis. Curr Opin Rheumatol 2017;29(1):96–102. [27] Ruppe MD, Zhang X, Imel EA, Weber TJ, Klausner MA, Ito T, et al. Effect of four monthly doses of a human monoclonal anti-FGF23 antibody (KRN23) on quality of life in X-linked hypophosphatemia. Bone Rep 2016;5:158–62. [28] Huang Y, Wan G, Tao J. C1q/TNF-related protein-3 exerts the chondroprotective effects in IL-1b-treated SW1353 cells by regulating the FGFR1 signaling. Biomed Pharmacother 2017;85:41–6. [29] Fafilek B, Hampl M, Ricankova N, Vesela I, Balek L, Kunova Bosakova M, et al. Statins do not inhibit the FGFR signaling in chondrocytes. Osteoarthritis Cartilage 2017;25(9):1522–30. [30] El-Seoudi A, Abd El Kader T, Nishida T, Eguchi T, Aoyama E, Takigawa M, et al. Catabolic effects of FGF-1 on chondrocytes and its possible role in osteoarthritis. J Cell Commun Signal 2017;11(3):255–63.
Contents lists available at ScienceDirect
The Egyptian Rheumatologist journal homepage: www.elsevier.com/locate/ejr
Original Article
Relation of plasma fibroblast growth factor-23 (FGF-23) to radiographic severity in primary knee osteoarthritis patients Mai A. Mohammed a, Shaimaa A.K. Rady b,⇑, Rabab A. Mohammed c, Samia M.H. Fadda d a
Beni-Suef Hospital, Ministry of Health, Beni-Suef, Egypt Rheumatology Department, Faculty of Medicine, Beni Suef University, Egypt c Clinical Pathology Department, Faculty of Medicine , Beni Suef University, Egypt d Rheumatology Department, Faculty of Medicine, Cairo University, Egypt b
a r t i c l e
i n f o
Article history: Received 13 January 2018 Accepted 20 January 2018 Available online 4 February 2018 Keywords: Fibroblast growth factor-23 Osteoarthritis KL score WOMAC score
a b s t r a c t Aim of the work: This study aimed to investigate the plasma level of fibroblast growth factor-23 (FGF-23) in patients with primary knee osteoarthritis (KOA) and to elaborate its relation with radiographic and symptomatic severity of OA. Patients and methods: 50 KOA patients were recruited from the Rheumatology and Rehabilitation Department, Beni-Suef University Hospital and 20 matched controls were also included. Plasma FGF23 level was estimated by ELISA. Severity of the disease was assessed clinically by Western Ontario and McMaster Universities Osteoarthritis (WOMAC) score and radiologically by Kellgren-Lawrence (KL) grading scale. Results: The mean age of the patients was 59.8 ± 8.02 years (51–75 years) and disease duration 3.8 ± 2.1 years (1–9 years); they were 8 males (16%) and 42 (84%) females with a body mass index of 34.04 ± 5.3 (23.6–48.4). FGF-23 level was higher in KOA patients (96.2 ± 148.9 pg/ml; 3.4–14814.6 pg/ml) than in control (18.3 ± 11.1 pg/ml; 5–38.4 pg/ml) (p = .023). There was no significant difference in FGF-23 between males and females. FGF-23 was significantly increased in patients who had effusion (p = .004) or bilateral involvement (p = .023). Plasma FGF-23 level significantly correlated with disease severity sores; WOMAC and KL (p = .009, p = .01 respectively) and also with the age (p = .016), disease duration (p = .006) and body mass idex (p = .008) Conclusions: FGF-23 might be a potential biomarker for diagnosing and evaluating the onset and development of KOA and significantly correlated with the symptomatic and radiographic severity of the disease. Controlling KOA progression by inhibitors of FGF23 may be an issue of interest in further studies. Ó 2018 Publishing services provided by Elsevier B.V. on behalf of Egyptian Society of Rheumatic Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
1. Introduction Osteoarthritis (OA) is the most common form of rheumatic disease, leading ultimately to chronic pain, restriction of joint mobility, disability and reduced quality of life (QoL) of the population over 65 years [1]. Clinical characteristics of OA show marked heterogeneity of clinical presentation including severe pain, joint stiffness, limited range of motion (ROM), swelling, crepitation and disability [2].
Peer review under responsibility of Egyptian Society of Rheumatic Diseases. ⇑ Corresponding author at: Rheumatology Department, Faculty of Medicine, Beni Suef University, Beni-Suef, Egypt. E-mail addresses: [email protected], [email protected] (S.A.K. Rady).
Although radiographs are practically used to assess the OA severity, it would be advantageous to have a biochemical parameter that could precisely reflect disease severity and OA progression [3]. Biomarkers of cartilage degeneration have been extensively investigated in other rheumatic diseases as rheumatoid arthritis (RA) and systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) [4–6]. Several biomarkers have been assessed in Egyptian patients with OA with a potential role in the disease pathogenesis [7–11]. Fibroblast growth factor-23 (FGF-23) is a novel member of the FGF family and is an important circulating phosphaturic factor in serum, which is essential in chondrocyte differentiation and mineral metabolism [12]. It has been actively involved in phosphate homeostasis and skeletogenesis, yet no role was found in another rheumatic disease as systemic sclerosis [13]. Zhou and colleagues
https://doi.org/10.1016/j.ejr.2018.01.007 1110-1164/Ó 2018 Publishing services provided by Elsevier B.V. on behalf of Egyptian Society of Rheumatic Diseases. 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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[14] found that FGF-23 was significantly higher in knee OA (KOA) patients. Furthermore, FGF-23 levels signficantly correlated with radiographic grading and symptomatic severity of KOA. In a previous study on Egyptian KOA patients studying FGF, it was found to be signficantly increased and plays a chief role in the disease pathogenesis [15]. The present study aimed at investigating the plasma level of FGF-23 in KOA patients and to evaluate its relation to radiographic severity according to the Kellgren-Lawrence (KL) grading scale. 2. Patients and methods The study was conducted on 50 primary KOA patients diagnosed according to clinical symptomatic criteria of the American College of Rheumatology (ACR) [16]. The patients included in the study were selected from the Rheumatology and Rehabilitation Department in Beni-Suef University Hospital. 20 healthy volunteers of matched age and sex with no clinical features of OA were included serving as a control group. Inclusion criteria included knee gelling <30 min., crepitus on active motion, bony tenderness or enlargement, no palpable warmth. Patients were excluded if KOA was secondary to an autoimmune disease, metabolic or crystal disease or post traumatic, with chronic kidney diseases. The study was approved by the local ethics committee of BeniSuef University, and informed consent was obtained from all patients according to the Declaration of Helsinki. All patients will be subjected to full history taking including demographic data and all established risk factors and detailed clinical examination. The symptomatic severity was evaluated according to the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) [17]. Routine laboratory investigations including lipid profile were performed and other investigastions needed to exclude secondary OA as C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor and serum uric acid. Level of fibroblast growth factor-23 (FGF-23) in plasma was assessed using enzyme-linked immunosorbent assay (ELISA) KITS BATCH NO.430074, Wuhan ElAab Science Co.,Ltd, Optics valley, China, normal range: 15.6–10 00 Pg/ml. Radiographic assessment of disease severity was considered by weight bearing anteroposterior views of the affected knee in standing position and the X-ray beam was centered on the joint according to the Kellgren-Lawrence (K-L) grading scale [18]. Statistical analysis: Analysis of data was done by IBM computer using SPSS (statistical program for social science) version 18. Description of quantitative variables were presented as mean, SD and range while qualitative variables as number and percentage. Unpaired t-test was used to compare quantitative variables and Pearson’s correlation was performed. P value < .05 was considered significant. 3. Results The study included 50 KOA patients with a mean age of 59.8 ± 8. 02 years (51–75 years) and disease duration 3.8 ± 2.1 years (1–9 years); they were 8 males (16%) and 42 (84%) females with a body mass index of 34.04 ± 5.3 (23.6–48.4). The 20 control were age (57. 2 ± 6.3 years) and sex (3 males and 17 females) and BMI (27.7 ± 4. 4; 19.8–31.6) matched (p = .3 and p = .29 respectively) while the BMI was lower (27.7 ± 4.4; 19.8–31.6)(p = .03). Serum triglycerides, cholesterol and very low density lipoprotein (VLDL) were higher in KOA patients than control (p = .008; p = .03 and p = .004 respectively) (Table 1). FGF-23 level was higher in KOA patients (96.2 ± 148.9 pg/ml; 3.4–14814.6 pg/ml) than in control (18.3 ± 11.1 pg/ml; 5–38.4 pg/ml) (p = .023). There was no
Table 1 Comparison between the knee osteoarthritis patients and the control regarding lipid profile. Parameter mean ± SD
KOA patients (n = 50)
Control (n = 20)
p
Triglycerides Cholesterol VLDL LDL HDL
187.9 ± 79.9 201.2 ± 67.9 37.6 ± 16.0 122.9 ± 72.3 41.2 ± 16.9
134.1 ± 43.8 161.8 ± 68.4 26.4 ± 8.9 96.8 ± 74.3 38.9 ± 15.1
0.006 0.03 0.004 0.18 0.6
KOA: knee osteoarthritis, VLDL: very low density lipoprotein, LDL: low density lipoprotein, HDL: high density lipoprotein. Bold values are significant at p < .05.
significant difference in FGF-23 between males and females. FGF23 was significantly increased in patients who had effusion (p = .004) or bilateral involvement (p = .023) (Table 2). Plasma FGF-23 level significantly correlated with disease severity sores; WOMAC and KL (p = .009, p = .01 respectively)(Fig. 1) and also with the age (p = .016), disease duration (p = .006) and body mass idex (p = .008) (Table 3). 4. Discussion Osteoarthritis (OA) is a degenerative joint disease causing pain and limitations in joint movement. At the tissue level, OA affects predominantly articular cartilage, although other tissues, such as bone, meniscus and synovium, are also involved. Indirectly, this may lead to social isolation, decrease in work ability and depression, i.e., decrease in the general QoL [19]. A central role for inflammatory pathways in processes relevant to OA, including regulation of the chondrocyte catabolic response, development of low grade synovitis, and modulation of pain responses continues to be supported [20]. A variety of the inflammatory mediators are produced by multiple joint tissues and cell types can promote inflammatory and catabolic responses in chondrocytes. Many of these mediators may be biomarkers of inflammatory activity but their clinical utility in early detection, diagnosis, or prognosis needs further assessment [21]. Fibroblast Growth Factor 23 drives matrix metalloproteinase expression and sustains differentiation of OA chondrocytes [22]. FGF-23 has been shown to be highly expressed in osteoarthritic chondrocytes and have low expression levels in normal chondrocytes [23]. In osteoarthritic chondrocytes, FGF-23 binds to FGFR1c with greater ability than in normal chondrocytes, confirming thus the enhanced activation of FGF23 signaling in OA. FGF23 signaling contributes to late hypertrophic events and impaired mineralization in osteoarthritic chondrocytes. This link between chondrocyte hypertrophy and matrix mineralization is well established in endochondral ossification at late stage OA, which is associated with FGF-23 overexpression [24]. These results demonstrate that endogenous FGF-23 is up-regulated during joint injury, which may be a risk factor for OA [14]. In the present study the role of FGF-23 in the progression and development of OA was investigated. There was a significant increase in the plasma FGF-23 levels in KOA patients. Also, a significant correlation was found with radiographic grading and symptomatic severity of KOA. Additionally, this observation indicated a significant elevation in the systemic levels of FGF-23 correlation with WOMAC scores in patients with KOA. These findings are in agreement with [14] a study reporting that serum level of FGF-23 was significantly higher in KOA patients and significantly correlated with WOMAC and KL score. These results indicated that the measurements of serum levels of FGF-23 might possibly serve as a biomarker for determining disease severity in KOA.
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Table 2 Fibroblast growth factor-23, clinical and radiographic severity scores in knee osteoarthritis patients according to unilateral vs bilateral involvement, the presence and absence of joint swelling and hand osteoarthritis. Clinical finding mean ± SD (p)
KOA patients (n = 50) FGF-23 (pg/ml)
Unilateral (n = 12) Bilateral (n = 38) Joint swelling (n = 39) No joint swelling (n = 11) Hand OA (n = 5) No hand OA (=45)
33.4 ± 22.6 116.1 ± 165.9 114.6 ± 163.8 31.3 ± 27.5 97.4 ± 153.5 82.5 ± 91.8
WOMAC 0.02 0.004 0.85
36.2 ± 17.9 42.9 ± 21.4 45.6 ± 21.5 29.1 ± 15.4 43.02 ± 21.8 29.5 ± 10.1
KL 0.69 0.02 0.2
2.3 ± 0.78 2.6 ± 0.82 2.7 ± 0.7 1.9 ± 0.8 2.6 ± 0.8 2 ± 0.8
0.87 0.002 0.15
FGF: fibroblast growth factor-23, KOA: knee osteoarthritis patients, BMI: body mass index, WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index, KL: Kellgren-Lawrence. Bold values are significant at p < .05.
Fig. 1. Correlation between the serum levels of fibroblast growth factor-23 (FGF-23) with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (left) and the Kellgren-Lawrence (K-L) radiological grading scale (right).
Table 3 Correlation between fibroblast growth factor-23 (FGF-23) with age, disease duration, body mass index, clinical and radiological severity scores in knee osteoarthritis patients. Parameters r (p)
FGF-23 in KOA patients (n = 50)
Age Disease duration BMI WOMAC-score KL-score
0.34 0.39 0.37 0.36 0.36
(0.016) (0.006) (0.008) (0.009) (0.01)
FGF: fibroblast growth factor-23, KOA: knee osteoarthritis patients, BMI: body mass index, WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index, KL: Kellgren-Lawrence. Bold values are significant at p < .05.
In another study on Egyptian patients with KOA, FGF levels were significantly increased and significantly correlated with the degree of radiographic severity evaluated by KL grading scale and cartilage degeneration evaluated by ultrasound. They concluded that FGF levels may be monitor the disease severity and could play an essential part in the pathophysiology of degenerative process in OA [15]. FGF-21 might be a potential biomarker for predicting radiographic bone loss of OA. Therapeutic interventions by blocking FGF signaling pathways to delay the degenerative process of OA warrants further investigations [25]. Despite the tremendous individual suffering and socioeconomic burden caused by OA, there are currently no effective diseasemodifying treatment options. This is in part because of our incomplete understanding of OA disease mechanism [26]. Anti-FGF antibody administration was associated with significantly
improved patient perception of their physical functioning and stiffness due to their disease as assessed by WOMAC [27]. Suppressing the FGF signaling may indicate a potential agent against OA [28]. As cartilage anabolism and prevention of cartilage degradation has been shown to result from growth factor signaling modulation as FGF making it a potential therapeutic target in OA aiming to improve overall joint health [26]. Statins were not found to inhibit the FGFR signaling in chondrocytes thus opposed to the previously described statin-mediated rescue of FGFR3-related chondrodysplasia [29]. However, there is a remarkable pathological role of FGF in OA development and an insufficient cartilage regeneration response [30]. Among this study’s limitations is the relatively small number of patietns and not taking into consideration the effect of medications received. A larger scale longitudinal study is recommended to confirm the present results. In conclusion, FGF-23 might be a potential biomarker for diagnosing and evaluating the onset and development of KOA and significantly correlated with the symptomatic and radiographic severity of the disease. Controlling KOA progression by inhibitors of FGF23 may be an issue of interest in further studies. Conflict of interest None. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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