International Journal of Biometeorology

, Volume 61, Issue 12, pp 2153–2158 | Cite as

Can balneotherapy modify microRNA expression levels in osteoarthritis? A comparative study in patients with knee osteoarthritis

  • C. Giannitti
  • A. De Palma
  • N. A. Pascarelli
  • S. Cheleschi
  • N. Giordano
  • M. Galeazzi
  • Antonella Fioravanti
Original Paper


The aim of this study was to evaluate the whole-blood levels of miR-155, miR-223, miR-181a, miR-146a, and miR-let-7e in patients with bilateral knee osteoarthritis (OA) after a cycle of mud-bath therapy (MBT). Thirty-two patients with knee OA defined by the ACR criteria were included. Twenty-one patients (MBT group) were daily treated with a combination of local mud-packs at 42 °C and baths in mineral water, at 37 °C for 15 min, for 12 applications over a period of 2 weeks, in addition to standard therapy; 11 patients (control group) continued their conventional treatment alone. Global pain score evaluated by visual analog scale (VAS), WOMAC subscores, and microRNA expression were evaluated at baseline and after 2 weeks. Peripheral whole blood was collected into PAXgene™ Blood RNA tubes, stored at − 80 °C, and total RNA was extracted. The expression of miR-155, miR-223, miR-181a, miR-146a, and miR-let-7e was determined by qRT-PCR. After MBT, we observed a statistically significant improvement of clinical parameters and a significant decrease of miR-155, miR-181a, miR-146a (p < 0.001), and miR-223 (p < 0.01) expression levels. No clinical and biochemical modifications were detected in the control group. No significant variations of miR-let-7e were shown in both groups after 2 weeks. In conclusion, MBT can modify the expression of miR-155, miR-181a, miR-146a, and miR-223, which are upregulated in OA. It could be due to the heat stress and the hydrostatic pressure, since some miRNAs were found to be temperature- and mechano-responsive. Further studies are needed to better explain the mechanism of action of MBT and the role of miRNAs in OA.


Balneotherapy MicroRNA Knee osteoarthritis Heat Hydrostatic pressure 



The authors affirm that there are no undeclared contributors, funding sources or study sponsors.

Compliance with ethical standards

The study was performed according to the Declaration of Helsinki; it was approved by the medical ethics committee (Siena University Hospital, decision no. 340, August 12, 2010) and was registered on (NCT01538043).

Competing interests

The authors declare that they have no conflict of interest.


  1. Altman R, Asch E, Bloch D et al (1986) 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 29:1039–1049CrossRefGoogle Scholar
  2. Aziz F (2016) The emerging role of miR-223 as novel potential diagnostic and therapeutic target for inflammatory disorders. Cell Immunol 303:1–6. doi: 10.1016/j.cellimm.2016.04.003 CrossRefGoogle Scholar
  3. Bellamy N, Buchanan WW, Goldsmith CH et al (1988) 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 15:1833–1840Google Scholar
  4. Bender T, Karagülle Z, Bálint GP et al (2005) Hydrotherapy, balneotherapy, and spa treatment in pain management. Rheumatol Int 25:220–224CrossRefGoogle Scholar
  5. Beyer C, Zampetaki A, Lin NY et al (2015) Signature of circulating microRNAs in osteoarthritis. Ann Rheum Dis 74:e18. doi: 10.1136/annrheumdis-2013-204698 CrossRefGoogle Scholar
  6. Cheleschi S, De Palma A, Pecorelli A et al (2017) Hydrostatic pressure regulates microRNA expression levels in osteoarthritic chondrocyte cultures via the Wnt/β-catenin pathway. Int J Mol Sci 18:E133. doi: 10.3390/ijms18010133 CrossRefGoogle Scholar
  7. Ciani O, Pascarelli NA, Giannitti C et al (2016) Mud-bath therapy in addition to usual care in bilateral knee osteoarthritis: economic evaluation alongside a randomized controlled trial. Arthritis Care Res (Hoboken). doi: 10.1002/acr.23116
  8. De Palma A, Cheleschi S, Pascarelli NA et al (2017) Do MicroRNAs have a key epigenetic role in osteoarthritis and in mechanotransduction? Clin Exp Rheumatol 35:518Google Scholar
  9. Díaz-Prado S, Cicione C, Muiños-López E et al (2012) Characterization of microRNA expression profiles in normal and osteoarthritic human chondrocytes. BMC Musculoskelet Disord 13:144. doi: 10.1186/1471-2474-13-144 CrossRefGoogle Scholar
  10. Fioravanti A, Cantarini L, Guidelli GM et al (2011) Mechanisms of action of spa therapies in rheumatic diseases: what scientific evidence is there? Rheumatol Int 31:1–8. doi: 10.1007/s00296-010-1628-6 CrossRefGoogle Scholar
  11. Fioravanti A, Bacaro G, Giannitti C et al (2015) One-year follow-up of mud-bath therapy in patients with bilateral knee osteoarthritis: a randomized, single-blind controlled trial. Int J Biometeorol 59:1333–1343. doi: 10.1007/s00484-014-0943-0 CrossRefGoogle Scholar
  12. Guan YJ, Yang X, Wei L et al (2011) MiR-365: a mechanosensitive microRNA stimulates chondrocyte differentiation through targeting histone deacetylase 4. FASEB J 25:4457–4466. doi: 10.1096/fj.11-185132 CrossRefGoogle Scholar
  13. Hochberg MC, Altman RD, April KT et al (2012) 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) 64:465–474CrossRefGoogle Scholar
  14. Marques-Rocha JL, Samblas M, Milagro FI et al (2015) Noncoding RNAs, cytokines, and inflammation-related diseases. FASEB J 29:3595–3611. doi: 10.1096/fj.14-260323 CrossRefGoogle Scholar
  15. McAlindon TE, Bannuru RR, Sullivan MC et al (2014) OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthr Cartil 22:363–388. doi: 10.1016/j.joca.2014.01.003 CrossRefGoogle Scholar
  16. Murata K, Yoshitomi H, Tanida S et al (2010) Plasma and synovial fluid microRNAs as potential biomarkers of rheumatoid arthritis and osteoarthritis. Arthritis Res Ther 12:R86. doi: 10.1186/ar3013 CrossRefGoogle Scholar
  17. Nakamura A, Rampersaud YR, Sharma A et al (2016) Identification of microRNA-181a-5p and microRNA-4454 as mediators of facet cartilage degeneration. JCI Insight 1(12):e86820CrossRefGoogle Scholar
  18. Okuhara A, Nakasa T, Shibuya H et al (2012) Changes in microRNA expression in peripheral mononuclear cells according to the progression of osteoarthritis. Mod Rheumatol 22:446–457. doi: 10.1007/s10165-011-0536-2 CrossRefGoogle Scholar
  19. Potla R, Singh IS, Atamas SP et al (2015) Shifts in temperature within the physiologic range modify strand-specific expression of select human microRNAs. RNA 21:1261–1273. doi: 10.1261/rna.049122.114 CrossRefGoogle Scholar
  20. Rainen L, Oelmueller U, Jurgensen S et al (2002) Stabilization of mRNA expression in whole-blood samples. Clin Chem 48:1883–1890Google Scholar
  21. Ramakers C, Ruijter JM, Deprez RH et al (2003) Assumption-free analysis of quantitative real-time polymerase chain reaction (PCR) data. Neurosci Lett 339:62–66CrossRefGoogle Scholar
  22. Salaffi F, Leardini G, Canesi B et al (2003) Reliability and validity of the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index in Italian patients with osteoarthritis of the knee. Osteoarthr Cartil 11:551–560CrossRefGoogle Scholar
  23. Tenti S, Cheleschi S, Galeazzi M et al (2015) Spa therapy: can be a valid option for treating knee osteoarthritis? Int J Biometeorol 59:1133–1143. doi: 10.1007/s00484-014-0913-6 CrossRefGoogle Scholar
  24. Vandesompele J, De Preter K, Pattyn F et al (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3:1–12CrossRefGoogle Scholar
  25. Wilmink GJ, Roth CL, Ibey BL et al (2010) Identification of microRNAs associated with hyperthermia-induced cellular stress response. Cell Stress Chaperones 15:1027–1038. doi: 10.1007/s12192-010-0189-7 CrossRefGoogle Scholar
  26. Yuan Y, Zhang L, Tong X et al (2017) Mechanical stress regulates bone metabolism through microRNAs. J Cell Physiol 232:1239–1245. doi: 10.1002/jcp.2568 CrossRefGoogle Scholar

Copyright information

© ISB 2017

Authors and Affiliations

  1. 1.Rheumatology UnitAzienda Ospedaliera Universitaria SeneseSienaItaly
  2. 2.Department of Medical Biotechnologies, Policlinico Le ScotteUniversity of SienaSienaItaly
  3. 3.Department of Medicine, Surgery and Neurosciences, Scleroderma UnitUniversity of SienaSienaItaly
  4. 4.Department of Medicine, Surgery and Neuroscience, Rheumatology Unit, Policlinico Le ScotteUniversity of SienaSienaItaly

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