Cytokine regulation of synovial fluid (SF) lubricants, hyaluronan (HA), and proteoglycan 4 (PRG4) is important in health, injury, and disease of synovial joints, and may also provide powerful regulation of lubricant secretion in bioreactors for articulating tissues. This study assessed lubricant secretion rates by human synoviocytes and the molecular weight (MW) of secreted lubricants in response to interleukin (IL)-1β, IL-17, IL-32, transforming growth factor-beta 1 (TGF-β1), and tumor necrosis factor-alpha (TNF-α), applied individually and in all combinations. Lubricant secretion rates were assessed using ELISA and binding assays, and lubricant MW was assessed using gel electrophoresis and Western blotting. HA secretion rates were increased ∼40-fold by IL-1β, and increased synergistically to ∼80-fold by the combination of IL-1β + TGF-β1 or TNF-α + IL-17. PRG4 secretion rates were increased ∼80-fold by TGF-β1, and this effect was counterbalanced by IL-1β and TNF-α. HA MW was predominantly <1 MDa for controls and individual cytokine stimulation, but was concentrated at >3 MDa after stimulation by IL-1β + TGF-β1 + TNF-α to resemble the distribution in human SF. PRG4 MW was unaffected by cytokines and similar to that in human SF. These results contribute to an understanding of the relationship between SF cytokine and lubricant content in health, injury, and disease, and provide approaches for using cytokines to modulate lubricant secretion rates and MW to help achieve desired lubricant composition of fluid in bioreactors.
Get full access to this article
View all access options for this article.
References
1.
HaubeckH.-D., KockR., FischerD.-C., van de LeurE., HoffmeisterK., GreilingH.Transforming growth factor β1, a major stimulator of hyaluronan synthesis in human synovial lining cells. Arthritis Rheum, 38:669. 1995.
2.
ColemanP.J., ScottD., RayJ., MasonR.M., LevickJ.R.Hyaluronan secretion into the synovial cavity of rabbit knees and comparison with albumin turnover. J Physiol, 503,Pt 3:645. 1997.
3.
JayG.D., BrittD.E., ChaD.-J.Lubricin is a product of megakaryocyte stimulating factor gene expression by human synovial fibroblasts. J Rheumatol, 27:594. 2000.
4.
JonesA.R., FlanneryC.R.Bioregulation of lubricin expression by growth factors and cytokines. Eur Cell Mater, 13:40discussion 45, 2007.
5.
SchumacherB.L., BlockJ.A., SchmidT.M., AydelotteM.B., KuettnerK.E.A novel proteoglycan synthesized and secreted by chondrocytes of the superficial zone of articular cartilage. Arch Biochem Biophys, 311:144. 1994.
6.
SchumacherB.L., HughesC.E., KuettnerK.E., CatersonB., AydelotteM.B.Immunodetection and partial cDNA sequence of the proteoglycan, superficial zone protein, synthesized by cells lining synovial joints. J Orthop Res, 17:110. 1999.
7.
LevickJ.R.A method for estimating macromolecular reflection by human synovium, using measurements of intra-articular half-lives. Ann Rheum Dis, 57:339. 1998.
8.
BlewisM.E., Nugent-DerfusG.E., SchmidtT.A., SchumacherB.L., SahR.L.A model of synovial fluid lubricant composition in normal and injured joints. Eur Cell Mater, 13:26. 2007.
9.
AsariA., MiyauchiS., SekiguchiT., MachidaA., KuriyamaS., MiyazakiK., NamikiO.Hyaluronan, cartilage destruction and hydrarthrosis in traumatic arthritis. Osteoarthritis Cartilage, 2:79. 1994.
10.
ElsaidK.A., JayG.D., WarmanM.L., RheeD.K., ChichesterC.O.Association of articular cartilage degradation and loss of boundary-lubricating ability of synovial fluid following injury and inflammatory arthritis. Arthritis Rheum, 52:1746. 2005.
11.
BelcherC., YaqubR., FawthropF., BaylissM., DohertyM.Synovial fluid chondroitin and keratan sulphate epitopes, glycosaminoglycans, and hyaluronan in arthritic and normal knees. Ann Rheum Dis, 56:299. 1997.
12.
DahlL.B., DahlI.M., Engstrom-LaurentA., GranathK.Concentration and molecular weight of sodium hyaluronate in synovial fluid from patients with rheumatoid arthritis and other arthropathies. Ann Rheum Dis, 44:817. 1985.
13.
BalazsE.A.The Physical Properties of Synovial Fluid and the Special Role of Hyaluronic Acid. Philadelphia: Lippincott Co., 1974; 63–75.
14.
RopesM.W., RossmeislE.C., BauerW.The origin and nature of normal human synovial fluid. J Clin Invest, 19:795. 1940.
15.
JawedS., GaffneyK., BlakeD.R.Intra-articular pressure profile of the knee joint in a spectrum of inflammatory arthropathies. Ann Rheum Dis, 56:686. 1997.
16.
KatzY., NadivO., BeerY.Interleukin-17 enhances tumor necrosis factor alpha-induced synthesis of interleukins 1,6, and 8 in skin and synovial fibroblasts: a possible role as a “fine-tuning cytokine” in inflammation processes. Arthritis Rheum, 44:2176. 2001.
17.
JoostenL.A., NeteaM.G., KimS.H., YoonD.Y., Oppers-WalgreenB., RadstakeT.R., BarreraP., van de LooF.A., DinarelloC.A., van den BergW.B.IL-32, a proinflammatory cytokine in rheumatoid arthritis. Proc Natl Acad Sci USA, 103:3298. 2006.
18.
KehlenA., PachnioA., ThieleK., LangnerJ.Gene expression induced by interleukin-17 in fibroblast-like synoviocytes of patients with rheumatoid arthritis: upregulation of hyaluronan-binding protein TSG-6. Arthritis Res Ther, 5:R186. 2003.
19.
GranetC., MaslinskiW., MiossecP.Increased AP-1 and NF-kappaB activation and recruitment with the combination of the proinflammatory cytokines IL-1beta, tumor necrosis factor alpha and IL-17 in rheumatoid synoviocytes. Arthritis Res Ther, 6:R190. 2004.
20.
Alvaro-GraciaJ.M., ZvaiflerN.J., FiresteinG.S.Cytokines in chronic inflammatory arthritis. V. Mutual antagonism between interferon-gamma and tumor necrosis factor-alpha on HLA-DR expression, proliferation, collagenase production, and granulocyte macrophage colony-stimulating factor production by rheumatoid arthritis synoviocytes. J Clin Invest, 86:1790. 1990.
21.
Alvaro-GraciaJ.M., ZvaiflerN.J., BrownC.B., KaushanskyK., FiresteinG.S.Cytokines in chronic inflammatory arthritis. VI. Analysis of the synovial cells involved in granulocyte-macrophage colony-stimulating factor production and gene expression in rheumatoid arthritis and its regulation by IL-1 and tumor necrosis factor-alpha. J Immunol, 146:3365. 1991.
22.
MarksP.H., DonaldsonM.L.Inflammatory cytokine profiles associated with chondral damage in the anterior cruciate ligament-deficient knee. Arthroscopy, 21:1342. 2005.
23.
BertoneA.L., PalmerJ.L., JonesJ.Synovial fluid cytokines and eicosanoids as markers of joint disease in horses. Vet Surg, 30:528. 2001.
24.
WeiX., MessnerK.Age- and injury-dependent concentrations of transforming growth factor-beta 1 and proteoglycan fragments in rabbit knee joint fluid. Osteoarthritis Cartilage, 6:10. 1998.
25.
KotakeS., UdagawaN., TakahashiN., MatsuzakiK., ItohK., IshiyamaS., SaitoS., InoueK., KamataniN., GillespieM.T., MartinT.J., SudaT.IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest, 103:1345. 1999.
26.
Chenevier-GobeauxC., Morin-RobinetS., LemarechalH., PoiraudeauS., EkindjianJ.C., BorderieD.Effects of pro- and anti-inflammatory cytokines and nitric oxide donors on hyaluronic acid synthesis by synovial cells from patients with rheumatoid arthritis. Clin Sci (Lond), 107:291. 2004.
27.
ReckliesA.D., WhiteC., MelchingL., RoughleyP.J.Differential regulation and expression of hyaluronan synthases in human articular chondrocytes, synovial cells and osteosarcoma cells. Biochem J, 354:17. 2001.
28.
KawakamiM., SuzukiK., MatsukiY., IshizukaT., HidakaT., KonishiT., MatsumotoM., KataharadaK., NakamuraH.Hyaluronan production in human rheumatoid fibroblastic synovial lining cells is increased by interleukin 1 beta but inhibited by transforming growth factor beta 1. Ann Rheum Dis, 57:602. 1998.
29.
BlewisM.E., LaoB.J., JadinK.D., McCartyW.J., AntonacciJ.M., BugbeeW.D., FiresteinG.S., SahR.L.Biomimetic bioengineering of synovial fluid: a bioreactor for a functional lubricant solution. Trans Orthop Res Soc, 34:121. 2009.
GradS., GogolewskiS., AliniM., WimmerM.A.Effects of simple and complex motion patterns on gene expression of chondrocytes seeded in 3D scaffolds. Tissue Eng, 12:3171. 2006.
32.
TehranzadehJ., BooyaF., RootJ.Cartilage metabolism in osteoarthritis and the influence of viscosupplementation and steroid: a review. Acta Radiol, 46:288. 2005.
33.
McGowanK.B., KurtisM.S., LottmanL.M., WatsonD., SahR.L.Biochemical quantification of DNA in human articular and septal cartilage using PicoGreen and Hoechst 33258. Osteoarthritis Cartilage, 10:580. 2002.
34.
SuJ.-L., SchumacherB.L., LindleyK.M., SoloveychikV., BurkhartW., TriantafillouJ.A., KuettnerK.E., SchmidT.M.Detection of superficial zone protein in human and animal body fluids by cross-species monoclonal antibodies specific to superficial zone protein. Hybridoma, 20:149. 2001.
35.
AfifyA., LynneL.C., HowellL.Correlation of cytologic examination with ELISA assays for hyaluronan and soluble CD44v6 levels in evaluation of effusions. Diagn Cytopathol, 35:105. 2007.
36.
LeeH.G., CowmanM.K.An agarose gel electrophoretic method for analysis of hyaluronan molecular weight distribution. Anal Biochem, 219:278. 1994.
37.
FiresteinG.S.Invasive fibroblast-like synoviocytes in rheumatoid arthritis. Passive responders or transformed aggressors?Arthritis Rheum, 39:1781. 1996.
38.
KhalafiA., SchmidT.M., NeuC., ReddiA.H.Increased accumulation of superficial zone protein (SZP) in articular cartilage in response to bone morphogenetic protein-7 and growth factors. J Orthop Res, 25:293. 2007.
39.
NiikuraT., ReddiA.H.Differential regulation of lubricin/superficial zone protein by transforming growth factor beta/bone morphogenetic protein superfamily members in articular chondrocytes and synoviocytes. Arthritis Rheum, 56:2312. 2007.
40.
EdwardsC.J.Immunological therapies for rheumatoid arthritis. Br Med Bull, 73:71. 2005.
41.
ChristodoulouC., ChoyE.H.Joint inflammation and cytokine inhibition in rheumatoid arthritis. Clin Exp Med, 6:13. 2006.
42.
StuhlmeierK.M., PollaschekC.Differential effect of transforming growth factor beta (TGF-beta) on the genes encoding hyaluronan synthases and utilization of the p38 MAPK pathway in TGF-beta-induced hyaluronan synthase 1 activation. J Biol Chem, 279:8753. 2004.
43.
StuhlmeierK.M.Prostaglandin E2: a potent activator of hyaluronan synthase 1 in type-B-synoviocytes. Biochim Biophys Acta, 1770:121. 2007.
El HajjajiH., ColeA.A., ManicourtD.H.Chondrocytes, synoviocytes and dermal fibroblasts all express PH-20, a hyaluronidase active at neutral pH. Arthritis Res Ther, 7:R756. 2005.
46.
HascallV.C., MajorsA.K., De La MotteC.A., EvankoS.P., WangA., DrazbaJ.A., StrongS.A., WightT.N.Intracellular hyaluronan: a new frontier for inflammation?Biochim Biophys Acta, 1673:3. 2004.
47.
PummillP.E., DeAngelisP.L.Alteration of polysaccharide size distribution of a vertebrate hyaluronan synthase by mutation. J Biol Chem, 278:19808. 2003.
48.
HutadilokN., GhoshP., BrooksP.M.Binding of haptoglobin, inter-alpha-trypsin inhibitor, and alpha 1 proteinase inhibitor to synovial fluid hyaluronate and the influence of these proteins on its degradation by oxygen derived free radicals. Ann Rheum Dis, 47:377. 1988.
49.
NeuC.P., KhalafiA., KomvopoulosK., SchmidT.M., ReddiA.H.Mechanotransduction of bovine articular cartilage superficial zone protein by transforming growth factor beta signaling. Arthritis Rheum, 56:3706. 2007.
50.
LevickJ.R.An analysis of the interaction between interstitial plasma protein, interstitial flow, and fenestral filtration and its application to synovium. Microvasc Res, 47:90. 1994.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
