Skip to main content
SpringerLink
Log in

Influence of TNF-α and biomechanical stress on matrix metalloproteinases and lysyl oxidases expressions in human knee synovial fibroblasts

  • Knee
  • Published:
Knee Surgery, Sports Traumatology, Arthroscopy Aims and scope

Abstract

Purpose

It was reported that not only ACL but also the synovium may be the major regulator of matrix metalloproteinases (MMPs) in synovial fluids after ACL injury. In order to further confirm whether synovium is capable of regulating the microenvironment in the process of ACL injury, the complicated microenvironment of joint cavity after ACL injury was mimicked and the combined effects of mechanical injury and inflammatory factor [tumour necrosis factor-α (TNF-α)] on expressions of lysyl oxidases (LOXs) and MMPs in synovial fibroblasts derived from normal human synovium were studied.

Methods

Human normal knee joint synovial fibroblasts were stimulated for 1–6 h with mechanical stretch and inflammatory factor (TNF-α). Total RNA was harvested, reverse transcribed and assessed by real-time polymerase chain reaction for the expression of LOXs and MMP-1, 2, 3 messenger RNAs. MMP-2 activity was assayed from the collected culture media samples using zymography.

Results

Compared to control group, our results showed that 6 % physiological stretch increased MMP-2 and LOXs (except LOXL-3), decreased MMP-1 and MMP-3; injurious stretch (12 %) decreased LOXs (except LOXL-2)and increased MMP-1, 2 and 3; the combination of injurious stretch and TNF-α decreased LOXs and increased MMP-1, 2 and 3 in synovial fibroblasts in a synergistical manner.

Conclusion

This study demonstrated that combination of mechanical injury and inflammatory factors up-regulated the expressions of MMPs and down-regulated the expressions of LOXs in synovial fibroblasts, eventually alter the balance of tissue healing. Thus, synovium may be involved in regulating the microenvironment of joint cavity. Based on the mechanism, early interventions to inhibit the production of MMPs or promote the production of LOXs in the synovial fibroblasts should be performed to facilitate the healing of tissue.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Anitua E, Sanchez M, De la Fuente M et al (2012) Plasma rich in growth factors (PRGF-Endoret) stimulates tendon and synovial fibroblasts migration and improves the biological properties of hyaluronic acid. Knee Surg Sports Traumatol Arthrosc 20:1657–1665

    Article  CAS  PubMed  Google Scholar 

  2. Asundi KR, Rempel DM (2008) Cyclic loading inhibits expression of MMP-3 but not MMP-1 in an in vitro rabbit flexor tendon model. Clin Biomech 23:117–121

    Article  Google Scholar 

  3. Bray RC, Leonard CA, Salo PT (2002) Vascular physiology and long-term healing of partial ligament tears. J Orthop Res 20:984–989

    Article  PubMed  Google Scholar 

  4. Breshears LA, Cook JL, Stoker AM et al (2010) The effect of uniaxial cyclic tensile load on gene expression in canine cranial cruciate ligamentocytes. Vet Surg 39:433–443

    Article  PubMed  Google Scholar 

  5. Catrina AI, Lampa J, Ernestam S et al (2002) TNF-α as a promising therapeutic target in chronic asthma: a lesson from rheumatoid arthritis. Rheumatology 41:484–489

    Article  CAS  PubMed  Google Scholar 

  6. Chamberlain CS, Brounts SH, Sterken DG et al (2011) Gene profiling of the rat medial collateral ligament during early healing using microarray analysis. J Appl Physiol 111:552–565

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Chithra P, Sajithlal GB, Chandrakasan G (1998) Influence of Aloe vera on collagen characteristics in healing dermal wounds in rats. Mol Cell Biochem 181:71–76

    Article  CAS  PubMed  Google Scholar 

  8. DesRosiers EA, Yahia L, Rivard CH (1996) Proliferative and matrix synthesis response of canine anterior cruciate ligament fibroblasts submitted to combined growth factors. J Orthop Res 14:200–208

    Article  CAS  PubMed  Google Scholar 

  9. Di Sabatino A, Pender SL, Jackson CL et al (2007) Functional modulation of Crohn’s disease myofibroblasts by anti-tumor necrosis factor antibodies. Gastroenterology 133:137–149

    Article  PubMed  Google Scholar 

  10. Fisher JF, Mobashery S (2006) Recent advances in MMP inhibitor design. Cancer Metastasis Rev 25:115–136

    Article  CAS  PubMed  Google Scholar 

  11. Fleming BC, Beynnon BD (2004) In vivo measurement of ligament/tendon strains and forces: a review. Ann Biomed Eng 32:318–328

    Article  PubMed  Google Scholar 

  12. Fu FH, Bennett CH, Lattermann C et al (2000) Current trends in anterior cruciate ligament reconstruction. Am J Sports Med 28:124–130

    CAS  PubMed  Google Scholar 

  13. Greenwel P, Tanaka S, Penkov D et al (2000) Tumor necrosis factor alpha inhibits type I collagen synthesis through repressive CCAAT/enhancer-binding proteins. Mol Cell Biol 20:912–918

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Hou WS, Li Z, Gordon RE et al (2001) Cathepsin K is a critical protease in synovial fibroblast-mediated collagen degradation. Am J Pathol 159:2167–2177

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Hsieh AH, Sah RL, Sung KL (2002) Biomechanical regulation of type I collagen gene expression in ACLs in organ culture. J Orthop Res 20:325–331

    Article  PubMed  Google Scholar 

  16. Hsieh AH, Tsai CMH, Ma QJ et al (2000) Time-dependent increase in type-III collagen gene expression in medial collateral ligament fibroblasts under cyclic strains. J Bone Joint Surg 18:220–227

    CAS  Google Scholar 

  17. Irie K, Uchiyama E, Iwaso H (2003) Intraarticular inflammatory cytokines in acute anterior cruciate ligament injured knee. Knee 10:93–96

    Article  PubMed  Google Scholar 

  18. Ishiguro N, Shimizu T, Ito T et al (2000) The expression of matrix metalloproteinases and inhibitors in acute rupture of the anterior cruciate ligament. Mod Rheumatol 10:95–102

    Article  CAS  PubMed  Google Scholar 

  19. Kagan HM, Li W (2003) Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. J Cell Biochem 88:660–672

    Article  CAS  PubMed  Google Scholar 

  20. Kerrigan JJ, Mansell JP, Sandy JR (2000) Matrix turnover. J Orthod 27:227–233

    CAS  PubMed  Google Scholar 

  21. Lee AA, Delhaas T, McCulloch AD et al (1999) Differential responses of adult rat cardiac fibroblasts to in vitro biaxial strain patterns. J Mol Cell Cardiol 31:1833–1843

    Article  CAS  PubMed  Google Scholar 

  22. Lee AA, Delhaas T, Waldman LK et al (1996) An equibiaxial strain system for cultured cells. Am J Physiol 271:C1400–C1408

    CAS  PubMed  Google Scholar 

  23. Lohmander LS, Englund PM, Dahl LL, Dahl LL, Roos EM (2007) The long-term consequence of anterior cruciate ligament and meniscus injuries. Am J Sports Med 35:1756–1769

    Article  PubMed  Google Scholar 

  24. Muir P, Danova NA, Argyle DJ et al (2005) Collagenolytic protease expression in cranial cruciate ligament and stifle synovial fluid in dogs with cranial cruciate ligament rupture. Vet Surg 34:482–490

    Article  PubMed  Google Scholar 

  25. Murakami H, Shinomiya N, Kikuchi T et al (2006) Upregulated expression of inducible nitric oxide synthase plays a key role in early apoptosis after anterior cruciate ligament injury. J Orthop Res 24:1521–1534

    Article  CAS  PubMed  Google Scholar 

  26. Nagineni CN, Amiel D, Green MH et al (1992) Characterization of the intrinsic properties of the anterior cruciate and medial collateral ligament cells: an in vitro cell culture study. J Orthop Res 10:465–475

    Article  CAS  PubMed  Google Scholar 

  27. Pap T, Müller-Ladner U, Gay RE et al (2000) Fibroblast biology. Role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis. Arthritis Res 2:361–367

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Patwari P, Cook MN, DiMicco MA et al (2003) Proteoglycan degradation after injurious compression of bovine and human articular cartilage in vitro: interaction with exogenous cytokines. Arthritis Rheum 48:1292–1301

    Article  CAS  PubMed  Google Scholar 

  29. Poole AR (1997) Cartilage in health and disease. In: Koopman WJ (ed) Arthritis and allied conditions, 13th edn. Williams and Wilkins, Baltimore

    Google Scholar 

  30. Powers JC, Asgian JL, Ekici OD et al (2002) Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases. Chem Rev 102:4639–4750

    Article  CAS  PubMed  Google Scholar 

  31. Russo C, Polosa R (2005) Anti-tumor necrosis factor (TNF)-α therapy (etanercept) down-regulates serum matrix metalloproteinase (MMP)-3 and MMP-1 in rheumatoid arthritis. Clin Sci 109:135–142

    Article  CAS  PubMed  Google Scholar 

  32. Spindler KP, Clark SW, Nanney LB et al (1996) Expression of collagen and matrix metalloproteinases in ruptured human anterior cruciate ligament: an in situ hybridization study. J Orthop Res 14:857–861

    Article  CAS  PubMed  Google Scholar 

  33. Sung KL, Yang L, Whittemore DE et al (1996) The differential adhesion forces of anterior cruciate ligament and medial collateral ligament fibroblasts: effects of tropomodulin, talin, vinculin, and alpha-actinin. Proc Natl Acad Sci USA 93:9182–9187

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Sun HB, Yokota H (2001) Messenger-RNA expression of matrix metalloproteinases, tissue inhibitors of metalloproteinases, and transcription factors in rheumatic synovial cells under mechanical stimuli. Bone 28:303–309

    Article  CAS  PubMed  Google Scholar 

  35. Tandara AA, Mustoe TA (2004) Oxygen in wound healing—more than a nutrient. World J Surg 28:294–300

    Article  PubMed  Google Scholar 

  36. Tang Z, Yang L, Wang Y et al (2009) Contributions of different intraarticular tissues to the acute phase elevation of synovial fluid MMP-2 following rat ACL rupture. J Orthop Res 27:243–248

    Article  CAS  PubMed  Google Scholar 

  37. Tchetverikov I, Lohmander LS, Verzijl N et al (2005) MMP protein and activity levels in synovial fluid from patients with joint injury, inflammatory arthritis, and osteoarthritis. Ann Rheum Dis 64:694–698

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Vater CA, Harris ED Jr, Siegel RC (1979) Native cross-links in collagen fibrils induce resistance to human synovial collagenase. Biochem J 181:639–645

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Wang P, Yang L, You X et al (2009) Mechanical stretch regulates the expression of matrix metalloproteinases in rheumatoid arthritis fibroblast-like synoviocytes. Connect Tissue Res 50:98–109

    Article  CAS  PubMed  Google Scholar 

  40. Wang Y, Tang Z, Xue R et al (2011) Combined effects of TNF-α, IL-1β, and HIF-1α on MMP-2 production in ACL fibroblasts under mechanical stretch: an in vitro study. J Orthop Res 29:1008–1014

    Article  CAS  PubMed  Google Scholar 

  41. Wang Y, Yang L, Zhang J et al (2009) Differential MMP-2 activity induced by mechanical compression and inflammatory factors in human synoviocytes. Mol Cell Biomech 7:105–114

    Google Scholar 

  42. Wiig ME, Amiel D, Ivarsson M et al (1991) Type I procollagen gene expression in normal and early healing of the medial collateral and anterior cruciate ligaments in rabbits: an in situ hybridization study. J Orthop Res 9:374–382

    Article  CAS  PubMed  Google Scholar 

  43. Witkowski J, Yang L, Wood DJ et al (1997) Migration and healing of ligament cells under inflammatory conditions. J Orthop Res 15:269–277

    Article  CAS  PubMed  Google Scholar 

  44. Xie J, Jiang J, Zhang Y et al (2012) Up-regulation expressions of lysyl oxidase family in ACL and MCL fibroblasts induced by TGF-β1. Int Orthop 36:207–213

    Article  PubMed Central  PubMed  Google Scholar 

  45. Xie J, Wang C, Yin L et al (2012) IL-1β influences on lysyl oxidases and matrix metalloproteinases profile of injured anterior cruciate ligament and medial collateral ligament fibroblasts. Int Orthop. PMID: 22588690

  46. Yan C, Boyd DD (2007) Regulation of matrix metalloproteinase gene expression. J Cell Physiol 211:19–26

    Article  CAS  PubMed  Google Scholar 

  47. Yokota H, Goldring MB, Sun HB (2003) CITED2-mediated regulation of MMP-1 and MMP-13 in human chondrocytes under flow shear. J Biol Chem 278:47275

    Article  CAS  PubMed  Google Scholar 

  48. Zhou D, Lee HS, Villarreal F et al (2005) Differential MMP-2 activity of ligament cells under mechanical stretch injury: an in vitro study on human ACL and MCL fibroblasts. J Orthop Res 23:949–957

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the Innovation and Attracting Talents Program for College and University (“111” Project) (B06023), NSF Projects (10672195, 30870607), CSTC2008BB5192, Sharing fund of Chongqing university’s large-scale equipment (2009063038) and by NIH AR45635 (USA).

Conflict of interest

  The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. “111” Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing, 400044, China

    Yanjun Zhang, Jiahuang Jiang, Jing Xie, Chunmin Xu, Chunli Wang, Lin Yin, Li Yang, Kevin Zhou & KL Paul Sung

  2. Department of Orthopaedics, University of California at San Diego, La Jolla, CA, USA

    Peter Chen & KL Paul Sung

  3. Departments of Bioengineering, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0412, USA

    KL Paul Sung

  4. Department of Orthopaedics, Chongqing University of Medical Sciences, Chongqing, 400000, China

    Wei Huang

  5. College of Bioengineering, Chongqing University, Chongqing, 400044, China

    KL Paul Sung

Authors
  1. Yanjun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiahuang Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chunmin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chunli Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lin Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Li Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kevin Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Peter Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. KL Paul Sung
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to KL Paul Sung.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 81 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, Y., Huang, W., Jiang, J. et al. Influence of TNF-α and biomechanical stress on matrix metalloproteinases and lysyl oxidases expressions in human knee synovial fibroblasts. Knee Surg Sports Traumatol Arthrosc 22, 1997–2006 (2014). https://doi.org/10.1007/s00167-013-2425-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00167-013-2425-z

Keywords

Search

Navigation