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Effect of Low-Intensity Pulsed Ultrasound on MMP-13 and MAPKs Signaling Pathway in Rabbit Knee Osteoarthritis

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Abstract

We evaluated the effect of low-intensity pulsed ultrasound (LIPUS) on MMP-13 and MAPKs expression in rabbit knee osteoarthritis (OA). For this purpose, 18 New Zealand white rabbits were randomly and equally divided into O + L, O – L, and SO groups. In O + L group, animals underwent right back leg ACLT operation and LIPUS radiation. In O − L group, animals underwent ACLT but no LIPUS treatment. In SO (control) group, animals underwent sham operation without LIPUS. After 6 weeks, we assessed the pathologic changes in the articular surface of femoral condyle and compared using Mankin scores. Also, expression of type-II collagen, MMP-13, ERK1/2, p38, and JNK was measured by Western blot. Compared with controls, Mankin scores were higher in O + L (P < 0.05)/O − L (P < 0.01) groups. Compared with O + L group, score was higher in O − L group (P < 0.05). Compared with controls, type-II collagen expression was less in O + L/O − L groups, with more significant decrease in O − L group (P < 0.05). Contrarily, expression of MMP-13, p-ERK1/2, and p-p38 was enhanced in O + L/O − L groups as compared with controls, with more significant increase in O − L group (P < 0.01). Compared with O + L group, expression was higher in O − L group (P < 0.05). We, therefore, concluded that LIPUS application promoted cartilage repair in OA through the downregulation of MMP-13, ERK1/2, and p38.

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References

  1. Pearle, A. D., Warren, R. F., & Rodeo, S. A. (2005). Basic science of articular cartilage and osteoarthritis. Clinical Sports Medicine, 24, 1–12.

    Article  Google Scholar 

  2. Lawrence, R. C., Helmick, C. G., Arnett, F. C., et al. (1998). Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis and Rheumatism, 41, 778–799.

    Article  CAS  PubMed  Google Scholar 

  3. Guccione, A. A., Felson, D. T., Anderson, J. J., et al. (1994). The effects of specific medical conditions on the functional limitations of elders in the Framingham Study. American Journal of Public Health, 84, 351–358.

    Article  CAS  PubMed  Google Scholar 

  4. Hunter, D. J. (2009). Imaging insights on the epidemiology and pathophysiology of osteoarthritis. Rheumatic Disease Clinics of North America, 35, 447–463.

    Article  PubMed  Google Scholar 

  5. Takaishi, H., Kimura, T., Dalal, S., Okada, Y., & D’Armiento, J. (2008). Joint diseases and matrix metalloproteinases: A role for MMP-13. Current Pharmaceutical Biotechnology, 9, 47–54.

    Article  CAS  PubMed  Google Scholar 

  6. Reboul, P., Pelletier, J. P., Tardif, G., Cloutier, J. M., & Martel-Pelletier, J. (1996). The new collagenase, collagenase-3, is expressed and synthesized by human chondrocytes but not by synoviocytes. A role in osteoarthritis. The Journal of Clinical Investigation, 97, 2011–2019.

    Article  CAS  PubMed  Google Scholar 

  7. Blain, E. J. (2007). Mechanical regulation of matrix metalloproteinases. Frontiers in Bioscience, 12, 507–527.

    Article  CAS  PubMed  Google Scholar 

  8. Mitchell, P. G., Magna, H. A., Reeves, L. M., et al. (1996). Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. The Journal of Clinical Investigation, 97, 761–768.

    Article  CAS  PubMed  Google Scholar 

  9. Knäuper, V., Will, H., López-Otin, C., et al. (1996). Cellular mechanisms for human procollagenase-3 (MMP-13) activation. Evidence that MT1-MMP (MMP-14) and gelatinase a (MMP-2) are able to generate active enzyme. The Journal of Biological Chemistry, 271, 17124–17131.

    Article  PubMed  Google Scholar 

  10. Billinghurst, R. C., Dahlberg, L., Ionescu, M., et al. (1997). Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage. The Journal of Clinical Investigation, 99, 1534–1545.

    Article  CAS  PubMed  Google Scholar 

  11. Mengshol, J. A., Vincenti, M. P., Coon, C. I., Barchowsky, A., & Brinckerhoff, C. E. (2000). Interleukin-1 induction of collagenase 3 (matrix metalloproteinase 13) gene expression in chondrocytes requires p38, c-Jun N-terminal kinase, and nuclear factor kappaB: Differential regulation of collagenase 1 and collagenase 3. Arthritis and Rheumatism, 43, 801–811.

    Article  CAS  PubMed  Google Scholar 

  12. Ho, L. J., Lin, L. C., Hung, L. F., et al. (2005). Retinoic acid blocks pro-inflammatory cytokine-induced matrix metalloproteinase production by down-regulating JNK-AP-1 signaling in human chondrocytes. Biochemical Pharmacology, 70, 200–208.

    Article  CAS  PubMed  Google Scholar 

  13. Rossa, C., Jr., Liu, M., Patil, C., & Kirkwood, K. L. (2005). MKK3/6-p38 MAPK negatively regulates murine MMP-13 gene expression induced by IL-1beta and TNF-alpha in immortalized periodontal ligament fibroblasts. Matrix Biology, 24, 478–488.

    Article  CAS  PubMed  Google Scholar 

  14. Yang, F. J., Yu, Y. L., Xia, J., Ren, Z. W., & Qiao, J. (2007). Expression of MMP-1, MMP-13 and ERK 1/2 in joint cartilage of an osteoarthritis rabbit model. Geriatric Health Care, 13, 338–342.

    CAS  Google Scholar 

  15. Malizos, K. N., Hantes, M. E., Protopappas, V., & Papachristos, A. (2006). Low-intensity pulsed ultrasound for bone healing: An overview. Injury, 37, S56–S62.

    Article  PubMed  Google Scholar 

  16. Wiltink, A., Nijweide, P. J., Oosterbaan, W. A., Hekkenberg, R. T., & Helders, P. J. (1995). Effect of therapeutic ultrasound on endochondral ossification. Ultrasound in Medicine and Biology, 21, 121–127.

    Article  CAS  PubMed  Google Scholar 

  17. Cook, S. D., Salkeld, S. L., Popich-Patron, L. S., Ryaby, J. P., Jones, D. G., & Barrack, R. L. (2001). Improved cartilage repair after treatment with low-intensity pulsed ultrasound. Clinical Orthopaedics and Related Research, 391S, S231–S243.

    Article  Google Scholar 

  18. Cook, S. D., Salkeld, S. L., Patron, L. P., Doughty, E. S., & Jones, D. G. (2008). The effect of low-intensity pulsed ultrasound on autologous osteochondral plugs in a Canine model. The American Journal of Sports Medicine, 36, 1733–1741.

    Article  PubMed  Google Scholar 

  19. Iwashina, T., Mochida, J., Miyazaki, T., et al. (2006). Low-intensity pulsed ultrasound stimulates cell proliferation and proteoglycan production in rabbit intervertebral disc cells cultured in alginate. Biomaterials, 27, 354–361.

    Article  CAS  PubMed  Google Scholar 

  20. Korstjens, C. M., van der Rijt, R. H., Albers, G. H., Semeins, C. M., & Klein-Nulend, J. (2008). Low-intensity pulsed ultrasound affects human articular chondrocytes in vitro. Medical and Biological Engineering and Computing, 46, 1263–1270.

    Article  CAS  PubMed  Google Scholar 

  21. Choi, B. H., Choi, M. H., Kwak, M. G., Min, B. H., Woo, Z. H., & Park, S. R. (2007). Mechanotransduction pathways of low-intensity ultrasound in C-28/I2 human chondrocyte cell line. Proceedings of the Institution of Mechanical Engineers (Part H), Journal of Engineering in Medicine, 221, 527–535.

    Article  CAS  Google Scholar 

  22. Takeuchi, R., Ryo, A., Komitsu, N., et al. (2008). Low-intensity pulsed ultrasound activates the phosphatidylinositol 3 kinase/Akt pathway and stimulates the growth of chondrocytes in three-dimensional cultures: A basic science study. Arthritis Research & Therapy, 10, R77.

    Article  Google Scholar 

  23. Gurkan, I., Ranganathan, A., Yang, X., et al. (2010). Modification of osteoarthritis in the guinea pig with pulsed low-intensity ultrasound treatment. Osteoarthritis Cartilage, 18, 724–733.

    Article  CAS  PubMed  Google Scholar 

  24. Jean, Y. H., Wen, Z. H., Chang, Y. C., et al. (2008). Increase in excitatory amino acid concentration and transporters expression in osteoarthritic knees of anterior cruciate ligament transected rabbits. Osteoarthritis Cartilage, 16, 1442–1449.

    Article  PubMed  Google Scholar 

  25. Bendele, A. M., & Hulman, J. F. (1988). Spontaneous cartilage degeneration in guinea pigs. Arthritis and Rheumatism, 31, 561–565.

    Article  CAS  PubMed  Google Scholar 

  26. Bendele, A. M., White, S. L., & Hulman, J. F. (1989). Osteoarthritis in guinea pigs: Histopathologic and scanning electron microscopic features. Laboratory Animal Science, 39, 115–1211.

    CAS  PubMed  Google Scholar 

  27. Salminen, H., Perälä, M., Lorenzo, P., et al. (2000). Up-regulation of cartilage oligomeric matrix protein at the onset of articular cartilage degeneration in a transgenic mouse model of osteoarthritis. Arthritis and Rheumatism, 43, 1742–1748.

    Article  CAS  PubMed  Google Scholar 

  28. Säämänen, A. K., Salminen, H. J., Dean, P. B., De Crombrugghe, B., Vuorio, E. I., & Metsäranta, M. P. (2000). Osteoarthritis-like lesions in transgenic mice harboring a small deletion mutation in the type II collagen gene. Osteoarthritis Cartilage, 8, 248–257.

    Article  PubMed  Google Scholar 

  29. Huang, M. H., Ding, H. J., Chai, C. Y., Huang, Y. F., & Yang, R. C. (1997). Effects of sonication on articular cartilage in experimental osteoarthritis. The Journal of Rheumatology, 24, 1978–1984.

    CAS  PubMed  Google Scholar 

  30. Lindhorst, E., Vail, T. P., Guilak, F., et al. (2000). Longitudinal characterization of synovial fluid biomarkers in the canine meniscectomy model of osteoarthritis. Journal of Orthopedic Research, 18, 269–280.

    Article  CAS  Google Scholar 

  31. Marshall, K. W., & Chan, A. D. (1996). Arthroscopic anterior cruciate ligament transection induces canine osteoarthritis. Journal of Rheumatology, 23, 338–343.

    CAS  PubMed  Google Scholar 

  32. Visco, D. M., Hill, M. A., Widmer, W. R., Johnstone, B., & Myers, S. L. (1996). Experimental osteoarthritis in dogs: a comparison of the Pond-Nuki and medial arthrotomy methods. Osteoarthritis Cartilage, 4, 9–22.

    Article  CAS  PubMed  Google Scholar 

  33. Colombo, C., Butler, M., O’Byrne, E., et al. (1983). A new model of osteoarthritis in rabbits. I. Development of knee joint pathology following lateral meniscectomy and section of the fibular collateral and sesamoid ligaments. Arthritis and Rheumatism, 26, 875–886.

    Article  CAS  PubMed  Google Scholar 

  34. Kapadia, R. D., Stoup, G. B., Badger, A. M., et al. (1998). Applications of micro-CT MR microscopy to study pre-clinical models of osteoporosis and osteoarthritis. Technology & Health Care, 6, 361–372.

    CAS  Google Scholar 

  35. Sah, R. L., Yang, A. S., Chen, A. C., et al. (1997). Physical properties of rabbit articular cartilage after transection of the anterior cruciate ligament. Journal of Orthopedic Research, 15, 197–203.

    Article  CAS  Google Scholar 

  36. Boulocher, C., Duclos, M. E., Arnault, F., et al. (2008). Knee joint ultrasonography of the ACLT rabbit experimental model of osteoarthritis: Relevance and effectiveness in detecting meniscal lesions. Osteoarthritis and Cartilage, 16, 470–479.

    Article  CAS  PubMed  Google Scholar 

  37. Batiste, D. L., Kirkley, A., Laverty, S., Thain, L. M., Spouge, A. R., & Holdsworth, D. W. (2004). Ex vivo characterization of articular cartilage and bone lesions in a rabbit ACL transection model of osteoarthritis using MRI and micro-CT. Osteoarthritis and Cartilage, 12, 986–996.

    Article  PubMed  Google Scholar 

  38. Stoop, R., Buma, P., van der Kraan, P. M., et al. (2000). Differences in type II collagen degradation between peripheral and central cartilage of rat stifle joints after cranial cruciate ligament transection. Arthritis and Rheumatism, 43, 2121–2131.

    Article  CAS  PubMed  Google Scholar 

  39. Hollander, A. P., Heathfield, T. F., Webber, C., et al. (1994). Increased damage to type II collagen in osteoarthritic cartilage detected by a new immunoassay. The Journal of Clinical Investigation, 93, 1722–1732.

    Article  CAS  PubMed  Google Scholar 

  40. Dahlberg, L., Billinghurst, R. C., Manner, P., et al. (2000). Selective enhancement of collagenase-mediated cleavage of resident type II collagen in cultured osteoarthritic cartilage and arrest with a synthetic inhibitor that spares collagenase 1 (matrix metalloproteinase 1). Arthritis and Rheumatism, 43, 673–682.

    Article  CAS  PubMed  Google Scholar 

  41. Bluteau, G., Gouttenoire, J., Conrozier, T., et al. (2002). Differential gene expression analysis in a rabbit model of osteoarthritis induced by anterior cruciate ligament (ACL) section. Biorheology, 39, 247–258.

    CAS  PubMed  Google Scholar 

  42. Blaney, D. E. N., Remst, D. F., Vitters, E. L., et al. (2009). Increase in ALK1/ALK5 ratio as a cause for elevated MMP-13 expression in osteoarthritis in humans and mice. The Journal of Immunology, 182, 7937–7945.

    Article  Google Scholar 

  43. Zhang, M., Zhou, Q., Liang, Q. Q., et al. (2009). IGF-1 regulation of type II collagen and MMP-13 expression in rat endplate chondrocytes via distinct signaling pathways. Osteoarthritis and Cartilage, 17, 100–106.

    Article  CAS  PubMed  Google Scholar 

  44. Ahmed, S., Wang, N., Hafeez, B. B., Cheruvu, V. K., & Haqqi, T. M. (2005). Punica granatum L. extract inhibits IL-1beta-induced expression of matrix metalloproteinases by inhibiting the activation of MAP kinases and NF-kappaB in human chondrocytes in vitro. Journal of Nutrition, 135, 2096–2102.

    CAS  PubMed  Google Scholar 

  45. Joos, H., Albrecht, W., Laufer, S., & Brenner, R. E. (2010). Differential effects of p38MAP kinase inhibitors on the expression of inflammation-associated genes in primary, interleukin-1beta-stimulated human chondrocytes. British Journal of Pharmacology, 160, 1252–1262.

    Article  CAS  PubMed  Google Scholar 

  46. Zhang, Z. J., Huckle, J., Francomano, C. A., & Spencer, R. G. (2003). The effects of pulsed low-intensity ultrasound on chondrocyte viability, proliferation, gene expression and matrix production. Ultrasound in Medicine and Biology, 29, 1645–1651.

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank Dr. Huang Wenbin and Mr. Wang Jinsong from Department of Pathology, Nanjing First Hospital affiliated to Nanjing Medical University for generous help with tissue production and scoring. We also thank: (1) National Key Program for Developing Basic Research (Grant # 2007CB936104); (2) National High Technology Research and Development Program of China (Grant # 2007AA021905); and (3) Science & Technology Support Project of Jiangsu Province (Grant # BE2010697) for financial support.

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Authors and Affiliations

  1. Department of Rehabilitation, Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing, 210006, China

    Xueping Li, Kai Cheng, Qiang Lin, Hongfei Zhang, Hengyuan An, Mingxia Gao & Anliang Chen

  2. Department of Rehabilitation, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

    Jianan Li

  3. Clinical Medical College, Yangzhou University, Yangzhou, 225001, China

    Daxin Wang

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  1. Xueping Li
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Li, X., Li, J., Cheng, K. et al. Effect of Low-Intensity Pulsed Ultrasound on MMP-13 and MAPKs Signaling Pathway in Rabbit Knee Osteoarthritis. Cell Biochem Biophys 61, 427–434 (2011). https://doi.org/10.1007/s12013-011-9206-4

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