Molecular Biology Reports

, Volume 38, Issue 5, pp 2879–2885 | Cite as

Lubricin: a novel potential biotherapeutic approaches for the treatment of osteoarthritis

  • Jia-peng Bao
  • Wei-ping Chen
  • Li-dong WuEmail author


Osteoarthritis (OA) is a multi-factor disorder of sinovial joints, which characterized by escalated degeneration and loss of articular cartilage. Treatment of OA is a critical unmet need in medicine for regeneration of damaged articular cartilage in elderly. On the other hand, lubricin, a glycoprotein specifically synthesized by chondrocytes located at the surface of articular cartilage, has been shown to provide boundary lubrication of congruent articular surfaces under conditions of high contact pressure and near zero sliding speed. Lubrication of these surfaces is critical to normal joint function, while different gene expressions of lubricin had been found in the synovium of rheumatoid arthritis (RA) and OA. Moreover, mutations or lacking of lubricin gene have been shown to link to the joint disease such as camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP), synovial hyperplasia and failure of joint function, suggesting an important role of lubricin in the pathogenesis of these joint disease. Recent studies demonstrate that administration with recombinant lubricin in the joint cavity would be effective in the prevention of cartilage degeneration in animal OA models. Therefore, a treatment with lubricin which would protect cartilage in vivo would be desirable. This article reviews recent findings with regard to the possible role of lubricin in the progression of OA, and further discusses lubricin as a novel potential biotherapeutic approaches for the treatment of OA.


Lubricin Osteoarthritis Therapeutic target 


  1. 1.
    Buckwalter JA, Mankin HJ (1998) Articular cartilage: degeneration and osteoarthritis, repair, regeneration, and transplantation. Instr Course Lect 47:487–504PubMedGoogle Scholar
  2. 2.
    Swann DA, Slayter HS, Silver FH (1981) The molecular structure of lubricating glycoprotein-I, the boundary lubricant for articular cartilage. J Biol Chem 256:5921–5925PubMedGoogle Scholar
  3. 3.
    Rhee DK, Marcelino J, Baker M et al (2005) The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth. J Clin Invest 115:622–631PubMedGoogle Scholar
  4. 4.
    Schumacher BL, Block JA, Schmid TM, Aydelotte MB, Kuettner KE (1994) A novel proteoglycan synthesized and secreted by chondrocytes of the superficial zone of articular cartilage. Arch Biochem Biophys 311:144–152PubMedCrossRefGoogle Scholar
  5. 5.
    Jay GD, Harris DA, Cha CJ (2001) Boundary lubrication by lubricin is mediated by O-linked beta(1–3)Gal-GalNAc oligosaccharides. Glycoconj J 18:807–815PubMedCrossRefGoogle Scholar
  6. 6.
    Justen HP, Grunewald E, Totzke G et al (2000) Differential gene expression in synovium of rheumatoid arthritis and osteoarthritis. Mol Cell Biol Res Commun 3:165–172PubMedCrossRefGoogle Scholar
  7. 7.
    Flannery CR, Zollner R, Corcoran C et al (2009) Prevention of cartilage degeneration in a rat model of osteoarthritis by intraarticular treatment with recombinant lubricin. Arthritis Rheum 60:840–847PubMedCrossRefGoogle Scholar
  8. 8.
    Ikegawa S, Sano M, Koshizuka Y, Nakamura Y (2000) Isolation, characterization and mapping of the mouse and human PRG4 (proteoglycan 4) genes. Cytogenet Cell Genet 90:291–297PubMedCrossRefGoogle Scholar
  9. 9.
    Jay GD, Cha CJ (1999) The effect of phospholipase digestion upon the boundary lubricating ability of synovial fluid. J Rheumatol 26:2454–2457PubMedGoogle Scholar
  10. 10.
    Flannery CR, Hughes CE, Schumacher BL et al (1999) Articular cartilage superficial zone protein (SZP) is homologous to megakaryocyte stimulating factor precursor and Is a multifunctional proteoglycan with potential growth-promoting, cytoprotective, and lubricating properties in cartilage metabolism. Biochem Biophys Res Commun 254:535–541PubMedCrossRefGoogle Scholar
  11. 11.
    Liu YJ, Lu SH, Xu B et al (2004) Hemangiopoietin, a novel human growth factor for the primitive cells of both hematopoietic and endothelial cell lineages. Blood 103:4449–4456PubMedCrossRefGoogle Scholar
  12. 12.
    Jay GD (1992) Characterization of a bovine synovial fluid lubricating factor. I. Chemical, surface activity and lubricating properties. Connect Tissue Res 28:71–88PubMedCrossRefGoogle Scholar
  13. 13.
    Zappone B, Ruths M, Greene GW, Jay GD, Israelachvili JN (2007) Adsorption, lubrication, and wear of lubricin on model surfaces: polymer brush-like behavior of a glycoprotein. Biophys J 92:1693–1708PubMedCrossRefGoogle Scholar
  14. 14.
    Jay GD, Tantravahi U, Britt DE, Barrach HJ, Cha CJ (2001) Homology of lubricin and superficial zone protein (SZP): products of megakaryocyte stimulating factor (MSF) gene expression by human synovial fibroblasts and articular chondrocytes localized to chromosome 1q25. J Orthop Res 19:677–687PubMedCrossRefGoogle Scholar
  15. 15.
    Deng G, Curriden SA, Hu G, Czekay RP, Loskutoff DJ (2001) Plasminogen activator inhibitor-1 regulates cell adhesion by binding to the somatomedin B domain of vitronectin. J Cell Physiol 189:23–33PubMedCrossRefGoogle Scholar
  16. 16.
    Schvartz I, Seger D, Shaltiel S (1999) Vitronectin. Int J Biochem Cell Biol 31:539–544PubMedCrossRefGoogle Scholar
  17. 17.
    Seiffert D, Smith JW (1997) The cell adhesion domain in plasma vitronectin is cryptic. J Biol Chem 272:13705–13710PubMedCrossRefGoogle Scholar
  18. 18.
    Hrkal Z, Kuzelova K, Muller-Eberhard U, Stern R (1996) Hyaluronan-binding properties of human serum hemopexin. FEBS Lett 383:72–74PubMedCrossRefGoogle Scholar
  19. 19.
    Nugent-Derfus GE, Chan AH, Schumacher BL, Sah RL (2007) PRG4 exchange between the articular cartilage surface and synovial fluid. J Orthop Res 25:1269–1276PubMedCrossRefGoogle Scholar
  20. 20.
    Jones AR, Gleghorn JP, Hughes CE et al (2007) Binding and localization of recombinant lubricin to articular cartilage surfaces. J Orthop Res 25:283–292PubMedCrossRefGoogle Scholar
  21. 21.
    Swann DA, Silver FH, Slayter HS, Stafford W, Shore E (1985) The molecular structure and lubricating activity of lubricin isolated from bovine and human synovial fluids. Biochem J 225:195–201PubMedGoogle Scholar
  22. 22.
    Jay GD, Haberstroh K, Cha CJ (1998) Comparison of the boundary-lubricating ability of bovine synovial fluid, lubricin, and Healon. J Biomed Mater Res 40:414–418PubMedCrossRefGoogle Scholar
  23. 23.
    Su JL, Schumacher BL, Lindley KM et al (2001) Detection of superficial zone protein in human and animal body fluids by cross-species monoclonal antibodies specific to superficial zone protein. Hybridoma 20:149–157PubMedCrossRefGoogle Scholar
  24. 24.
    Schumacher BL, Hughes CE, Kuettner KE, Caterson B, Aydelotte MB (1999) Immunodetection and partial cDNA sequence of the proteoglycan, superficial zone protein, synthesized by cells lining synovial joints. J Orthop Res 17:110–120PubMedCrossRefGoogle Scholar
  25. 25.
    Schumacher BL, Schmidt TA, Voegtline MS, Chen AC, Sah RL (2005) Proteoglycan 4 (PRG4) synthesis and immunolocalization in bovine meniscus. J Orthop Res 23:562–568PubMedCrossRefGoogle Scholar
  26. 26.
    Rees SG, Davies JR, Tudor D et al (2002) Immunolocalisation and expression of proteoglycan 4 (cartilage superficial zone proteoglycan) in tendon. Matrix Biol 21:593–602PubMedCrossRefGoogle Scholar
  27. 27.
    Lee SY, Nakagawa T, Reddi AH (2008) Induction of chondrogenesis and expression of superficial zone protein (SZP)/lubricin by mesenchymal progenitors in the infrapatellar fat pad of the knee joint treated with TGF-beta1 and BMP-7. Biochem Biophys Res Commun 376:148–153PubMedCrossRefGoogle Scholar
  28. 28.
    Sun Y, Berger EJ, Zhao C, An KN, Amadio PC, Jay G (2006) Mapping lubricin in canine musculoskeletal tissues. Connect Tissue Res 47:215–221PubMedCrossRefGoogle Scholar
  29. 29.
    Jay GD, Elsaid KA, Zack J et al (2004) Lubricating ability of aspirated synovial fluid from emergency department patients with knee joint synovitis. J Rheumatol 31:557–564PubMedGoogle Scholar
  30. 30.
    Kumar P, Oka M, Toguchida J et al (2001) Role of uppermost superficial surface layer of articular cartilage in the lubrication mechanism of joints. J Anat 199:241–250PubMedCrossRefGoogle Scholar
  31. 31.
    Neu CP, Khalafi A, Komvopoulos K, Schmid TM, Reddi AH (2007) Mechanotransduction of bovine articular cartilage superficial zone protein by transforming growth factor beta signaling. Arthritis Rheum 56:3706–3714PubMedCrossRefGoogle Scholar
  32. 32.
    Marcelino J, Carpten JD, Suwairi WM et al (1999) CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Nat Genet 23:319–322PubMedCrossRefGoogle Scholar
  33. 33.
    Bahabri SA, Suwairi WM, Laxer RM, Polinkovsky A, Dalaan AA, Warman ML (1998) The camptodactyly-arthropathy-coxa vara-pericarditis syndrome: clinical features and genetic mapping to human chromosome 1. Arthritis Rheum 41:730–735PubMedCrossRefGoogle Scholar
  34. 34.
    Schmidt TA, Schumacher BL, Klein TJ, Voegtline MS, Sah RL (2004) Synthesis of proteoglycan 4 by chondrocyte subpopulations in cartilage explants, monolayer cultures, and resurfaced cartilage cultures. Arthritis Rheum 50:2849–2857PubMedCrossRefGoogle Scholar
  35. 35.
    Schmidt TA, Gastelum NS, Han EH, Nugent-Derfus GE, Schumacher BL, Sah RL (2008) Differential regulation of proteoglycan 4 metabolism in cartilage by IL-1alpha, IGF-I, and TGF-beta1. Osteoarthr Cartil 16:90–97PubMedCrossRefGoogle Scholar
  36. 36.
    Khalafi A, Schmid TM, Neu C, Reddi AH (2007) Increased accumulation of superficial zone protein (SZP) in articular cartilage in response to bone morphogenetic protein-7 and growth factors. J Orthop Res 25:293–303PubMedCrossRefGoogle Scholar
  37. 37.
    Darling EM, Athanasiou KA (2005) Growth factor impact on articular cartilage subpopulations. Cell Tissue Res 322:463–473PubMedCrossRefGoogle Scholar
  38. 38.
    Niikura T, Reddi AH (2007) Differential regulation of lubricin/superficial zone protein by transforming growth factor beta/bone morphogenetic protein superfamily members in articular chondrocytes and synoviocytes. Arthritis Rheum 56:2312–2321PubMedCrossRefGoogle Scholar
  39. 39.
    Jones AR, Flannery CR (2007) Bioregulation of lubricin expression by growth factors and cytokines. Eur Cell Mater 13:40–45 discussion 45PubMedGoogle Scholar
  40. 40.
    Elsaid KA, Fleming BC, Oksendahl HL et al (2008) Decreased lubricin concentrations and markers of joint inflammation in the synovial fluid of patients with anterior cruciate ligament injury. Arthritis Rheum 58:1707–1715PubMedCrossRefGoogle Scholar
  41. 41.
    Buschmann MD, Kim YJ, Wong M, Frank E, Hunziker EB, Grodzinsky AJ (1999) Stimulation of aggrecan synthesis in cartilage explants by cyclic loading is localized to regions of high interstitial fluid flow. Arch Biochem Biophys 366:1–7PubMedCrossRefGoogle Scholar
  42. 42.
    Wong M, Siegrist M, Goodwin K (2003) Cyclic tensile strain and cyclic hydrostatic pressure differentially regulate expression of hypertrophic markers in primary chondrocytes. Bone 33:685–693PubMedCrossRefGoogle Scholar
  43. 43.
    Grad S, Lee CR, Gorna K, Gogolewski S, Wimmer MA, Alini M (2005) Surface motion upregulates superficial zone protein and hyaluronan production in chondrocyte-seeded three-dimensional scaffolds. Tissue Eng 11:249–256PubMedCrossRefGoogle Scholar
  44. 44.
    Nugent-Derfus GE, Takara T, O’Neill JK et al (2007) Continuous passive motion applied to whole joints stimulates chondrocyte biosynthesis of PRG4. Osteoarthr Cartil 15:566–574PubMedCrossRefGoogle Scholar
  45. 45.
    Li Z, Yao S, Alini M, Grad S (2007) Different response of articular chondrocyte subpopulations to surface motion. Osteoarthr Cartil 15:1034–1041PubMedCrossRefGoogle Scholar
  46. 46.
    Grad S, Lee CR, Wimmer MA, Alini M (2006) Chondrocyte gene expression under applied surface motion. Biorheology 43:259–269PubMedGoogle Scholar
  47. 47.
    Nugent GE, Schmidt TA, Schumacher BL et al (2006) Static and dynamic compression regulate cartilage metabolism of PRoteoGlycan 4 (PRG4). Biorheology 43:191–200PubMedGoogle Scholar
  48. 48.
    Nugent GE, Aneloski NM, Schmidt TA, Schumacher BL, Voegtline MS, Sah RL (2006) Dynamic shear stimulation of bovine cartilage biosynthesis of proteoglycan 4. Arthritis Rheum 54:1888–1896PubMedCrossRefGoogle Scholar
  49. 49.
    Das RH, Jahr H, Verhaar JA, van der Linden JC, Van Osch GJ, Weinans H (2008) In vitro expansion affects the response of chondrocytes to mechanical stimulation. Osteoarthr Cartil 16:385–391PubMedCrossRefGoogle Scholar
  50. 50.
    Schaefer DB, Wendt D, Moretti M et al (2004) Lubricin reduces cartilage–cartilage integration. Biorheology 41:503–508PubMedGoogle Scholar
  51. 51.
    DuRaine G, Neu CP, Chan SM, Komvopoulos K, June RK, Reddi AH (2009) Regulation of the friction coefficient of articular cartilage by TGF-beta1 and IL-1beta. J Orthop Res 27:249–256PubMedCrossRefGoogle Scholar
  52. 52.
    Young AA, McLennan S, Smith MM et al (2006) Proteoglycan 4 downregulation in a sheep meniscectomy model of early osteoarthritis. Arthritis Res Ther 8:R41PubMedCrossRefGoogle Scholar
  53. 53.
    Jay GD, Torres JR, Warman ML, Laderer MC, Breuer KS (2007) The role of lubricin in the mechanical behavior of synovial fluid. Proc Natl Acad Sci USA 104:6194–6199PubMedCrossRefGoogle Scholar
  54. 54.
    Englert C, McGowan KB, Klein TJ, Giurea A, Schumacher BL, Sah RL (2005) Inhibition of integrative cartilage repair by proteoglycan 4 in synovial fluid. Arthritis Rheum 52:1091–1099PubMedCrossRefGoogle Scholar
  55. 55.
    Elsaid KA, Jay GD, Warman ML, Rhee DK, Chichester CO (2005) Association of articular cartilage degradation and loss of boundary-lubricating ability of synovial fluid following injury and inflammatory arthritis. Arthritis Rheum 52:1746–1755PubMedCrossRefGoogle Scholar
  56. 56.
    Jay GD, Torres JR, Rhee DK et al (2007) Association between friction and wear in diarthrodial joints lacking lubricin. Arthritis Rheum 56:3662–3669PubMedCrossRefGoogle Scholar
  57. 57.
    Elsaid KA, Jay GD, Chichester CO (2007) Reduced expression and proteolytic susceptibility of lubricin/superficial zone protein may explain early elevation in the coefficient of friction in the joints of rats with antigen-induced arthritis. Arthritis Rheum 56:108–116PubMedCrossRefGoogle Scholar
  58. 58.
    Zhang D, Johnson LJ, Hsu HP, Spector M (2007) Cartilaginous deposits in subchondral bone in regions of exposed bone in osteoarthritis of the human knee: histomorphometric study of PRG4 distribution in osteoarthritic cartilage. J Orthop Res 25:873–883PubMedCrossRefGoogle Scholar
  59. 59.
    Skotnicki JS, DiGrandi MJ, Levin JI (2003) Design strategies for the identification of MMP-13 and Tace inhibitors. Curr Opin Drug Discov Dev 6:742–759Google Scholar
  60. 60.
    Teeple E, Elsaid KA, Fleming BC et al (2008) Coefficients of friction, lubricin, and cartilage damage in the anterior cruciate ligament-deficient guinea pig knee. J Orthop Res 26:231–237PubMedCrossRefGoogle Scholar
  61. 61.
    Klein TJ, Schumacher BL, Schmidt TA et al (2003) Tissue engineering of stratified articular cartilage from chondrocyte subpopulations. Osteoarthr Cartil 11:595–602PubMedCrossRefGoogle Scholar
  62. 62.
    Creamer P, Hochberg MC (1997) Osteoarthritis. Lancet 350:503–508PubMedCrossRefGoogle Scholar
  63. 63.
    Frizziero L, Govoni E, Bacchini P (1998) Intra-articular hyaluronic acid in the treatment of osteoarthritis of the knee: clinical and morphological study. Clin Exp Rheumatol 16:441–449PubMedGoogle Scholar
  64. 64.
    Adams ME, Atkinson MH, Lussier AJ et al (1995) The role of viscosupplementation with hylan G-F 20 (Synvisc) in the treatment of osteoarthritis of the knee: a Canadian multicenter trial comparing hylan G-F 20 alone, hylan G-F 20 with non-steroidal anti-inflammatory drugs (NSAIDs) and NSAIDs alone. Osteoarthr Cartil 3:213–225PubMedCrossRefGoogle Scholar
  65. 65.
    Balazs EA, Denlinger JL (1993) Viscosupplementation: a new concept in the treatment of osteoarthritis. J Rheumatol 39:3–9Google Scholar
  66. 66.
    Rydell N, Balazs EA (1971) Effect of intra-articular injection of hyaluronic acid on the clinical symptoms of osteoarthritis and on granulation tissue formation. Clin Orthop Relat Res 80:25–32PubMedCrossRefGoogle Scholar
  67. 67.
    Schmidt TA, Gastelum NS, Nguyen QT, Schumacher BL, Sah RL (2007) Boundary lubrication of articular cartilage: role of synovial fluid constituents. Arthritis Rheum 56:882–891PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.Department of Orthopedics Surgery, The Second Hospital of Medical CollegeZhejiang UniversityHangzhouPeople’s Republic of China

Personalised recommendations