Articular synovial fluid (SF) is a complex mixture of components that regulate nutrition, communication, shock absorption, and lubrication. Alterations in its composition can be pathogenic. This lipidomic investigation aims to quantify the composition of sphingolipids (sphingomyelins, ceramides, and hexosyl- and dihexosylceramides) and minor glycerophospholipid species, including (lyso)phosphatidic acid, (lyso)phosphatidylglycerol, and bis(monoacylglycero)phosphate species, in the SF of knee joints from unaffected controls and from patients with early (eOA) and late (lOA) stages of osteoarthritis (OA), and rheumatoid arthritis (RA). SF without cells and cellular debris from 9 postmortem donors (control), 18 RA, 17 eOA, and 13 lOA patients were extracted to measure lipid species using electrospray ionization tandem mass spectrometry - directly or coupled with hydrophilic interaction liquid chromatography. We provide a novel, detailed overview of sphingolipid and minor glycerophospholipid species in human SF. A total of 41, 48, and 50 lipid species were significantly increased in eOA, lOA, and RA SF, respectively when compared with normal SF. The level of 21 lipid species differed in eOA SF versus SF from lOA, an observation that can be used to develop biomarkers. Sphingolipids can alter synovial inflammation and the repair responses of damaged joints. Thus, our lipidomic study provides the foundation for studying the biosynthesis and function of lipid species in health and most prevalent joint diseases.
References
[1]
Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, et al. (2006) Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev CD005321. doi: 10.1002/14651858.cd005321
[2]
Ludwig TE, McAllister JR, Lun V, Wiley JP, Schmidt TA (2012) Diminished cartilage-lubricating ability of human osteoarthritic synovial fluid deficient in proteoglycan 4: Restoration through proteoglycan 4 supplementation. Arthritis Rheum 64: 3963–3971. doi: 10.1002/art.34674
[3]
Schmidt TA, Gastelum NS, Nguyen QT, Schumacher BL, Sah RL (2007) Boundary lubrication of articular cartilage: role of synovial fluid constituents. Arthritis Rheum 56: 882–891. doi: 10.1002/art.22446
[4]
Lahiri S, Futerman AH (2007) The metabolism and function of sphingolipids and glycosphingolipids. Cell Mol Life Sci 64: 2270–2284. doi: 10.1007/s00018-007-7076-0
[5]
Merrill AH Jr (2011) Sphingolipid and glycosphingolipid metabolic pathways in the era of sphingolipidomics. Chem Rev 111: 6387–6422. doi: 10.1021/cr2002917
[6]
Marchesini N, Hannun YA (2004) Acid and neutral sphingomyelinases: roles and mechanisms of regulation. Biochem Cell Biol 82: 27–44. doi: 10.1139/o03-091
[7]
Gerritsen ME, Shen CP, Perry CA (1998) Synovial fibroblasts and the sphingomyelinase pathway: sphingomyelin turnover and ceramide generation are not signaling mechanisms for the actions of tumor necrosis factor-alpha. Am J Pathol 152: 505–512.
[8]
Cutler RG, Mattson MP (2001) Sphingomyelin and ceramide as regulators of development and lifespan. Mech Ageing Dev 122: 895–908. doi: 10.1016/s0047-6374(01)00246-9
[9]
Spiegel S, Milstien S (2003) Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol 4: 397–407. doi: 10.1038/nrm1103
[10]
Luberto C, Kraveka JM, Hannun YA (2002) Ceramide regulation of apoptosis versus differentiation: a walk on a fine line. Lessons from neurobiology. Neurochem Res 27: 609–617.
[11]
Ichinose Y, Eguchi K, Migita K, Kawabe Y, Tsukada T, et al. (1998) Apoptosis induction in synovial fibroblasts by ceramide: in vitro and in vivo effects. J Lab Clin Med 131: 410–416. doi: 10.1016/s0022-2143(98)90141-x
[12]
Schlame M, Ren M (2009) The role of cardiolipin in the structural organization of mitochondrial membranes. Biochim Biophys Acta 1788: 2080–2083. doi: 10.1016/j.bbamem.2009.04.019
[13]
Houtkooper RH, Vaz FM (2008) Cardiolipin, the heart of mitochondrial metabolism. Cell Mol Life Sci 65: 2493–2506. doi: 10.1007/s00018-008-8030-5
[14]
Schug ZT, Gottlieb E (2009) Cardiolipin acts as a mitochondrial signalling platform to launch apoptosis. Biochim Biophys Acta 1788: 2022–2031. doi: 10.1016/j.bbamem.2009.05.004
[15]
Yin H, Zhu M (2012) Free radical oxidation of cardiolipin: chemical mechanisms, detection and implication in apoptosis, mitochondrial dysfunction and human diseases. Free Radic Res 46: 959–974. doi: 10.3109/10715762.2012.676642
[16]
Ji J, Kline AE, Amoscato A, Samhan-Arias AK, Sparvero LJ, et al. (2012) Lipidomics identifies cardiolipin oxidation as a mitochondrial target for redox therapy of brain injury. Nat Neurosci 15: 1407–1413. doi: 10.1038/nn.3195
[17]
Ventura-Clapier R, Garnier A, Veksler V (2004) Energy metabolism in heart failure. J Physiol 555: 1–13. doi: 10.1113/jphysiol.2003.055095
[18]
Ellis CE, Murphy EJ, Mitchell DC, Golovko MY, Scaglia F, et al. (2005) Mitochondrial lipid abnormality and electron transport chain impairment in mice lacking alpha-synuclein. Mol Cell Biol 25: 10190–10201. doi: 10.1128/mcb.25.22.10190-10201.2005
[19]
Schlame M, Ren M (2006) Barth syndrome, a human disorder of cardiolipin metabolism. FEBS Lett 580: 5450–5455. doi: 10.1016/j.febslet.2006.07.022
[20]
Meikle PJ, Duplock S, Blacklock D, Whitfield PD, Macintosh G, et al. (2008) Effect of lysosomal storage on bis(monoacylglycero)phosphate. Biochem J 411: 71–78. doi: 10.1042/bj20071043
[21]
Hullin-Matsuda F, Luquain-Costaz C, Bouvier J, Delton-Vandenbroucke I (2009) Bis(monoacylglycero)phosphate, a peculiar phospholipid to control the fate of cholesterol: Implications in pathology. Prostaglandins Leukot Essent Fatty Acids 81: 313–324. doi: 10.1016/j.plefa.2009.09.006
[22]
Tokumura A (2002) Physiological and pathophysiological roles of lysophosphatidic acids produced by secretory lysophospholipase D in body fluids. Biochim Biophys Acta 1582: 18–25. doi: 10.1016/s1388-1981(02)00133-6
[23]
Masuda I, Okada K, Momohara S (2013) Cyclic phosphatidic acid (CPA) stimulates the production of hyaluronic acid (HA) in human osteoarthritic articular chondrocytes, and intraarticular administration of CPA supresses pain, swelling, and cartilage destruction in rabbit experimental osteoarthritis. Osteoarthritis Cartilage 21:: Abstracts:S296–S297. doi: 10.1016/j.joca.2013.02.622
[24]
Outerbridge RE (1961) The etiology of chondromalacia patellae. J Bone Joint Surg Br 43-B: 752–757.
[25]
Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, et al. (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31: 315–324. doi: 10.1002/art.1780310302
[26]
Kosinska MK, Liebisch G, Lochnit G, Wilhelm J, Klein H, et al. (2013) A lipidomic study of phospholipid classes and species in human synovial fluid. Arthritis Rheum 65: 2323–2333. doi: 10.1002/art.38053
[27]
Berckmans RJ, Nieuwland R, Kraan MC, Schaap MC, Pots D, et al. (2005) Synovial microparticles from arthritic patients modulate chemokine and cytokine release by synoviocytes. Arthritis Res Ther 7: R536–544.
[28]
Liebisch G, Lieser B, Rathenberg J, Drobnik W, Schmitz G (2004) High-throughput quantification of phosphatidylcholine and sphingomyelin by electrospray ionization tandem mass spectrometry coupled with isotope correction algorithm. Biochim Biophys Acta 1686: 108–117. doi: 10.1016/j.bbalip.2004.09.003
[29]
Scherer M, Leuthauser-Jaschinski K, Ecker J, Schmitz G, Liebisch G (2010) A rapid and quantitative LC-MS/MS method to profile sphingolipids. J Lipid Res 51: 2001–2011. doi: 10.1194/jlr.d005322
[30]
Scherer M, Schmitz G, Liebisch G (2009) High-throughput analysis of sphingosine 1-phosphate, sphinganine 1-phosphate, and lysophosphatidic acid in plasma samples by liquid chromatography-tandem mass spectrometry. Clin Chem 55: 1218–1222. doi: 10.1373/clinchem.2008.113779
[31]
Scherer M, Schmitz G, Liebisch G (2010) Simultaneous quantification of cardiolipin, bis(monoacylglycero)phosphate and their precursors by hydrophilic interaction LC-MS/MS including correction of isotopic overlap. Anal Chem 82: 8794–8799. doi: 10.1021/ac1021826
[32]
Liebisch G, Drobnik W, Reil M, Trumbach B, Arnecke R, et al. (1999) Quantitative measurement of different ceramide species from crude cellular extracts by electrospray ionization tandem mass spectrometry (ESI-MS/MS). J Lipid Res 40: 1539–1546.
[33]
Liebisch G, Vizcaino JA, Kofeler H, Trotzmuller M, Griffiths WJ, et al. (2013) Shorthand notation for lipid structures derived from mass spectrometry. J Lipid Res 54: 1523–1530. doi: 10.1194/jlr.m033506
[34]
Kraus VB, Huebner JL, Fink C, King JB, Brown S, et al. (2002) Urea as a passive transport marker for arthritis biomarker studies. Arthritis Rheum 46: 420–427. doi: 10.1002/art.10124
[35]
Niemela PS, Hyvonen MT, Vattulainen I (2006) Influence of chain length and unsaturation on sphingomyelin bilayers. Biophys J 90: 851–863. doi: 10.1529/biophysj.105.067371
[36]
Drobnik W, Liebisch G, Audebert FX, Frohlich D, Gluck T, et al. (2003) Plasma ceramide and lysophosphatidylcholine inversely correlate with mortality in sepsis patients. J Lipid Res 44: 754–761. doi: 10.1194/jlr.m200401-jlr200
[37]
Mizushima N, Kohsaka H, Miyasaka N (1998) Ceramide, a mediator of interleukin 1, tumour necrosis factor alpha, as well as Fas receptor signalling, induces apoptosis of rheumatoid arthritis synovial cells. Ann Rheum Dis 57: 495–499. doi: 10.1136/ard.57.8.495
[38]
Sabatini M, Rolland G, Leonce S, Thomas M, Lesur C, et al. (2000) Effects of ceramide on apoptosis, proteoglycan degradation, and matrix metalloproteinase expression in rabbit articular cartilage. Biochem Biophys Res Commun 267: 438–444. doi: 10.1006/bbrc.1999.1983
[39]
Sabatini M, Thomas M, Deschamps C, Lesur C, Rolland G, et al. (2001) Effects of ceramide on aggrecanase activity in rabbit articular cartilage. Biochem Biophys Res Commun 283: 1105–1110. doi: 10.1006/bbrc.2001.4920
[40]
Tetlow LC, Adlam DJ, Woolley DE (2001) Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: associations with degenerative changes. Arthritis Rheum 44: 585–594. doi: 10.1002/1529-0131(200103)44:3<585::aid-anr107>3.0.co;2-c
[41]
Colosimo M, McCarthy N, Jayasinghe R, Morton J, Taylor K, et al. (2000) Diagnosis and management of subdural haematoma complicating bone marrow transplantation. Bone Marrow Transplant 25: 549–552. doi: 10.1038/sj.bmt.1702166
[42]
Kim MK, Lee HY, Park KS, Shin EH, Jo SH, et al. (2005) Lysophosphatidic acid stimulates cell proliferation in rat chondrocytes. Biochem Pharmacol 70: 1764–1771. doi: 10.1016/j.bcp.2005.09.015
[43]
Hurst-Kennedy J, Boyan BD, Schwartz Z (2009) Lysophosphatidic acid signaling promotes proliferation, differentiation, and cell survival in rat growth plate chondrocytes. Biochim Biophys Acta 1793: 836–846. doi: 10.1016/j.bbamcr.2009.01.020
[44]
Orosa B, Gonzalez A, Mera A, Gomez-Reino JJ, Conde C (2012) Lysophosphatidic acid receptor 1 suppression sensitizes rheumatoid fibroblast-like synoviocytes to tumor necrosis factor-induced apoptosis. Arthritis Rheum 64: 2460–2470. doi: 10.1002/art.34443
[45]
Song HY, Lee MJ, Kim MY, Kim KH, Lee IH, et al. (2010) Lysophosphatidic acid mediates migration of human mesenchymal stem cells stimulated by synovial fluid of patients with rheumatoid arthritis. Biochim Biophys Acta 1801: 23–30. doi: 10.1016/j.bbalip.2009.08.011
[46]
Pruzanski W, Keystone EC, Sternby B, Bombardier C, Snow KM, et al. (1988) Serum phospholipase A2 correlates with disease activity in rheumatoid arthritis. J Rheumatol 15: 1351–1355.
Quehenberger O, Armando AM, Brown AH, Milne SB, Myers DS, et al. (2010) Lipidomics reveals a remarkable diversity of lipids in human plasma. J Lipid Res 51: 3299–3305. doi: 10.1194/jlr.m009449
[49]
Lee JY, Min HK, Moon MH (2011) Simultaneous profiling of lysophospholipids and phospholipids from human plasma by nanoflow liquid chromatography-tandem mass spectrometry. Anal Bioanal Chem 400: 2953–2961. doi: 10.1007/s00216-011-4958-7
