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Physiological dynamic compression regulates central energy metabolism in primary human chondrocytes

  • Daniel Salinas
  • Brendan M. Mumey
  • Ronald K. June
Original Paper
  • 85 Downloads

Abstract

Chondrocytes use the pathways of central metabolism to synthesize molecular building blocks and energy for cartilage homeostasis. An interesting feature of the in vivo chondrocyte environment is the cyclical loading generated in various activities (e.g., walking). However, it is unknown whether central metabolism is altered by mechanical loading. We hypothesized that physiological dynamic compression alters central metabolism in chondrocytes to promote production of amino acid precursors for matrix synthesis. We measured the expression of central metabolites (e.g., glucose, its derivatives, and relevant co-factors) for primary human osteoarthritic chondrocytes in response to 0–30 minutes of compression. To analyze the data, we used principal components analysis and ANOVA-simultaneous components analysis, as well as metabolic flux analysis. Compression-induced metabolic responses consistent with our hypothesis. Additionally, these data show that chondrocyte samples from different patient donors exhibit different sensitivity to compression. Most importantly, we find that grade IV osteoarthritic chondrocytes are capable of synthesizing non-essential amino acids and precursors in response to mechanical loading. These results suggest that further advances in metabolic engineering of chondrocyte mechanotransduction may yield novel translational strategies for cartilage repair.

Keywords

Osteoarthritis Cartilage repair Mechanotransduction Chondrocyte Systems biology Metabolic flux analysis 

Notes

Acknowledgements

This study was funded by the National Science Foundation (1342420, 1554708 and 1542262) and the NIH (P20GM103474).

Compliance with ethical standards

Conflicts of interest

The authors have received license fees from technology used in this project. The corresponding author has a financial interest in a company that licensed the metabolic flux analysis technology.

Supplementary material

10237_2018_1068_MOESM1_ESM.xlsx (14 kb)
S1 Stoichiometric matrix used for metabolic flux analysis and flux balance analysis. An explanation of the reaction abbreviations used in the paper is included.
10237_2018_1068_MOESM2_ESM.xlsx (18 kb)
S2 Values for reaction fluxes over the first and second 15 minutes of compression for each donor. Fluxes that generate the third PCA axis and fluxes that generate the first ASCA axis are included.
10237_2018_1068_MOESM3_ESM.xlsx (13 kb)
S3 Values for PCA and ASCA decompositions of variation. The largest three components are included for PCA, and the largest two for ASCA.

References

  1. Alexopoulos LG, Williams GM, Upton ML, Setton LA, Guilak F (2005) Osteoarthritic changes in the biphasic mechanical properties of the chondrocyte pericellular matrix in articular cartilage. J Biomech 38(3):509–517CrossRefGoogle Scholar
  2. Blanco FJ, Rego I, Ruiz-Romero C (2011) The role of mitochondria in osteoarthritis. Nat Rev Rheumatol 7(3):161–169CrossRefGoogle Scholar
  3. Brouillette MJ, Ramakrishnan PS, Wagner V, Sauter E, Journot B, McKinley T, Martin JA (2014) Strain-dependent oxidant release in articular cartilage originates from mitochondria. Biomech Model Mechanobiol 13(3):565–572CrossRefGoogle Scholar
  4. Buschmann MD, Gluzband YA, Grodzinsky AJ, Hunziker EB (1995) Mechanical compression modulates matrix biosynthesis in chondrocyte/agarose culture. J Cell Sci 108(4):1497–1508Google Scholar
  5. Chan DD, Cai L, Butz KD, Trippel SB, Nauman EA, Neu CP (2016) In vivo articular cartilage deformation: noninvasive quantification of intratissue strain during joint contact in the human knee. Sci Rep 6(19):220Google Scholar
  6. Coleman MC, Ramakrishnan PS, Brouillette MJ, Martin JA (2016) Injurious loading of articular cartilage compromises chondrocyte respiratory function. Arthritis Rheumatol 68(3):662–671CrossRefGoogle Scholar
  7. Darling EM, Wilusz RE, Bolognesi MP, Zauscher S, Guilak F (2010) Spatial mapping of the biomechanical properties of the pericellular matrix of articular cartilage measured in situ via atomic force microscopy. Biophys J 98(12):2848–2856CrossRefGoogle Scholar
  8. Demarteau O, Wendt D, Braccini A, Jakob M, Schäfer D, Heberer M, Martin I (2003) Dynamic compression of cartilage constructs engineered from expanded human articular chondrocytes. Biochem Biophys Res Commun 310(2):580–588CrossRefGoogle Scholar
  9. Dimicco M, Kisiday J, Gong H, Grodzinsky A (2007) Structure of pericellular matrix around agarose-embedded chondrocytes. Osteoarthritis Cartil 15(10):1207–1216CrossRefGoogle Scholar
  10. Esko JD, Kimata K, Lindahl U (2009) Proteoglycans and sulfated glycosaminoglycansGoogle Scholar
  11. Griffin TM, Huebner JL, Kraus VB, Yan Z, Guilak F (2012) Induction of osteoarthritis and metabolic inflammation by a very high-fat diet in mice: Effects of short-term exercise. Arthritis Rheumatol 64(2):443–453CrossRefGoogle Scholar
  12. Griffiths EJ, Rutter GA (2009) Mitochondrial calcium as a key regulator of mitochondrial atp production in mammalian cells. Biochimica et Biophysica Acta (BBA)-Bioenergetics 1787(11):1324–1333CrossRefGoogle Scholar
  13. Grogan SP, Sovani S, Pauli C, Chen J, Hartmann A, Colwell CW Jr, Lotz MK, D’Lima DD (2012) Effects of perfusion and dynamic loading on human neocartilage formation in alginate hydrogels. Tissue Eng Part A 18(17–18):1784–1792CrossRefGoogle Scholar
  14. Handley C, Speight G, Leyden K, Lowther D (1980) Extracellular matrix metabolism by chondrocytes 7. evidence that l-glutamine is an essential amino acid for chondrocytes and other connective tissue cells. Biochimica et Biophysica Acta (BBA)-General Subj 627(3):324–331CrossRefGoogle Scholar
  15. Jutila AA, Zignego DL, Hwang BK, Hilmer JK, Hamerly T, Minor CA, Walk ST, June RK (2014) Candidate mediators of chondrocyte mechanotransduction via targeted and untargeted metabolomic measurements. Arch Biochem Biophys 545:116–123CrossRefGoogle Scholar
  16. Martin JA, Buckwalter JA (2002) Aging, articular cartilage chondrocyte senescence and osteoarthritis. Biogerontology 3(5):257–264CrossRefGoogle Scholar
  17. Martin JA, Martini A, Molinari A, Morgan W, Ramalingam W, Buckwalter JA, McKinley TO (2012) Mitochondrial electron transport and glycolysis are coupled in articular cartilage. Osteoarthritis Cartil 20(4):323–329CrossRefGoogle Scholar
  18. Pingguan-Murphy B, El-Azzeh M, Bader D, Knight M (2006) Cyclic compression of chondrocytes modulates a purinergic calcium signalling pathway in a strain rate-and frequency-dependent manner. J Cell Physiol 209(2):389–397CrossRefGoogle Scholar
  19. Salinas D, Minor CA, Carlson RP, McCutchen CN, Mumey BM, June RK (2017) Combining targeted metabolomic data with a model of glucose metabolism: toward progress in chondrocyte mechanotransduction. PloS one 12(1):e0168,326CrossRefGoogle Scholar
  20. Smilde AK, Jansen JJ, Hoefsloot HC, Lamers RJA, Van Der Greef J, Timmerman ME (2005) Anova-simultaneous component analysis (asca): a new tool for analyzing designed metabolomics data. Bioinformatics 21(13):3043–3048CrossRefGoogle Scholar
  21. Ten Berge JM, Kiers HA, Van der Stel V (1992) Simultaneous components analysis. Statistica Applicata 4(4):277–392Google Scholar
  22. Timmerman ME, Kiers HA (2003) Four simultaneous component models for the analysis of multivariate time series from more than one subject to model intraindividual and interindividual differences. Psychometrika 68(1):105–121MathSciNetCrossRefzbMATHGoogle Scholar
  23. Verbruggen G, Cornelissen M, Almqvist K, Wang L, Elewaut D, Broddelez C, De Ridder L, Veys E (2000) Influence of aging on the synthesis and morphology of the aggrecans synthesized by differentiated human articular chondrocytes. Osteoarthritis Cartil 8(3):170–179CrossRefGoogle Scholar
  24. Vertel BM (1995) The ins and outs of aggrecan. Trends Cell Biol 5(12):458–464CrossRefGoogle Scholar
  25. Vincent T, McLean C, Full L, Peston D, Saklatvala J (2007) Fgf-2 is bound to perlecan in the pericellular matrix of articular cartilage, where it acts as a chondrocyte mechanotransducer. Osteoarthritis Cartil 15(7):752–763CrossRefGoogle Scholar
  26. Vis DJ, Westerhuis JA, Smilde AK, van der Greef J (2007) Statistical validation of megavariate effects in asca. BMC Bioinform 8(1):322CrossRefGoogle Scholar
  27. Wann AK, Zuo N, Haycraft CJ, Jensen CG, Poole CA, McGlashan SR, Knight MM (2012) Primary cilia mediate mechanotransduction through control of atp-induced ca2+ signaling in compressed chondrocytes. The FASEB J 26(4):1663–1671CrossRefGoogle Scholar
  28. Wilusz RE, Sanchez-Adams J, Guilak F (2014) The structure and function of the pericellular matrix of articular cartilage. Matrix Biol 39:25–32CrossRefGoogle Scholar
  29. Xu X, Li Z, Cai L, Calve S, Neu CP (2016) Mapping the nonreciprocal micromechanics of individual cells and the surrounding matrix within living tissues. Sci Rep 6(24):272Google Scholar
  30. Zignego DL, Jutila AA, Gelbke MK, Gannon DM, June RK (2014) The mechanical microenvironment of high concentration agarose for applying deformation to primary chondrocytes. J Biomech 47(9):2143–2148CrossRefGoogle Scholar
  31. Zignego DL, Hilmer JK, June RK (2015) Mechanotransduction in primary human osteoarthritic chondrocytes is mediated by metabolism of energy, lipids, and amino acids. J Biomech 48(16):4253–4261CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Daniel Salinas
    • 1
  • Brendan M. Mumey
    • 1
  • Ronald K. June
    • 1
  1. 1.Montana State UniversityBozemanUSA

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