Ex vivo physiological compression of human osteoarthritis cartilage modulates cellular and matrix components

Autoři: Paolo Dolzani aff001;  Elisa Assirelli aff001;  Lia Pulsatelli aff001;  Riccardo Meliconi aff002;  Erminia Mariani aff001;  Simona Neri aff001
Působiště autorů: Laboratorio di Immunoreumatologia e Rigenerazione Tissutale, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy aff001;  Unità di Medicina e Reumatologia, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy aff002;  Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy aff003;  Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy aff004
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: 10.1371/journal.pone.0222947


Mechanical stimulation appears to play a key role in cartilage homeostasis maintenance, but it can also contribute to osteoarthritis (OA) pathogenesis. Accumulating evidence suggests that cartilage loading in the physiological range contributes to tissue integrity maintenance, whereas excessive or reduced loading have catabolic effects. However, how mechanical stimuli can regulate joint homeostasis is still not completely elucidated and few data are available on human cartilage. We aimed at investigating human OA cartilage response to ex vivo loading at physiological intensity. Cartilage explants from ten OA patients were subjected to ex vivo controlled compression, then recovered and used for gene and protein expression analysis of cartilage homeostasis markers. Compressed samples were compared to uncompressed ones in presence or without interleukin 1β (IL-1β) or interleukin 4 (IL-4). Cartilage explants compressed in combination with IL-4 treatment showed the best histological scores. Mechanical stimulation was able to significantly modify the expression of collagen type II (collagen 2), aggrecan, SOX9 transcription factor, cartilage oligomeric matrix protein (COMP), collagen degradation marker C2C and vascular endothelial growth factor (VEGF). Conversely, ADAMTS4 metallopeptidase, interleukin 4 receptor alpha (IL4Rα), chondroitin sulfate 846 epitope (CS846), procollagen type 2 C-propeptide (CPII) and glycosaminoglycans (GAG) appeared not modulated. Our data suggest that physiological compression of OA human cartilage modulates the inflammatory milieu by differently affecting the expression of components and homeostasis regulators of the cartilage extracellular matrix.

Klíčová slova:

Cartilage – Collagens – Compression – Extracellular matrix – Histology – Homeostasis – Osteoarthritis – Chondrocytes


1. Servin-Vences MR, Moroni M, Lewin GR, Poole K. Direct measurement of TRPV4 and PIEZO1 activity reveals multiple mechanotransduction pathways in chondrocytes. Elife. 2017;6.

2. Wojdasiewicz P, Poniatowski LA, Szukiewicz D. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediators Inflamm. 2014;2014:561459. doi: 10.1155/2014/561459 24876674

3. Varady NH, Grodzinsky AJ. Osteoarthritis year in review 2015: mechanics. Osteoarthritis Cartilage. 2016;24(1):27–35. doi: 10.1016/j.joca.2015.08.018 26707990

4. Wang N, Tytell JD, Ingber DE. Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus. Nat Rev Mol Cell Biol. 2009;10(1):75–82. doi: 10.1038/nrm2594 19197334

5. Sanchez-Adams J, Leddy HA, McNulty AL, O’Conor CJ, Guilak F. The mechanobiology of articular cartilage: bearing the burden of osteoarthritis. Curr Rheumatol Rep. 2014;16(10):451. doi: 10.1007/s11926-014-0451-6 25182679

6. Saxby DJ, Lloyd DG. Osteoarthritis year in review 2016: mechanics. Osteoarthritis Cartilage. 2017;25(2):190–8. doi: 10.1016/j.joca.2016.09.023 28100420

7. Clements KM, Bee ZC, Crossingham GV, Adams MA, Sharif M. How severe must repetitive loading be to kill chondrocytes in articular cartilage? Osteoarthritis Cartilage. 2001;9(5):499–507. doi: 10.1053/joca.2000.0417 11467899

8. Nishimuta JF, Levenston ME. Response of cartilage and meniscus tissue explants to in vitro compressive overload. Osteoarthritis Cartilage. 2012;20(5):422–9. doi: 10.1016/j.joca.2012.01.004 22289896

9. Sun HB. Mechanical loading, cartilage degradation, and arthritis. Ann N Y Acad Sci. 2010;1211:37–50. doi: 10.1111/j.1749-6632.2010.05808.x 21062294

10. Leong DJ, Hardin JA, Cobelli NJ, Sun HB. Mechanotransduction and cartilage integrity. Ann N Y Acad Sci. 2011;1240:32–7. doi: 10.1111/j.1749-6632.2011.06301.x 22172037

11. Ex vivo mechanical stimulation counteracts IL-1 effect on human oa cartilage explants Assirelli E, Pulsatelli L, Dolzani P, Meliconi R, Facchini A, Neri S. Osteoarthritis and Cartilage, Volume 20, S242—S243

12. Davis MA, Ettinger WH, Neuhaus JM, Cho SA, Hauck WW. The association of knee injury and obesity with unilateral and bilateral osteoarthritis of the knee. Am J Epidemiol. 1989;130(2):278–88. doi: 10.1093/oxfordjournals.aje.a115334 2750727

13. Rytter S, Egund N, Jensen LK, Bonde JP. Occupational kneeling and radiographic tibiofemoral and patellofemoral osteoarthritis. J Occup Med Toxicol. 2009;4:19. doi: 10.1186/1745-6673-4-19 19594940

14. Leung YY, Bin Abd Razak HR, Talaei M, Ang LW, Yuan JM, Koh WP. Duration of physical activity, sitting, sleep and the risk of total knee replacement among Chinese in Singapore, the Singapore Chinese Health Study. PLoS One. 2018;13(9):e0202554. doi: 10.1371/journal.pone.0202554 30180156

15. Buckwalter JA, Lane NE. Does participation in sports cause osteoarthritis? Iowa Orthop J. 1997;17:80–9. 9234978

16. Anderson DE, Johnstone B. Dynamic Mechanical Compression of Chondrocytes for Tissue Engineering: A Critical Review. Front Bioeng Biotechnol. 2017;5:76. doi: 10.3389/fbioe.2017.00076 29322043

17. Gassner R, Buckley MJ, Georgescu H, Studer R, Stefanovich-Racic M, Piesco NP, et al. Cyclic tensile stress exerts antiinflammatory actions on chondrocytes by inhibiting inducible nitric oxide synthase. J Immunol. 1999;163(4):2187–92. 10438960

18. Torzilli PA, Bhargava M, Park S, Chen CT. Mechanical load inhibits IL-1 induced matrix degradation in articular cartilage. Osteoarthritis Cartilage. 2010;18(1):97–105. doi: 10.1016/j.joca.2009.07.012 19747586

19. Chen CH, Kuo CY, Chen JP. Effect of Cyclic Dynamic Compressive Loading on Chondrocytes and Adipose-Derived Stem Cells Co-Cultured in Highly Elastic Cryogel Scaffolds. Int J Mol Sci. 2018;19(2).

20. Grogan SP, Sovani S, Pauli C, Chen J, Hartmann A, Colwell CW Jr., et al. Effects of perfusion and dynamic loading on human neocartilage formation in alginate hydrogels. Tissue Eng Part A. 2012;18(17–18):1784–92. doi: 10.1089/ten.TEA.2011.0506 22536910

21. McCutchen CN, Zignego DL, June RK. Metabolic responses induced by compression of chondrocytes in variable-stiffness microenvironments. J Biomech. 2017;64:49–58. doi: 10.1016/j.jbiomech.2017.08.032 28985893

22. O’Conor CJ, Leddy HA, Benefield HC, Liedtke WB, Guilak F. TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading. Proc Natl Acad Sci U S A. 2014;111(4):1316–21. doi: 10.1073/pnas.1319569111 24474754

23. Wang QG, Magnay JL, Nguyen B, Thomas CR, Zhang Z, El Haj AJ, et al. Gene expression profiles of dynamically compressed single chondrocytes and chondrons. Biochem Biophys Res Commun. 2009;379(3):738–42. doi: 10.1016/j.bbrc.2008.12.111 19118531

24. Goset M, Berenbaum F, Levy A, Pigenet A, Thirion S, Saffar JL, et al. Prostaglandin E2 synthesis in cartilage explants under compression: mPGES-1 is a mechanosensitive gene. Arthritis Res Ther. 2006;8(4):R135. doi: 10.1186/ar2024 16872525

25. Pritzker KP, Gay S, Jimenez SA, Ostergaard K, Pelletier JP, Revell PA, et al. Osteoarthritis cartilage histopathology: grading and staging. Osteoarthritis Cartilage. 2006;14(1):13–29. doi: 10.1016/j.joca.2005.07.014 16242352

26. Neri S, Vannini F, Desando G, Grigolo B, Ruffilli A, Buda R, et al. Ankle bipolar fresh osteochondral allograft survivorship and integration: transplanted tissue genetic typing and phenotypic characteristics. J Bone Joint Surg Am. 2013;95(20):1852–60. doi: 10.2106/JBJS.L.01715 24132359

27. Barbosa I, Garcia S, Barbier-Chassefiere V, Caruelle JP, Martelly I, Papy-Garcia D. Improved and simple micro assay for sulfated glycosaminoglycans quantification in biological extracts and its use in skin and muscle tissue studies. Glycobiology. 2003;13(9):647–53. doi: 10.1093/glycob/cwg082 12773478

28. Assirelli E, Pulsatelli L, Dolzani P, Platano D, Olivotto E, Filardo G, et al. Human osteoarthritic cartilage shows reduced in vivo expression of IL-4, a chondroprotective cytokine that differentially modulates IL-1beta-stimulated production of chemokines and matrix-degrading enzymes in vitro. PLoS One. 2014;9(5):e96925. doi: 10.1371/journal.pone.0096925 24819779

29. Scholtes S, Kramer E, Weisser M, Roth W, Luginbuhl R, Grossner T, et al. Global chondrocyte gene expression after a single anabolic loading period: Time evolution and re-inducibility of mechano-responses. J Cell Physiol. 2018;233(1):699–711. doi: 10.1002/jcp.25933 28369921

30. Erhart-Hledik JC, Favre J, Asay JL, Smith RL, Giori NJ, Mundermann A, et al. A relationship between mechanically-induced changes in serum cartilage oligomeric matrix protein (COMP) and changes in cartilage thickness after 5 years. Osteoarthritis Cartilage. 2012;20(11):1309–15. doi: 10.1016/j.joca.2012.07.018 22868052

31. Pulsatelli L, Dolzani P, Silvestri T, Frizziero L, Facchini A, Meliconi R. Vascular endothelial growth factor activities on osteoarthritic chondrocytes. Clin Exp Rheumatol. 2005;23(4):487–93. 16095117

32. Beckmann R, Houben A, Tohidnezhad M, Kweider N, Fragoulis A, Wruck CJ, et al. Mechanical forces induce changes in VEGF and VEGFR-1/sFlt-1 expression in human chondrocytes. Int J Mol Sci. 2014;15(9):15456–74. doi: 10.3390/ijms150915456 25257525

33. Jeon JE, Schrobback K, Hutmacher DW, Klein TJ. Dynamic compression improves biosynthesis of human zonal chondrocytes from osteoarthritis patients. Osteoarthritis Cartilage. 2012;20(8):906–15. doi: 10.1016/j.joca.2012.04.019 22548797

34. Jorgensen AEM, Kjaer M, Heinemeier KM. The Effect of Aging and Mechanical Loading on the Metabolism of Articular Cartilage. J Rheumatol. 2017;44(4):410–7. doi: 10.3899/jrheum.160226 28250141

35. Goldring MB, Marcu KB. Cartilage homeostasis in health and rheumatic diseases. Arthritis Res Ther. 2009;11(3):224. doi: 10.1186/ar2592 19519926

36. Racunica TL, Teichtahl AJ, Wang Y, Wluka AE, English DR, Giles GG, et al. Effect of physical activity on articular knee joint structures in community-based adults. Arthritis Rheum. 2007;57(7):1261–8. doi: 10.1002/art.22990 17907212

37. Quicke JG, Foster NE, Thomas MJ, Holden MA. Is long-term physical activity safe for older adults with knee pain?: a systematic review. Osteoarthritis Cartilage. 2015;23(9):1445–56. doi: 10.1016/j.joca.2015.05.002 26003947

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