Serum RANKL levels and bioelectric impedance assessments in knee osteoarthritis patients

Abstract

Aim: Osteoarthritis (OA) is a common joint disease that is caused by mechanical, genetic, and biochemical factors, and knee OA is one of the reasons of mobility limitation and disability. The receptor activator of NF-κB ligand (RANKL) is directly involved in the differentiation of osteoclasts through its receptor RANK. In this study, we aimed to study circulating serum levels of RANKL, and assess knee bioelectric impedance in control and patients with knee OA.
Methods: In this case-control study, OA severity was evaluated by the Kellgren–Lawrence grading scale, based on which we categorized patient groups. There were 22 control individuals (Grades 0 and 1), 11 early (Grade 2) and 30 late OA patients (Grades 3 and 4). We evaluated the performance of the bioimpedance phase angle values at 50 kHz. The RANKL protein levels in the serum were quantified using Enzyme-Linked Immunosorbent Assay (ELISA).
Results: It was observed that the control group could not be differentiated from the study group by using phase angle values (P=0.925). Concerning the RANKL levels, although it shows a relative increase in the study group, it did not reach a significant level (P=0.116).
Conclusion: The phase angle values at 50 kHz and RANKL levels may not be used in predictive detection of knee OA. Additional studies with larger sample sizes are needed to interpret if these changes are consistent and clinically related. 

Keywords

• RANKL,Bioimpedance,Knee osteoarthritis

Diz osteoartritli hastalarda serum RANKL düzeyleri ve biyoelektrik empedans değerlendirmeleri

Öz

Amaç: Osteoartrit (OA), mekanik, genetik ve biyokimyasal faktörlerin etkilerinden kaynaklanan yaygın bir eklem hastalığıdır ve diz OA’i, hareket kısıtlaması ve engel nedenlerinden biridir. Bu çalışmada NF-κB ligandının (RANKL) reseptör aktivatörünün dolaşımdaki serum seviyelerini incelemeyi ve kontrolde ve diz OA'i olan hastalarda biyoelektrik empedansını değerlendirmeyi amaçladık.
Yöntemler: Çalışmamız bir vaka-kontrol çalışması olarak tasarlanmıştır. OA şiddeti Kellgren-Lawrence derecelendirme skalası ile değerlendirildi, gruplar 22 sağlıklı kontrol (derece 0 ve 1), ve çalışma grubu 11 erken (derece 2) ve 30 geç OA (derece 3 ve 4) olarak tanımlandı. 50kHz’te biyoimpedans faz açısı değerlendirildi. Serumdaki RANKL protein seviyeleri Enzyme Linked Immunosorbent Assay (ELISA) metodu ile ölçüldü.
Bulgular: Kontrol grubunun faz açısı değerleri kullanılarak diz OA grubundan ayırt edilemediği gözlendi (P=0,925). RANKL düzeyleri ile ilgili olarak, çalışma grubunda göreceli bir artış tespit edilse de, anlamlı bir seviyeye ulaşmadı (P=0,116).
Sonuç: 50 kHz faz açısı değerleri ve RANKL seviyeleri, diz OA'sının tespitinin öngörülmesinde kullanılamayabileceği belirlenmiştir. Bu değişikliklerin tutarlı ve klinik olarak ilişkili olup olmadığını yorumlamak için daha büyük örnek büyüklüklerine sahip ek araştırmalara ihtiyaç vardır.

Anahtar Kelimeler

• RANKL,Biyoimpedans,Diz osteoartiriti

Kaynakça

1. 1. Guccione AA, Felson DT, Anderson JJ, Anthony JM, Zhang Y, Wilson PW, et al. The effects of specific medical conditions on the functional limitations of elders in the Framingham Study. Am J Public Health. 1994;84:351-8. 2. Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58:26-35. 3. Okada Y, Shinmei M, Tanaka O, Naka K, Kimura A, Nakanishi I, et al. Localization of matrix metalloproteinase 3 (stromelysin) in osteoarthritic cartilage and synovium. Lab Invest. 1992;66:680-90. 4. Grimnes S, Martinsen ØG. Chapter 8-Instrumentation and Measurements. Bioimpedance and Bioelectricity Basics. In: Bioimpedance and Bioelectricity Basics (Third Edition). Oxford: Academic; 2015. pp. 255-328. 5. Denkçeken T, Çört A. Determination of cancer progression in breast cells by fiber optic bioimpedance spectroscopy system. J Surg Med. 2020;4(1):84-8. 6. Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology. 2001;142:5050-5. 7. Kwan Tat S, Padrines M, Theoleyre S, Heymann D, Fortun Y. IL-6, RANKL, TNF-alpha/IL-1: interrelations in bone resorption pathophysiology. Cytokine Growth Factor Rev. 2004;15:49-60. 8. Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev. 2008;29:155-92. 9. Kostenuik PJ, Shalhoub V. Osteoprotegerin: a physiological and pharmacological inhibitor of bone resorption. Curr Pharm Des. 2001;7:613-35. 10. Favero M, Ramonda R, Goldring MB, Goldring SR, Punzi L. Early knee osteoarthritis. RMD Open. 2015;1:e000062. 11. 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. 12. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis. 1957;16:494-502.
2. 13. Neves EB, Pino AV, de Almeida RM, de Souza MN. Knee bioelectric impedance assessment in healthy/with osteoarthritis subjects. Physiol Meas. 2010;31:207-19.
3. 14. Krishnan GH, Nanda A, Natarajan R. A Synovial Fluid Density Measurement for Diagnosis of Arthritis. Biochem Pharmacol. 2014;7:221-4.
4. 15. Baumgartner RN, Chumlea WC, Roche AF. Bioelectric impedance phase angle and body composition. Am J Clin Nutr. 1988;48:16–23.
5. 16. Lawrence RC, Helmick CG, Arnett FC, Deyo RA, Felson DT, Giannini EH, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum. 1998;41:778-99.
6. 17. Felson DT. Epidemiology of hip and knee osteoarthritis. Epidemiol Rev. 1988;10:1-28.
7. 18. Spector TD, Cicuttini F, Baker J, Loughlin J, Hart D. Genetic influences on osteoarthritis in women: a twin study. BMJ. 1996;312:940-3.
8. 19. Eckstein F, Cicuttini F, Raynauld JP, Waterton JC, Peterfy C. Magnetic resonance imaging (MRI) of articular cartilage in knee osteoarthritis (OA): morphological assessment. Osteoarthr Cartilage. 2006;14 Suppl A:A46-75.

9. 20. Lohmander LS. Markers of altered metabolism in osteoarthritis. J Rheumatol Suppl. 2004;70:28-35.
10. 21. Lawrence JS, Bremner JM, Bier F. Osteo-arthrosis. Prevalence in the population and relationship between symptoms and x-ray changes. Ann Rheum Dis. 1966;25:1-24.
11. 22. Hannan MT, Felson DT, Pincus T. Analysis of the discordance between radiographic changes and knee pain in osteoarthritis of the knee. J Rheumatol. 2000;27:1513-7.
12. 23. De Gruttola VG, Clax P, DeMets DL, Downing GJ, Ellenberg SS, Friedman L, et al. Considerations in the evaluation of surrogate endpoints in clinical trials. summary of a National Institutes of Health workshop. Control Clin Trials. 2001;22:485-502.
13. 24. Saidenberg-Kermanac'h N, Corrado A, Lemeiter D, deVernejoul MC, Boissier MCCohen-Solal ME. TNF-alpha antibodies and osteoprotegerin decrease systemic bone loss associated with inflammation through distinct mechanisms in collagen-induced arthritis. Bone. 2004;35:1200-7.
14. 25. Page G, Miossec P. RANK and RANKL expression as markers of dendritic cell-T cell interactions in paired samples of rheumatoid synovium and lymph nodes. Arthritis Rheum. 2005;52:2307-12.
15. 26. Knapik JJ, Pope R, Orr R, Schram B. Osteoarthritis: Pathophysiology, Prevalence, Risk Factors, and Exercise for Reducing Pain and Disability. J Spec Oper Med.18:94-102.
16. 27. Ashley DT, O'Sullivan EP, Davenport C, Devlin N, Crowley RK, McCaffrey N, et al. Similar to adiponectin, serum levels of osteoprotegerin are associated with obesity in healthy subjects. Metabolism. 2011;60:994-1000.
17. 28. Pilichou A, Papassotiriou I, Michalakakou K, Fessatou S, Fandridis E, Papachristou G, et al. High levels of synovial fluid osteoprotegerin (OPG) and increased serum ratio of receptor activator of nuclear factor-kappa B ligand (RANKL) to OPG correlate with disease severity in patients with primary knee osteoarthritis. Clin Biochem. 2008;41:746-9.
18. 29. Li H, Li L, Min J, Yang H, Xu X, Yuan Y, et al. Levels of metalloproteinase (MMP-3, MMP-9), NF-kappaB ligand (RANKL), and nitric oxide (NO) in peripheral blood of osteoarthritis (OA) patients. Clin Lab. 2012;58:755-62.
19. 30. Gupta D, Lammersfeld CA, Burrows JL, Dahlk SL, Vashi PG, Grutsch JF, et al. Bioelectrical impedance phase angle in clinical practice: implications for prognosis in advanced colorectal cancer. Am J Clin Nutr. 2004;80:1634-8.
20. 31. Schloerb PR, Forster J, Delcore R, Kindscher JD. Bioelectrical impedance in the clinical evaluation of liver disease. Am J Clin Nutr. 1996;64:510S-514S.
21. 32. Norman K, Stobaus N, Zocher D, Bosy-Westphal A, Szramek A, Scheufele R, et al. Cutoff percentiles of bioelectrical phase angle predict functionality, quality of life, and mortality in patients with cancer. Am J Clin Nutr. 2010;92:612-9.
22. 33. Alvarenga RL, Souza MN. Assessment of knee osteoarthritis by bioelectrical impedance. In: Proceedings of the 25th Annual International Conference of the IEEE Engineering in Medicine and Biology Society; 2003 Sept 17-21; Cancun, Mexico: IEEE; 2003. p. 3118-3121.