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Anti-Osteoarthritic Effects of Cartilage-Derived Extracellular Matrix in a Rat Osteoarthritis Model

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Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

BACKGROUND:

The extracellular matrix (ECM) has many functions, such as segregating tissues, providing support, and regulating intercellular communication. Cartilage-derived ECM (CECM) can be prepared via consecutive processes of chemical decellularization and enzyme treatment. The purpose of this study was to improve and treat osteoarthritis (OA) using porcine knee articular CECM.

METHODS:

We assessed the rheological characteristics and pH of CECM solutions. Furthermore, we determined the effects of CECM on cell proliferation and cytotoxicity in the chondrocytes of New Zealand rabbits. The inhibitory effect of CECM on tumor necrosis factor (TNF)-α-induced cellular apoptosis was assessed using New Zealand rabbit chondrocytes and human synoviocytes. Finally, we examined the in vivo effects of CECM on inflammation control and cartilage degradation in an experimental OA-induced rat model. The rat model of OA was established by injecting monosodium iodoacetate into the intra-articular knee joint. The rats were then injected with CECM solution. Inflammation control and cartilage degradation were assessed by measuring the serum levels of proinflammatory cytokines and C-telopeptide of type II collagen and performing a histomorphological analysis.

RESULTS:

CECM was found to be biocompatible and non-immunogenic, and could improve cell proliferation without inducing a toxic reaction. CECM significantly reduced cellular apoptosis due to TNF-α, significantly improved the survival of cells in inflammatory environments, and exerted anti-inflammatory effects.

CONCLUSION:

Our findings suggest that CECM is an appropriate injectable material that mediates OA-induced inflammation.

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References

  1. Hunter DJ, Guermazi A, Roemer F, Zhang Y, Neogi T. Structural correlates of pain in joints with osteoarthritis. Osteoarthritis Cartilage. 2013;21:1170–8.

    Article  CAS  Google Scholar 

  2. Chapple CM, Nicholson H, Baxter GD, Abbott JH. Patient characteristics that predict progression of knee osteoarthritis: a systematic review of prognostic studies. Arthritis Care Res (Hoboken). 2011;63:1115–25.

    Article  Google Scholar 

  3. Laasila K, Laasonen L, Leirisalo-Repo M. Antibiotic treatment and long term prognosis of reactive arthritis. Ann Rheum Dis. 2003;62:655–8.

    Article  CAS  Google Scholar 

  4. Pelletier JP, Martel-Pelletier J, Abramson SB. Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. Arthritis Rheum. 2001;44:1237–47.

    Article  CAS  Google Scholar 

  5. Dieppe PA, Lohmander LS. Pathogenesis and management of pain in osteoarthritis. Lancet. 2005;365:965–73.

    Article  CAS  Google Scholar 

  6. Bhatia D, Bejarano T, Novo M. Current interventions in the management of knee osteoarthritis. J Pharm Bioallied Sci. 2013;5:30–8.

    Article  Google Scholar 

  7. Billesberger LM, Fisher KM, Qadri YJ, Boortz-Marx RL. Procedural treatments for knee osteoarthritis: a review of current injectable therapies. Pain Res Manag. 2020;2020:3873098.

    Article  Google Scholar 

  8. Jacobs HN, Rathod S, Wolf MT, Elisseeff JH. Intra-articular injection of urinary bladder matrix reduces osteoarthritis development. AAPS J. 2017;19:141–9.

    Article  Google Scholar 

  9. Li Y, Cao J, Han S, Liang Y, Zhang T, Zhao H, et al. ECM based injectable thermo-sensitive hydrogel on the recovery of injured cartilage induced by osteoarthritis. Artif Cells Nanomed Biotechnol. 2018;46:152–60.

    Article  Google Scholar 

  10. Proffen BL, Sieker JT, Murray MM, Akelman MR, Chin KE, Perrone GS, et al. Extracellular matrix-blood composite injection reduces post-traumatic osteoarthritis after anterior cruciate ligament injury in the rat. J Orthop Res. 2016;34:995–1003.

    Article  CAS  Google Scholar 

  11. Gilbert TW, Sellaro TL, Badylak SF. Decellularization of tissues and organs. Biomaterials. 2006;27:3675–83.

    CAS  Google Scholar 

  12. Crapo PM, Gilbert TW, Badylak SF. An overview of tissue and whole organ decellularization processes. Biomaterials. 2011;32:3233–43.

    Article  CAS  Google Scholar 

  13. Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran pathologic basis of disease. 9th edition. Professional edition e-book. Amsterdam: Elsevier health sciences; 2014.

    Google Scholar 

  14. Lo CM, Wang HB, Dembo M, Wang Y. Cell movement is guided by the rigidity of the substrate. Biophys J. 2000;79:144–52.

    Article  CAS  Google Scholar 

  15. Hadjipanayi E, Mudera V, Brown RA. Close dependence of fibroblast proliferation on collagen scaffold matrix stiffness. J Tissue Eng Regen Med. 2009;3:77–84.

    Article  CAS  Google Scholar 

  16. Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell. 2006;126:677–89.

    Article  CAS  Google Scholar 

  17. Wang HB, Dembo M, Wang YL. Substrate flexibility regulates growth and apoptosis of normal but not transformed cells. Am J Physiol Cell Physiol. 2000;279:C1345–50.

    Article  CAS  Google Scholar 

  18. Beachley VZ, Wolf MT, Sadtler K, Manda SS, Jacobs H, et al. Tissue matrix arrays for high-throughput screening and systems analysis of cell function. Nat Methods. 2015;12:1197–204.

    Article  CAS  Google Scholar 

  19. Kim HJ, Lee S, Yun HW, Yin XY, Kim SH, Choi BH, et al. In vivo degradation profile of porcine cartilage-derived extracellular matrix powder scaffolds using a non-invasive fluorescence imaging method. J Biomater Sci Polym Ed. 2016;27:177–90.

    Article  CAS  Google Scholar 

  20. Jhun J, Lee SH, Na HS, Seo HB, Kim EK, Moon SJ, et al. The chicken combs extract alleviates pain and cartilage degradation in rat model osteoarthritis. Tissue Eng Regen Med. 2015;12:352–61.

    Article  Google Scholar 

  21. Imamura M, Ezquerro F, Marcon Alfieri F, Vilas Boas L, Tozetto-Mendoza TR, Chen J, et al. Serum levels of proinflammatory cytokines in painful knee osteoarthritis and sensitization. Int J Inflamm. 2015;2015:1–8.

    Article  Google Scholar 

  22. Li TZ, Jin CZ, Choi BH, Kim MS, Kim YJ, Park SR, et al. Using cartilage extracellular matrix (CECM) membrane to enhance the reparability of the bone marrow stimulation technique for articular cartilage defect in canine model. Adv Func Mater. 2012;22:4292–300.

    Article  CAS  Google Scholar 

  23. Aigner T, Kim HA. Apoptosis and cellular vitality: issues in osteoarthritic cartilage degeneration. Arthritis Rheum. 2002;46:1986–96.

    Article  CAS  Google Scholar 

  24. Grogan SP, Chen X, Sovani S, Taniguchi N, Colwell CW Jr, Lotz MK, et al. Influence of cartilage extracellular matrix molecules on cell phenotype and neocartilage formation. Tissue Eng Part A. 2014;20:264–74.

    Article  CAS  Google Scholar 

  25. Tian G, Jiang S, Li J, Wei F, Li X, Ding Y, et al. Cell-free decellularized cartilage extracellular matrix scaffolds combined with interleukin 4 promote osteochondral repair through immunomodulatory macrophages: in vitro and in vivo preclinical study. Acta Biomater. 2021;127:131–45.

    Article  CAS  Google Scholar 

  26. Choi BH, Choi KH, Lee HS, Song BR, Park SR, Yang JW, et al. Inhibition of blood vessel formation by a chondrocyte-derived extracellular matrix. Biomaterials. 2014;35:5711–20.

    Article  CAS  Google Scholar 

  27. Kwon JS, Yoon SM, Shim SW, Park JH, Min KJ, Oh HJ, et al. Injectable extracellular matrix hydrogel developed using porcine articular cartilage. Int J Pharm. 2013;454:183–91.

    Article  CAS  Google Scholar 

  28. De Lange-Brokaar BJ, Ioan-Facsinay A, Van Osch GJ, Zuurmond A-M, Schoones J, Toes RE, et al. Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review. Osteoarthritis Cartilage. 2012;20:1484–99.

    Article  Google Scholar 

  29. Revell PA, Mayston V, Lalor P, Mapp P. The synovial membrane in osteoarthritis: a histological study including the characterisation of the cellular infiltrate present in inflammatory osteoarthritis using monoclonal antibodies. Ann Rheum Dis. 1988;47:300–7.

    Article  CAS  Google Scholar 

  30. Benito MJ, Veale DJ, FitzGerald O, van den Berg WB, Bresnihan B. Synovial tissue inflammation in early and late osteoarthritis. Ann Rheum Dis. 2005;64:1263–7.

    Article  CAS  Google Scholar 

  31. Bhuanantanondh P, Grecov D, Kwok E. Rheological study of viscosupplements and synovial fluid in patients with osteoarthritis. CMBES Proc. 2010;33:522.

  32. Park DY, Yun HW, Lim S, Truong MD, Yin XY, Park J, et al. Cross-linked cartilage acellular matrix film decreases postsurgical peritendinous adhesions. Artif Organs. 2020;44:E136–49.

    Article  CAS  Google Scholar 

  33. Nicholls M, Manjoo A, Shaw P, Niazi F, Rosen J. Rheological properties of commercially available hyaluronic acid products in the United States for the treatment of osteoarthritis knee pain. Clin Med Insights Arthritis Musculoskelet Disord. 2018;11:1179544117751622.

    Article  Google Scholar 

  34. Lynn AK, Yannas IV, Bonfield W. Antigenicity and immunogenicity of collagen. J Biomed Mater Res Part B: Appl Biomater Off J Soc Biomater Japan Soc Biomater Aust Soc Biomater Korean Soc Biomater. 2004;71:343–54.

    Article  CAS  Google Scholar 

  35. Kim HY, Kim WU, Cho ML, Lee SK, Youn J, Kim SI, et al. Enhanced T cell proliferative response to type II collagen and synthetic peptide CII (255–274) in patients with rheumatoid arthritis. Arthritis Rheum. 1999;42:2085–93.

    Article  CAS  Google Scholar 

  36. Ria F, Penitente R, De Santis M, Nicolò C, Di Sante G, Orsini M, et al. Collagen-specific T-cell repertoire in blood and synovial fluid varies with disease activity in early rheumatoid arthritis. Arthritis Res Ther. 2008;10:R135.

    Article  Google Scholar 

  37. Myers LK, Tang B, Rosioniec EF, Stuart JM, Kang AH. PART III Autoimmunity an altered peptide ligand of type ii collagen suppresses autoimmune arthritis. Crit RevTM Immunol. 2007;27:345–56.

    Article  CAS  Google Scholar 

  38. Cremer MA, Xiu JY, Myers LK, Brand DD, Rosloniec EF, Kang AH. T cell immunity to type II collagen in the biobreeding rat: The identification and characterization of RT1u-restricted T cell epitopes on α1 (II). J Immunol. 2004;173:1795–801.

    Article  CAS  Google Scholar 

  39. Im G-I. Perspective on intra-articular injection cell therapy for osteoarthritis treatment. Tissue Eng Regen Med. 2019;16:357–63.

    Article  CAS  Google Scholar 

  40. Lee SW, Lee HJ, Chung WT, Choi SM, Rhyu SH, Kim DK, et al. TRAIL induces apoptosis of chondrocytes and influences the pathogenesis of experimentally induced rat osteoarthritis. Arthritis Rheum. 2004;50:534–42.

    Article  CAS  Google Scholar 

  41. Lee SW, Song YS, Lee SY, Yoon YG, Lee SH, Park BS, et al. Downregulation of protein kinase CK2 activity facilitates tumor necrosis factor-α-mediated chondrocyte death through apoptosis and autophagy. PLoS One. 2011;6:e19163.

    Article  CAS  Google Scholar 

  42. Coustry F, Posey KL, Liu P, Alcorn JL, Hecht JT. D469del-COMP retention in chondrocytes stimulates caspase-independent necroptosis. Am J Pathol. 2012;180:738–48.

    Article  CAS  Google Scholar 

  43. Akkiraju H, Nohe A. Role of chondrocytes in cartilage formation, progression of osteoarthritis and cartilage regeneration. J dev biol. 2015;3:177–92.

    Article  Google Scholar 

  44. Toshihiko I, Mitsumori S, Hiroko K, Haruko Y, Kayoko NI. Morphology and functional roles of synoviocytes in the joint. Arch Histol Cytol. 2000;63:17–31.

    Article  Google Scholar 

  45. Lee SG, Lee EJ, Park WD, Kim JB, Kim EO, Choi SW. Anti-inflammatory and anti-osteoarthritis effects of fermented Achyranthes japonica Nakai. J Ethnopharmacol. 2012;142:634–41.

    Article  Google Scholar 

  46. Mobasheri A. Intersection of inflammation and herbal medicine in the treatment of osteoarthritis. Curr Rheumatol Rep. 2012;14:604–16.

    Article  Google Scholar 

  47. Ferrero-Miliani L, Nielsen OH, Andersen PS, Girardin S. Chronic inflammation: importance of NOD2 and NALP3 in interleukin-1β generation. Clin Exp Immunol. 2007;147:227–35.

    Article  CAS  Google Scholar 

  48. Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol. 2011;7:33–42.

    Article  CAS  Google Scholar 

  49. Jeong JH, Moon SJ, Jhun JY, Yang EJ, Cho ML, Min JK. Eupatilin exerts antinociceptive and chondroprotective properties in a rat model of osteoarthritis by downregulating oxidative damage and catabolic activity in chondrocytes. PLoS One. 2015;10:e0130882.

    Article  Google Scholar 

  50. Khodir SA, Al-Gholam MA, Salem HR. L-Carnitine potentiates the anti-inflammatory and antinociceptive effects of diclofenac sodium in an experimentally-induced knee osteoarthritis rat model. Iran J Basic Med Sci. 2020;23:1035-44.

    Google Scholar 

  51. Mobasheri A. Osteoarthritis year 2012 in review: biomarkers. Osteoarthritis Cartilage. 2012;20:1451–64.

    Article  CAS  Google Scholar 

  52. Felson DT. Developments in the clinical understanding of osteoarthritis. Arthritis Res Ther. 2009;11:203.

    Article  Google Scholar 

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Acknowledgements

Everyone who contributed significantly to the work has been listed. This research was supported by the National Research Foundation Grant (NRF- 2019M3E5D1A02070861.)

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Correspondence to Sang-Hyug Park.

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All animal studies were approved by the Institutional Review Board at the Pukyong National University (PKNUIACUC-2020–03).

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Lee, SH., Jo, SH., Kim, SH. et al. Anti-Osteoarthritic Effects of Cartilage-Derived Extracellular Matrix in a Rat Osteoarthritis Model. Tissue Eng Regen Med 20, 83–92 (2023). https://doi.org/10.1007/s13770-022-00508-7

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