Response of osteoarthritis biomarkers after a rehabilitation program: study protocol


  • Eliane Antonioli Hospital Israelita Albert Einstein, São Paulo, Brazil
  • Felipe B. D. Oliveira Hospital Israelita Albert Einstein, São Paulo, Brazil
  • Rosana R. Campedelli Hospital Israelita Albert Einstein, São Paulo, Brazil
  • Alessandro R. Zorzi Hospital Israelita Albert Einstein, São Paulo, Brazil
  • Danielli Specialli Hospital Israelita Albert Einstein, São Paulo, Brazil
  • Sudha Agarwal Department of Biomedical Engineering, Ohio State University, Columbus, OH, USA
  • Mario Ferretti Hospital Israelita Albert Einstein, São Paulo, Brazil



Osteoarthritis, Biomarkers, Rehabilitation, Pain, Knee


Background: Knee osteoarthritis is a progressive degenerative joint disease and remains a leading cause of pain, physical impairment and decline in health-related quality of life in adults.   Despite its incidence being amongst the highest in chronic diseases, effective biomarkers are not available to assist in its management. The main goal of this study is to identify mediators that serve as biomarkers and investigate if the levels of these biomarkers will be correlated to the efficacy of a rehabilitation program.

Methods: This is a prospective cohort study with 65 participants. Patients with mild-to-moderate symptomatic knee osteoarthritis will be recruited. The Rehabilitation Program will consist of three session/week during eight weeks. Assessment about functional evaluation will be performed before and after treatment, using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and EuroQOL-5D (Euro quality of life - five dimension) scales, Visual Analog Scale (VAS), and physical function tests (time up and go, isometric strength testing and kinematic gait analysis). Serum levels of classical pro-inflammatory cytokines, hyaluronan and high mobility group box 1 protein (HMGB-1) will be evaluated. The primary outcome is the change in WOMAC scale from baseline to end. Statistical analyses will be used to determine correlation of physical improvement and serum biomarkers. Adverse events will be monitored throughout the study.

Conclusions: This trial expect to study the correlation between the anti-inflammatory effects of rehabilitation program derived factors that may be involved in suppressing cytokine induction via suppressing HMGB-1.

Trial registration: - NCT02964624.


Weinstein SL, Jacobs JJ, Goldberg MJ. Osteoarthritis of the knee. N Engl J Med. 2006;354(23):2508-9.

Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol. 2011;7(1):33-42.

Cross M, Smith E, Hoy D, Nolte S, Ackerman I, Fransen M, et al. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014;73(7):1323-30.

McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Berenbaum F, Bierma-Zeinstra SM, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthrit Cartilage. 2014;22(3):363-88.

Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthrit Cartilage. 2008;16(2):137-62.

Henrotin Y, Raman R, Richette P, Bard H, Jerosch J, Conrozier T, et al. Consensus statement on viscosupplementation with hyaluronic acid for the management of osteoarthritis. Semin Arthritis Rheum. 2015;45(2):140-9.

Strand V, McIntyre LF, Beach WR, Miller LE, Block JE. Safety and efficacy of US-approved viscosupplements for knee osteoarthritis: a systematic review and meta-analysis of randomized, saline-controlled trials. J Pain Res. 2015;8:217-28.

Campbell KA, Erickson BJ, Saltzman BM, Mascarenhas R, Bach BRJ, Cole BJ, et al. Is Local Viscosupplementation Injection Clinically Superior to Other Therapies in the Treatment of Osteoarthritis of the Knee: A Systematic Review of Overlapping Meta-analyses. YJARS. 2015;31(10):2036–45.e14.

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(8):1039-49.

10. Hsueh M-F, Onnerfjord P, Kraus VB. Biomarkers and proteomic analysis of osteoarthritis. Matrix Biol. 2014;39:56-66.

Kurtz S, Ong K, Lau E, Mowat F, Halpern M. Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Joint Surg Am. 2007;89(4):780-5.

Kraus VB, Blanco FJ, Englund M, Henrotin Y, Lohmander LS, Losina E, et al. OARSI Clinical Trials Recommendations: Soluble biomarker assessments in clinical trials in osteoarthritis. Osteoarthrit Cartilage. 2015;23(5):686-97.

Kotlarz H, Gunnarsson CL, Fang H, Rizzo JA. Insurer and out-of-pocket costs of osteoarthritis in the US: evidence from national survey data. Arthritis Rheum. 2009;60(12):3546-53.

Little CB, Hunter DJ. Post-traumatic osteoarthritis: from mouse models to clinical trials. Nat Rev Rheumatol. 2013;9(8):485-97.

Saúde, Osteoartrose 2012. Available at: Accessed on 9 June 2015.

Christiansen BA, Guilak F, Lockwood KA, Olson SA, Pitsillides AA, Sandell LJ, et al. Non-invasive mouse models of post-traumatic osteoarthritis. Osteo Cart. 2015;23(10):1627-38.

Nam JP, Blazek A, Ferretti, M. Exercise suppresses HMGB1 expression and functions in activated macrophages. In submission; 2017.

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(4):465-74.

Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002;418(6894):191-5.

Terada C, Yoshida A, Nasu Y, Mori S, Tomono Y, Tanaka M, et al. Gene expression and localization of high-mobility group box chromosomal protein-1 (HMGB-1) in human osteoarthritic cartilage. Acta Med Okayama. 2011;65(6):369-77.

Hunt MA, Pollock CL, Kraus VB, Saxne T, Peters S, Huebner JL, et al. Relationships amongst osteoarthritis biomarkers, dynamic knee joint load, and exercise: results from a randomized controlled pilot study. BMC Musculoskel Dis. 2013;14:115.

Quicke JG, Foster NE, Thomas MJ, Holden MA. Is long-term physical activity safe for older adults with knee pain? a systematic review. Osteoarthrit Cartilage. 2015;23(9):1445-56.

Kyostio-Moore S, Nambiar B, Hutto E, Ewing PJ, Piraino S, Berthelette P, et al. STR/ort mice, a model for spontaneous osteoarthritis, exhibit elevated levels of both local and systemic inflammatory markers. Comp Med. 2011;61(4):346-55.

van Spil WE, DeGroot J, Lems WF, Oostveen JCM, Lafeber FPJG. Serum and urinary biochemical markers for knee and hip-osteoarthritis: a systematic review applying the consensus BIPED criteria. Osteoarthrit Cartilage. 2010;18(5):605-12.

Lafeber FPJG, van Spil WE. Osteoarthritis year 2013 in review: biomarkers; reflecting before moving forward, one step at a time. Osteoarthrit Cartilage. 2013;21(10):1452-64.

Mabey T, Honsawek S. Cytokines as biochemical markers for knee osteoarthritis. World J Orthop. 2015;6(1):95-105.

Jayadev C, Rout R, Price A, Hulley P, Mahoney D. Hyaluronidase treatment of synovial fluid to improve assay precision for biomarker research using multiplex immunoassay platforms. J Immunol Methods. 2012;386(1-2):22-30.

Imamura M, Ezquerro F, Marcon Alfieri F, Vilas Boas L, Tozetto-Mendoza TR, Chen J, et al. Serum levels of proinflammatory cytokines in painful knee osteoarthritis and sensitization. Int J Inflam. 2015;2015:329792.

Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol. 2005 Apr;5(4):331-42.

Kokkola R, Sundberg E, Ulfgren A, Palmblad K, Li J, Wang H, et al. High mobility group box chromosomal protein 1: A novel proinflammatory mediator in synovitis. Arthritis Rheum. 2002;46:2598-603.

Taniguchi N, Kawahara K-I, Yone K, Hashiguchi T, Yamakuchi M, Goto M, et al. High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine. Arthritis Rheum. 2003;48(4):971-81.

Li Z-C, Cheng G-Q, Hu K-Z, Li M-Q, Zang W-P, Dong Y-Q, et al. Correlation of synovial fluid HMGB-1 levels with radiographic severity of knee osteoarthritis. Clin Invest Med. 2011;34(5):E298.

Loeser RF, Beavers DP, Bay-Jensen AC, Karsdal MA, Nicklas BJ, Guermazi A, et al. Effects of dietary weight loss with and without exercise on interstitial matrix turnover and tissue inflammation biomarkers in adults with knee osteoarthritis: the Intensive Diet and Exercise for Arthritis trial (IDEA). Osteoarthrit Cartilage. 2017;25(11):1822-8.

Mobasheri A, Bay-Jensen AC, van Spil WE, Larkin J, Levesque MC. Osteoarthritis Year in Review 2016: biomarkers (biochemical markers). Osteoarthrit Cartilage. 2017;25(2):199-208.