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The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth

Affiliation

  • 1 Department of Genetics, Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.
  • PMID: 15719068
  • PMCID: PMC548698
  • DOI: 10.1172/JCI22263

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The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth

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Authors

Affiliation

  • 1 Department of Genetics, Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.
  • PMID: 15719068
  • PMCID: PMC548698
  • DOI: 10.1172/JCI22263

Abstract

The long-term integrity of an articulating joint is dependent upon the nourishment of its cartilage component and the protection of the cartilage surface from friction-induced wear. Loss-of-function mutations in lubricin (a secreted glycoprotein encoded by the gene PRG4) cause the human autosomal recessive disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP). A major feature of CACP is precocious joint failure. In order to delineate the mechanism by which lubricin protects joints, we studied the expression of Prg4 mRNA during mouse joint development, and we created lubricin-mutant mice. Prg4 began to be expressed in surface chondrocytes and synoviocytes after joint cavitation had occurred and remained strongly expressed by these cells postnatally. Mice lacking lubricin were viable and fertile. In the newborn period, their joints appeared normal. As the mice aged, we observed abnormal protein deposits on the cartilage surface and disappearance of underlying superficial zone chondrocytes. In addition to cartilage surface changes and subsequent cartilage deterioration, intimal cells in the synovium surrounding the joint space became hyperplastic, which further contributed to joint failure. Purified or recombinant lubricin inhibited the growth of these synoviocytes in vitro. Tendon and tendon sheath involvement was present in the ankle joints, where morphologic changes and abnormal calcification of these structures were observed. We conclude that lubricin has multiple functions in articulating joints and tendons that include the protection of surfaces and the control of synovial cell growth.

Figures

Lubricin structure and Prg4 gene…

Lubricin structure and Prg4 gene targeting in mice. ( A ) Schematic depicting…

Lubricin mRNA expression during elbow…

Lubricin mRNA expression during elbow joint formation and in adult knee joints. (…

Clinical appearance and radiographic changes…

Clinical appearance and radiographic changes in Prg4 –/– mice. Photograph of the hind…

Histologic and radiographic changes in…

Histologic and radiographic changes in Prg4 –/– mice. ( A ) H& E-stained…

Histologic changes in the articular…

Histologic changes in the articular cartilage and synovium of Prg4 –/– mice. H&E-stained…

PCNA staining within the knee…

PCNA staining within the knee synovium of 10-day-old heterozygous and Prg4 –/– mice.…

Effect of purified human lubricin…

Effect of purified human lubricin on the in vitro growth of Prg4 –/–…

Effect of reduction and heat…

Effect of reduction and heat denaturation on the ability of lubricin to inhibit…

The long-term integrity of an articulating joint is dependent upon the nourishment of its cartilage component and the protection of the cartilage surface from friction-induced wear. Loss-of-function mutations in lubricin (a secreted glycoprotein encoded by the gene PRG4) cause the human autosomal re …

SOFT TISSUE MECHANICS AND INTERFACE SCIENCE

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SOFT TISSUE MECHANICS AND INTERFACE SCIENCE

Lubrication of Human Joints – A First Post

Articular cartilage is the thin translucent layer of tissue that covers the ends of long bones (Figure 1A). This is the rubbery material that you find at the ends of chicken bones. The role of this tissue layer is to support load and allow nearly frictionless and wear-free motion of joints ADDIN CSL_CITATION < "citationItems" : [ < "id" : "ITEM-1", "itemData" : < "DOI" : "10.1016/0043-1648(62)90176-X", "ISBN" : "0043-1648", "ISSN" : "00431648", "abstract" : "The porosity and stiffness of cartilage were measured. These properties are discussed in relation to the hypothicated \u201cweeping bearing\u201d properties of animal joints. A series of friction experiments were performed which provide confirmation that animal joints are weeping bearings. These experiments also confirm that synovial fluid is an excellent lubricant for cartilage.", "author" : [ < "dropping-particle" : "", "family" : "McCutchen", "given" : "C.W. W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" >], “container-title” : “Wear”, “id” : “ITEM-1”, “issued” : < "date-parts" : [ [ "1962" ] ] >, “note” : “what happens when the coating wears off?\nlong term cell culture”, “page” : “1-17”, “title” : “The frictional properties of animal joints”, “type” : “article-journal”, “volume” : “5” >, “uris” : [ “http://www.mendeley.com/documents/?uuid=6eb6fc81-4f5a-4304-8803-8cfc370b9d5e” ] > ], “mendeley” : < "formattedCitation" : "[1]", "plainTextFormattedCitation" : "[1]", "previouslyFormattedCitation" : "[1]" >, “properties” : < >, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” > [1] . While there is much to still be understood about the mechanism/s that enable cartilage lubrication and load bearing, we have learned many things over the last 7 decades or so.

Figure 1. (A) Model of a human joint. (B-D) Different methods of cartilage lubrication. Images adapted with permission from ref ADDIN CSL_CITATION < "citationItems" : [ < "id" : "ITEM-1", "itemData" : < "author" : [ < "dropping-particle" : "", "family" : "Moore", "given" : "Axel C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" >], “id” : “ITEM-1”, “issued” : < "date-parts" : [ [ "2017" ] ] >, “publisher” : “University of Delaware”, “title” : “Independent and competing roles of fluid exudation and rehydration in cartilage mechanics and tribology”, “type” : “thesis” >, “uris” : [ “http://www.mendeley.com/documents/?uuid=f1ece122-8a66-404a-926a-8da44ff6ffcd” ] > ], “mendeley” : < "formattedCitation" : "[3]", "plainTextFormattedCitation" : "[3]", "previouslyFormattedCitation" : "[3]" >, “properties” : < >, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” > [3] .

20 percent of the total tissue mass by weight) and an interstitial fluid phase (

80 percent). The intrinsic mechanical properties of such phase as well as the mechanical interaction between these two phases afford the tissue its interesting rheological behavior. In this investigation, the solid matrix was assumed to be intrinsically incompressible, linearly elastic and nondissipative while the interstitial fluid was assumed to be intrinsically incompressible and nondissipative. Further, it was assumed that the only dissipation comes from the frictional drag of relative motion between the phases. However, more general constitutive equations, including a viscoelastic dissipation of the solid matrix as well as a viscous dissipation of interstitial fluid were also developed. A constant ‘average’ permeability of the tissue was assumed, i.e., independent of deformation, and a solid content function V(s)/V(1) (the ratio of the volume of each of the phases) was assumed to vary with depth in accordance with the experimentally determined weight ratios. This linear, nonhomogeneous theory was applied to describe the experimentally obtained biphasic creep and biphasic stress relaxation data via a nonlinear regression technique. The determined intrinsic ‘aggregate’ elastic modulus, from ten creep experiments, is 0.70 \u00b1 0.09 MN/m2 and, from six stress relaxation experiments, is 0.76 \u00b1 0.03 MN/m2. The ‘average’ permeability of the tissue is (0.76 \u00b1 0.42) x 10-14m4/N.s. We concluded that the large spread in the permeability coefficients is due to the assumption of a constant deformation independent permeability. We also concluded that 1) a nonlinearly permeable biphasic model, where the permeability function is given by an experimentally determined empirical law; K= A(p) exp [\u03b1(p)e], can be used to describe more accurately the rheological properties of articular cartilage, and 2) the frictional drag of relative motion is the most important factor governing the fluid/solid viscoelastic properties of the tissue in compression. Articular cartilage is a biphasic material composed of a solid matric phase ( approximately equals 20 percent of the total tissue mass by weight) and an interstitial fluid phase ( approximately equals 80 percent). The solid matrix was assumed to be intrinsically incompressible, linearly elastic and nondissipative while the interstitial fluid was assumed to be intrinsic\u2026″, “author” : [ < "dropping-particle" : "", "family" : "Mow", "given" : "V. C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" >, < "dropping-particle" : "", "family" : "Kuei", "given" : "S. C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" >, < "dropping-particle" : "", "family" : "Lai", "given" : "W. M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" >, < "dropping-particle" : "", "family" : "Armstrong", "given" : "C. G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" >], “container-title” : “Journal of Biomechanical Engineering”, “id” : “ITEM-1”, “issue” : “1”, “issued” : < "date-parts" : [ [ "1980" ] ] >, “note” : “what happens when the coating wears off?\nlong term cell culture”, “page” : “73”, “title” : “Biphasic Creep and Stress Relaxation of Articular Cartilage in Compression: Theory and Experiments”, “type” : “article-journal”, “volume” : “102” >, “uris” : [ “http://www.mendeley.com/documents/?uuid=f5bb0f06-f63d-49e4-99e8-c2b7dd88cc2d” ] >, < "id" : "ITEM-2", "itemData" : < "DOI" : "10.1016/j.jbiomech.2009.04.040", "ISBN" : "0021-9290", "ISSN" : "00219290", "PMID" : "19464689", "abstract" : "Over the last two decades, considerable progress has been reported in the field of cartilage mechanics that impacts our understanding of the role of interstitial fluid pressurization on cartilage lubrication. Theoretical and experimental studies have demonstrated that the interstitial fluid of cartilage pressurizes considerably under loading, potentially supporting most of the applied load under various transient or steady-state conditions. The fraction of the total load supported by fluid pressurization has been called the fluid load support. Experimental studies have demonstrated that the friction coefficient of cartilage correlates negatively with this variable, achieving remarkably low values when the fluid load support is greatest. A theoretical framework that embodies this relationship has been validated against experiments, predicting and explaining various outcomes, and demonstrating that a low friction coefficient can be maintained for prolonged loading durations under normal physiological function. This paper reviews salient aspects of this topic, as well as its implications for improving our understanding of boundary lubrication by molecular species in synovial fluid and the cartilage superficial zone. Effects of cartilage degeneration on its frictional response are also reviewed. (C) 2009 Elsevier Ltd. All rights reserved.", "author" : [ < "dropping-particle" : "", "family" : "Ateshian", "given" : "Gerard A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" >], “container-title” : “Journal of Biomechanics”, “id” : “ITEM-2”, “issue” : “9”, “issued” : < "date-parts" : [ [ "2009" ] ] >, “language” : “English”, “note” : “From Duplicate 2 (The role of interstitial fluid pressurization in articular cartilage lubrication – Ateshian, Gerard A.)\n\nFrom Duplicate 1 (The role of interstitial fluid pressurization in articular cartilage lubrication – Ateshian, Gerard A.)\n\nFrom Duplicate 2 (The role of interstitial fluid pressurization in articular cartilage lubrication – Ateshian, G A)\n\n468JT\nTimes Cited:0\nCited References Count:118\n\nFrom Duplicate 3 (The role of interstitial fluid pressurization in articular cartilage lubrication – Ateshian, G A)\n\n468JT\nTimes Cited:0\nCited References Count:118”, “page” : “1163-1176”, “title” : “The role of interstitial fluid pressurization in articular cartilage lubrication”, “type” : “article-journal”, “volume” : “42” >, “uris” : [ “http://www.mendeley.com/documents/?uuid=fee12308-8add-47e8-91c6-5838de144f9f” ] >, < "id" : "ITEM-3", "itemData" : < "ISBN" : "0954-4119", "abstract" : "Reciprocating motion friction tests were conducted upon cartilage-on-metal contacts while subjected to a constant load. Initial friction coefficients were compared with repeat friction coefficients following a sufficient load removal period. The repeat friction coefficients were marginally higher than the initial values and both were primarily dependent on the loading time. It was concluded that while a wear component had been identified, which modestly increased friction coefficients, the overriding parameter influencing friction was loading time. The authors postulate that fluid phase load carriage (being dependent on loading time) within the articular cartilage is largely responsible for low friction coefficients in the mixed and boundary lubrication regimes. This mechanism has been referred to as biphasic lubrication. Both synovial fluid and Ringer's solution were used as lubricants. Over the assessed 120 min loading time friction coefficients rose from 0.005 (for both lubricants) after 5 s to 0.50 and 0.57 for synovial fluid and Ringer's solution respectively. Synovial fluid was found to significantly reduce friction coefficients compared to Ringer's solution over broad ranges of the assessed loading times (p >, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” > [7–12] ) is based on the observation that when you squeeze cartilage fluid comes out, see Figure 1C. The reason fluid comes out is because the pressure of the fluid is greater inside the tissue than outside ADDIN CSL_CITATION < "citationItems" : [ < "id" : "ITEM-1", "itemData" : < "DOI" : "10.1016/0043-1648(62)90176-X", "ISBN" : "0043-1648", "ISSN" : "00431648", "abstract" : "The porosity and stiffness of cartilage were measured. These properties are discussed in relation to the hypothicated \u201cweeping bearing\u201d properties of animal joints. A series of friction experiments were performed which provide confirmation that animal joints are weeping bearings. These experiments also confirm that synovial fluid is an excellent lubricant for cartilage.", "author" : [ < "dropping-particle" : "", "family" : "McCutchen", "given" : "C.W. W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" >], “container-title” : “Wear”, “id” : “ITEM-1”, “issued” : < "date-parts" : [ [ "1962" ] ] >, “note” : “what happens when the coating wears off?\nlong term cell culture”, “page” : “1-17”, “title” : “The frictional properties of animal joints”, “type” : “article-journal”, “volume” : “5” >, “uris” : [ “http://www.mendeley.com/documents/?uuid=6eb6fc81-4f5a-4304-8803-8cfc370b9d5e” ] > ], “mendeley” : < "formattedCitation" : "[1]", "plainTextFormattedCitation" : "[1]", "previouslyFormattedCitation" : "[1]" >, “properties” : < >, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” > [1] . Similar to a balloon, the greater the pressure inside the stiffer the tissue feels. This pressurization of fluid is what allows cartilage to resist the massive forces found in joints. The fluid that is squeeze from the tissue is then able to lubricate the surface and reduce friction by as much as 60 times ADDIN CSL_CITATION < "citationItems" : [ < "id" : "ITEM-1", "itemData" : < "DOI" : "10.1016/j.jbiomech.2009.04.040", "ISBN" : "0021-9290", "ISSN" : "00219290", "PMID" : "19464689", "abstract" : "Over the last two decades, considerable progress has been reported in the field of cartilage mechanics that impacts our understanding of the role of interstitial fluid pressurization on cartilage lubrication. Theoretical and experimental studies have demonstrated that the interstitial fluid of cartilage pressurizes considerably under loading, potentially supporting most of the applied load under various transient or steady-state conditions. The fraction of the total load supported by fluid pressurization has been called the fluid load support. Experimental studies have demonstrated that the friction coefficient of cartilage correlates negatively with this variable, achieving remarkably low values when the fluid load support is greatest. A theoretical framework that embodies this relationship has been validated against experiments, predicting and explaining various outcomes, and demonstrating that a low friction coefficient can be maintained for prolonged loading durations under normal physiological function. This paper reviews salient aspects of this topic, as well as its implications for improving our understanding of boundary lubrication by molecular species in synovial fluid and the cartilage superficial zone. Effects of cartilage degeneration on its frictional response are also reviewed. (C) 2009 Elsevier Ltd. All rights reserved.", "author" : [ < "dropping-particle" : "", "family" : "Ateshian", "given" : "Gerard A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" >], “container-title” : “Journal of Biomechanics”, “id” : “ITEM-1”, “issue” : “9”, “issued” : < "date-parts" : [ [ "2009" ] ] >, “language” : “English”, “note” : “From Duplicate 2 (The role of interstitial fluid pressurization in articular cartilage lubrication – Ateshian, Gerard A.)\n\nFrom Duplicate 1 (The role of interstitial fluid pressurization in articular cartilage lubrication – Ateshian, Gerard A.)\n\nFrom Duplicate 2 (The role of interstitial fluid pressurization in articular cartilage lubrication – Ateshian, G A)\n\n468JT\nTimes Cited:0\nCited References Count:118\n\nFrom Duplicate 3 (The role of interstitial fluid pressurization in articular cartilage lubrication – Ateshian, G A)\n\n468JT\nTimes Cited:0\nCited References Count:118”, “page” : “1163-1176”, “title” : “The role of interstitial fluid pressurization in articular cartilage lubrication”, “type” : “article-journal”, “volume” : “42” >, “uris” : [ “http://www.mendeley.com/documents/?uuid=fee12308-8add-47e8-91c6-5838de144f9f” ] > ], “mendeley” : < "formattedCitation" : "[8]", "plainTextFormattedCitation" : "[8]", "previouslyFormattedCitation" : "[8]" >, “properties” : < >, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” > [8] ! Back to our previous example, if cartilage has a friction coefficient of 0.5 then this lubrication mechanism will reduce it to 0.008!

Furthermore, this mechanism of lubrication and boundary are assumed to be additive. In other words, if you have both mechanisms acting at once you could have a friction coefficient as low as 0.004!

Unlike the previous examples, there is no additive effect between hydrodynamic and interstitial or boundary lubrication.

A Recent Development (coupling between hydrodynamics and interstitial pressure)

Of particular importance to me (as it was my doctoral thesis) is how hydrodynamic pressure fields interact with interstitial pressures ADDIN CSL_CITATION < "citationItems" : [ < "id" : "ITEM-1", "itemData" : < "author" : [ < "dropping-particle" : "", "family" : "Moore", "given" : "Axel C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" >], “id” : “ITEM-1”, “issued” : < "date-parts" : [ [ "2017" ] ] >, “publisher” : “University of Delaware”, “title” : “Independent and competing roles of fluid exudation and rehydration in cartilage mechanics and tribology”, “type” : “thesis” >, “uris” : [ “http://www.mendeley.com/documents/?uuid=f1ece122-8a66-404a-926a-8da44ff6ffcd” ] > ], “mendeley” : < "formattedCitation" : "[3]", "plainTextFormattedCitation" : "[3]", "previouslyFormattedCitation" : "[3]" >, “properties” : < >, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” > [3] . As I mentioned previously it is unlikely that the effects are additive; however, that doesn’t mean they don’t interact with one another. To keep this example simple lets imagine the interaction between a hydrated sponge and a faucet or tap (as it is commonly referred to in the UK). The sponge is the cartilage and the faucet/tap is the hydrodynamic fluid pressure.

For further reading on this topic:

ADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY [1] C.W.W. McCutchen, The frictional properties of animal joints, Wear. 5 (1962) 1–17. doi:10.1016/0043-1648(62)90176-X.

[2] S.M.T. Chan, C.P. Neu, G. DuRaine, K. Komvopoulos, A.H. Reddi, Atomic force microscope investigation of the boundary-lubricant layer in articular cartilage, Osteoarthr. Cartil. 18 (2010) 956–963. doi:10.1016/j.joca.2010.03.012.

[3] A.C. Moore, Independent and competing roles of fluid exudation and rehydration in cartilage mechanics and tribology, University of Delaware, 2017.

[4] T.A. Schmidt, R.L. Sah, Effect of synovial fluid on boundary lubrication of articular cartilage, Osteoarthr. Cartil. 15 (2007) 35–47. doi:10.1016/j.joca.2006.06.005.

[5] J.P. Gleghorn, L.J. Bonassar, Lubrication mode analysis of articular cartilage using Stribeck surfaces, J. Biomech. 41 (2008) 1910–1918. doi:DOI 10.1016/j.jbiomech.2008.03.043.

[6] G.D. Jay, J.R. Torres, D.K. Rhee, H.J. Helminen, M.M. Hytinnen, C.J. Cha, K. Elsaid, K.S. Kim, Y.J. Cui, M.L. Warman, Association between friction and wear in diarthrodial joints lacking lubricin, Arthritis Rheum. 56 (2007) 3662–3669. doi:Doi 10.1002/Art.22974.

[7] V.C. Mow, S.C. Kuei, W.M. Lai, C.G. Armstrong, Biphasic Creep and Stress Relaxation of Articular Cartilage in Compression: Theory and Experiments, J. Biomech. Eng. 102 (1980) 73. doi:10.1115/1.3138202.

[8] G.A. Ateshian, The role of interstitial fluid pressurization in articular cartilage lubrication, J. Biomech. 42 (2009) 1163–1176. doi:10.1016/j.jbiomech.2009.04.040.

[9] H. Forster, J. Fisher, The influence of loading time and lubricant on the friction of articular cartilage, Proc. Inst. Mech. Eng. Part H-Journal Eng. Med. 210 (1996) 109–119.

[10] M.A. Accardi, D. Dini, P.M. Cann, Experimental and numerical investigation of the behaviour of articular cartilage under shear loading-Interstitial fluid pressurisation and lubrication mechanisms, Tribol. Int. 44 (2011) 565–578. doi:DOI 10.1016/j.triboint.2010.09.009.

[11] D. Dowson, A. Unsworth, V. Wright, Analysis of Boosted-Lubrication in Human Joints, J. Mech. Eng. Sci. 12 (1970) 364-.

[12] A.C. Moore, D.L. Burris, An analytical model to predict interstitial lubrication of cartilage in migrating contact areas, J. Biomech. 47 (2014) 148–153. doi:DOI 10.1016/j.jbiomech.2013.09.020.

[13] M.A. Macconaill, The function of intra-articular fibrocartilages, with special reference to the knee and inferior radio-ulnar joints, J. Anat. 66 (1932) 210–227.

[14] J. Charnley, The Lubrication of Animal Joints in Relation to Surgical Reconstruction by Arthroplasty, Ann. Rheum. Dis. 19 (1960) 10–19. doi:Doi 10.1136/Ard.19.1.10.

[15] D. Dowson, Z.-M. Jin, Micro-elastohydrodynamic lubrication of synovial joints, Eng. Med. 15 (1986) 63–65.

This post provides a simple and direct overview of what we know about the lubricaiton of human joints.