Combination of collagen scaffold with doxycycline for the treatment of cartilage and subchondral bone defects
Main Article Content
Abstract
The repair of cartilage and bone tissue post arthritis or injury in the knee joint is a challenge to the orthopedics. Both doxycycline and collagen scaffolds had been shown with positive influences on the repair of the tissue. Doxycycline inhibits catabolism related enzymes. Collagens provide tissue repair materials. In this study, the influence of doxycycline and jellyfish collagen (JFC) scaffold to the cells in vitro and tissue repair in vivo was studied. Doxycycline was found with a broad inhibition of the matrix metallopeptidases. It also had an enhancement to the progenitor chondrocytes but suppressed the maturation of chondrocytes. JFC (major type II collagen) was seen had improved both type I and type II collagen production during chondrogenesis of mesenchymal stem cells in vitro. Both doxycycline and JFC enhanced the bone formation and had synergistic effects in a late-stage during the bone repair process. However, the cartilage repair was found with no significant influence after the implantations. Overall, the control of metabolism by doxycycline and providing stimulation to collagen production by the implantation of JFC only contribute to bone growth but had little influence on cartilage repair. This indicates the growth of cartilage tissue needs more delicate regulation. The subchondral bone repair, even with some chondrocytes and proteoglycan deposition in the extracellular matrix could not convert to a repair with mature hyaluronic cartilage tissue.
Keywords:
Doxycycline, Jellyfish collagen, type II collagen, matrix metallopeptidases, bone defect, ; cartilage defect
Article Details
How to Cite
LIANG, Haixiang et al.
Combination of collagen scaffold with doxycycline for the treatment of cartilage and subchondral bone defects.
Medical Research Archives, [S.l.], v. 9, n. 1, jan. 2021.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2253>. Date accessed: 13 nov. 2024.
doi: https://doi.org/10.18103/mra.v9i1.2253.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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7. Bermueller C, Schwarz S, Elsaesser AF, et al. Marine collagen scaffolds for nasal cartilage repair: prevention of nasal septal perforations in a new orthotopic rat model using tissue engineering techniques. Tissue Eng Part A. 2013;19(19-20):2201–2214. doi:10.1089/ten.TEA.2012.0650
8. Hadzik J, Kubasiewicz-Ross P, Kunert-Keil C, et al. A silver carp skin derived collagen in bone defect treatment-A histological study in a rat model. Ann Anat. 2016;208:123–128. doi:10.1016/j.aanat.2016.07.009
9. Addad S, Exposito J-Y, Faye C, Ricard-Blum S, Lethias C. Isolation, characterization and biological evaluation of jellyfish collagen for use in biomedical applications. Mar Drugs. 2011;9(6):967–983. doi:10.3390/md9060967
10. Sewing J, Klinger M, Notbohm H. Jellyfish collagen matrices conserve the chondrogenic phenotype in two- and three-dimensional collagen matrices. J Tissue Eng Regen Med. 2017;11(3):916–925. doi:10.1002/term.1993
11. Shah SS, Liang H, Pandit S, et al. Optimization of Degradation Profile for New Scaffold in Cartilage Repair. Cartilage. 2018;9(4):438–449. doi:10.1177/1947603517700954
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15. Yu LP, Smith GN, Brandt KD, Myers SL, O'Connor BL, Brandt DA. Reduction of the severity of canine osteoarthritis by prophylactic treatment with oral doxycycline. Arthritis Rheum. 1992;35(10):1150–1159. doi:10.1002/art.1780351007
16. Rabillard M, Danger R, Doran IP, Niebauer GW, Brouard S, Gauthier O. Matrix metalloproteinase activity in stifle synovial fluid of cranial cruciate ligament deficient dogs and effect of postoperative doxycycline treatment. Vet J. 2012;193(1):271–273. doi:10.1016/j.tvjl.2011.10.028
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18. Ghasemi S, Sardari K, Mirshokraei P, Hassanpour H. In vitro study of matrix metalloproteinases 1, 2, 9, 13 and serum amyloid A mRNAs expression in equine fibroblast-like synoviocytes treated with doxycycline. Can J Vet Res. 2018;82(2):82–88.
19. Fortier LA, Motta T, Greenwald RA, Divers TJ, Mayr KG. Synoviocytes are more sensitive than cartilage to the effects of minocycline and doxycycline on IL-1alpha and MMP-13-induced catabolic gene responses. J Orthop Res. 2010;28(4):522–528. doi:10.1002/jor.21006
20. Jabłońska-Trypuć A, Matejczyk M, Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme Inhib Med Chem. 2016;31(sup1):177–183. doi:10.3109/14756366.2016.1161620
21. TeKoppele JM, Beekman B, Verzijl N, Koopman JL, DeGroot J, Bank RA. Doxycycline inhibits collagen synthesis by differentiated articular chondrocytes. Adv Dent Res. 1998;12(2):63–67. doi:10.1177/08959374980120012201
22. Davies SR, Cole AA, Schmid TM. Doxycycline inhibits type X collagen synthesis in avian hypertrophic chondrocyte cultures. J Biol Chem. 1996;271(42):25966–25970. doi:10.1074/jbc.271.42.25966
23. Ng LJ, Wheatley S, Muscat GE, et al. SOX9 binds DNA, activates transcription, and coexpresses with type II collagen during chondrogenesis in the mouse. Dev Biol. 1997;183(1):108–121. doi:10.1006/dbio.1996.8487
24. Bell DM, Leung KK, Wheatley SC, et al. SOX9 directly regulates the type-II collagen gene. Nat Genet. 1997;16(2):174–178. doi:10.1038/ng0697-174
25. Leung VYL, Gao B, Leung KKH, et al. SOX9 governs differentiation stage-specific gene expression in growth plate chondrocytes via direct concomitant transactivation and repression. PLoS Genet. 2011;7(11):e1002356. doi:10.1371/journal.pgen.1002356
26. Chen H, Ghori-Javed FY, Rashid H, et al. Runx2 regulates endochondral ossification through control of chondrocyte proliferation and differentiation. J Bone Miner Res. 2014;29(12):2653–2665. doi:10.1002/jbmr.2287
27. Orimo H. The mechanism of mineralization and the role of alkaline phosphatase in health and disease. J Nippon Med Sch. 2010;77(1):4–12. doi:10.1272/jnms.77.4
28. Komori T. Runx2, an inducer of osteoblast and chondrocyte differentiation. Histochem Cell Biol. 2018;149(4):313–323. doi:10.1007/s00418-018-1640-6
29. Park J-B. Effects of doxycycline, minocycline, and tetracycline on cell proliferation, differentiation, and protein expression in osteoprecursor cells. J Craniofac Surg. 2011;22(5):1839–1842. doi:10.1097/SCS.0b013e31822e8216
30. Gomes PS, Fernandes MH. Effect of therapeutic levels of doxycycline and minocycline in the proliferation and differentiation of human bone marrow osteoblastic cells. Arch Oral Biol. 2007;52(3):251–259. doi:10.1016/j.archoralbio.2006.10.005
31. Tchetina EV, Kobayashi M, Yasuda T, Meijers T, Pidoux I, Poole AR. Chondrocyte hypertrophy can be induced by a cryptic sequence of type II collagen and is accompanied by the induction of MMP-13 and collagenase activity: implications for development and arthritis. Matrix Biol. 2007;26(4):247–258. doi:10.1016/j.matbio.2007.01.006
32. Zhang S, Zhong Y, Li R, et al. Experimental chondrocyte hypertrophy is promoted by the activation of discoidin domain receptor 2. Mol Med Rep. 2014;10(3):1543–1548. doi:10.3892/mmr.2014.2340
33. Pustlauk W, Paul B, Brueggemeier S, Gelinsky M, Bernhardt A. Modulation of chondrogenic differentiation of human mesenchymal stem cells in jellyfish collagen scaffolds by cell density and culture medium. J Tissue Eng Regen Med. 2017;11(6):1710–1722. doi:10.1002/term.2065
34. Hoyer B, Bernhardt A, Lode A, et al. Jellyfish collagen scaffolds for cartilage tissue engineering. Acta Biomater. 2014;10(2):883–892. doi:10.1016/j.actbio.2013.10.022
35. Katagiri H, Mendes LF, Luyten FP. Definition of a Critical Size Osteochondral Knee Defect and its Negative Effect on the Surrounding Articular Cartilage in the Rat. Osteoarthr Cartil. 2017;25(9):1531–1540. doi:10.1016/j.joca.2017.05.006
36. Kalfas IH. Principles of bone healing. Neurosurg Focus. 2001;10(4):E1. doi:10.3171/foc.2001.10.4.2
37. Fowlkes JL, Nyman JS, Bunn RC, et al. Effects of long-term doxycycline on bone quality and strength in diabetic male DBA/2J mice. Bone Rep. 2015;1:16–19. doi:10.1016/j.bonr.2014.10.001
38. Alkan A, Erdem E, Günhan O, Karasu C. Histomorphometric evaluation of the effect of doxycycline on the healing of bone defects in experimental diabetes mellitus: a pilot study. J Oral Maxillofac Surg. 2002;60(8):898–904. doi:10.1053/joms.2002.33859
39. Shahabooei M, Razavi SM, Minaiyan M, et al. A histomorphometric study of the effect of doxycycline and erythromycin on bone formation in dental alveolar socket of rat. Adv Biomed Res. 2015;4:71. doi:10.4103/2277-9175.153895
40. Widdowson JP, Picton AJ, Vince V, Wright CJ, Mearns-Spragg A. In vivo comparison of jellyfish and bovine collagen sponges as prototype medical devices. J Biomed Mater Res Part B Appl Biomater. 2018;106(4):1524–1533. doi:10.1002/jbm.b.33959
41. Simkin PA. Consider the tidemark. J Rheumatol. 2012;39(5):890–892. doi:10.3899/jrheum.110942
42. Lyons TJ, McClure SF, Stoddart RW, McClure J. The normal human chondro-osseous junctional region: evidence for contact of uncalcified cartilage with subchondral bone and marrow spaces. BMC Musculoskelet Disord. 2006;7:52. doi:10.1186/1471-2474-7-52
43. Lyons TJ, Stoddart RW, McClure SF, McClure J. The tidemark of the chondro-osseous junction of the normal human knee joint. J Mol Histol. 2005;36(3):207–215. doi:10.1007/s10735-005-3283-x
2. Shlopov BV, Stuart JM, Gumanovskaya ML, Hasty KA. Regulation of cartilage collagenase by doxycycline. J Rheumatol. 2001;28(4):835–842.
3. Bowyer J, Heapy CG, Flannelly JK, Waterton JC, Maciewicz RA. Evaluation of a magnetic resonance biomarker of osteoarthritis disease progression: doxycycline slows tibial cartilage loss in the Dunkin Hartley guinea pig. Int J Exp Pathol. 2009;90(2):174–181. doi:10.1111/j.1365-2613.2008.00634.x
4. Gomes KdN, Alves APNN, Dutra PGP, Viana GSdB. Doxycycline induces bone repair and changes in Wnt signalling. Int J Oral Sci. 2017;9(3):158–166. doi:10.1038/ijos.2017.28
5. Muthukuru M, Sun J. Doxycycline counteracts bone morphogenic protein 2-induced osteogenic mediators. J Periodontol. 2013;84(5):656–665. doi:10.1902/jop.2012.120338
6. Aydin O, Korkusuz F, Korkusuz P, et al. In vitro and in vivo evaluation of doxycycline-chondroitin sulfate/PCLmicrospheres for intraarticular treatment of osteoarthritis. J Biomed Mater Res Part B Appl Biomater. 2015;103(6):1238–1248. doi:10.1002/jbm.b.33303
7. Bermueller C, Schwarz S, Elsaesser AF, et al. Marine collagen scaffolds for nasal cartilage repair: prevention of nasal septal perforations in a new orthotopic rat model using tissue engineering techniques. Tissue Eng Part A. 2013;19(19-20):2201–2214. doi:10.1089/ten.TEA.2012.0650
8. Hadzik J, Kubasiewicz-Ross P, Kunert-Keil C, et al. A silver carp skin derived collagen in bone defect treatment-A histological study in a rat model. Ann Anat. 2016;208:123–128. doi:10.1016/j.aanat.2016.07.009
9. Addad S, Exposito J-Y, Faye C, Ricard-Blum S, Lethias C. Isolation, characterization and biological evaluation of jellyfish collagen for use in biomedical applications. Mar Drugs. 2011;9(6):967–983. doi:10.3390/md9060967
10. Sewing J, Klinger M, Notbohm H. Jellyfish collagen matrices conserve the chondrogenic phenotype in two- and three-dimensional collagen matrices. J Tissue Eng Regen Med. 2017;11(3):916–925. doi:10.1002/term.1993
11. Shah SS, Liang H, Pandit S, et al. Optimization of Degradation Profile for New Scaffold in Cartilage Repair. Cartilage. 2018;9(4):438–449. doi:10.1177/1947603517700954
12. Burrage PS, Mix KS, Brinckerhoff CE. Matrix metalloproteinases: role in arthritis. Front Biosci. 2006;11:529–543. doi:10.2741/1817
13. Nguyen QT, Norelli JB, Graver A, et al. Therapeutic Effects of Doxycycline on the Quality of Repaired and Unrepaired Achilles Tendons. Am J Sports Med. 2017;45(12):2872–2881. doi:10.1177/0363546517716637
14. Zhang X, Deng X-H, Song Z, et al. Matrix Metalloproteinase Inhibition With Doxycycline Affects the Progression of Posttraumatic Osteoarthritis After Anterior Cruciate Ligament Rupture: Evaluation in a New Nonsurgical Murine ACL Rupture Model. Am J Sports Med. 2020;48(1):143–152. doi:10.1177/0363546519887158
15. Yu LP, Smith GN, Brandt KD, Myers SL, O'Connor BL, Brandt DA. Reduction of the severity of canine osteoarthritis by prophylactic treatment with oral doxycycline. Arthritis Rheum. 1992;35(10):1150–1159. doi:10.1002/art.1780351007
16. Rabillard M, Danger R, Doran IP, Niebauer GW, Brouard S, Gauthier O. Matrix metalloproteinase activity in stifle synovial fluid of cranial cruciate ligament deficient dogs and effect of postoperative doxycycline treatment. Vet J. 2012;193(1):271–273. doi:10.1016/j.tvjl.2011.10.028
17. Brandt KD, Mazzuca SA, Katz BP, et al. Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo-controlled, double-blind trial. Arthritis Rheum. 2005;52(7):2015–2025. doi:10.1002/art.21122
18. Ghasemi S, Sardari K, Mirshokraei P, Hassanpour H. In vitro study of matrix metalloproteinases 1, 2, 9, 13 and serum amyloid A mRNAs expression in equine fibroblast-like synoviocytes treated with doxycycline. Can J Vet Res. 2018;82(2):82–88.
19. Fortier LA, Motta T, Greenwald RA, Divers TJ, Mayr KG. Synoviocytes are more sensitive than cartilage to the effects of minocycline and doxycycline on IL-1alpha and MMP-13-induced catabolic gene responses. J Orthop Res. 2010;28(4):522–528. doi:10.1002/jor.21006
20. Jabłońska-Trypuć A, Matejczyk M, Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme Inhib Med Chem. 2016;31(sup1):177–183. doi:10.3109/14756366.2016.1161620
21. TeKoppele JM, Beekman B, Verzijl N, Koopman JL, DeGroot J, Bank RA. Doxycycline inhibits collagen synthesis by differentiated articular chondrocytes. Adv Dent Res. 1998;12(2):63–67. doi:10.1177/08959374980120012201
22. Davies SR, Cole AA, Schmid TM. Doxycycline inhibits type X collagen synthesis in avian hypertrophic chondrocyte cultures. J Biol Chem. 1996;271(42):25966–25970. doi:10.1074/jbc.271.42.25966
23. Ng LJ, Wheatley S, Muscat GE, et al. SOX9 binds DNA, activates transcription, and coexpresses with type II collagen during chondrogenesis in the mouse. Dev Biol. 1997;183(1):108–121. doi:10.1006/dbio.1996.8487
24. Bell DM, Leung KK, Wheatley SC, et al. SOX9 directly regulates the type-II collagen gene. Nat Genet. 1997;16(2):174–178. doi:10.1038/ng0697-174
25. Leung VYL, Gao B, Leung KKH, et al. SOX9 governs differentiation stage-specific gene expression in growth plate chondrocytes via direct concomitant transactivation and repression. PLoS Genet. 2011;7(11):e1002356. doi:10.1371/journal.pgen.1002356
26. Chen H, Ghori-Javed FY, Rashid H, et al. Runx2 regulates endochondral ossification through control of chondrocyte proliferation and differentiation. J Bone Miner Res. 2014;29(12):2653–2665. doi:10.1002/jbmr.2287
27. Orimo H. The mechanism of mineralization and the role of alkaline phosphatase in health and disease. J Nippon Med Sch. 2010;77(1):4–12. doi:10.1272/jnms.77.4
28. Komori T. Runx2, an inducer of osteoblast and chondrocyte differentiation. Histochem Cell Biol. 2018;149(4):313–323. doi:10.1007/s00418-018-1640-6
29. Park J-B. Effects of doxycycline, minocycline, and tetracycline on cell proliferation, differentiation, and protein expression in osteoprecursor cells. J Craniofac Surg. 2011;22(5):1839–1842. doi:10.1097/SCS.0b013e31822e8216
30. Gomes PS, Fernandes MH. Effect of therapeutic levels of doxycycline and minocycline in the proliferation and differentiation of human bone marrow osteoblastic cells. Arch Oral Biol. 2007;52(3):251–259. doi:10.1016/j.archoralbio.2006.10.005
31. Tchetina EV, Kobayashi M, Yasuda T, Meijers T, Pidoux I, Poole AR. Chondrocyte hypertrophy can be induced by a cryptic sequence of type II collagen and is accompanied by the induction of MMP-13 and collagenase activity: implications for development and arthritis. Matrix Biol. 2007;26(4):247–258. doi:10.1016/j.matbio.2007.01.006
32. Zhang S, Zhong Y, Li R, et al. Experimental chondrocyte hypertrophy is promoted by the activation of discoidin domain receptor 2. Mol Med Rep. 2014;10(3):1543–1548. doi:10.3892/mmr.2014.2340
33. Pustlauk W, Paul B, Brueggemeier S, Gelinsky M, Bernhardt A. Modulation of chondrogenic differentiation of human mesenchymal stem cells in jellyfish collagen scaffolds by cell density and culture medium. J Tissue Eng Regen Med. 2017;11(6):1710–1722. doi:10.1002/term.2065
34. Hoyer B, Bernhardt A, Lode A, et al. Jellyfish collagen scaffolds for cartilage tissue engineering. Acta Biomater. 2014;10(2):883–892. doi:10.1016/j.actbio.2013.10.022
35. Katagiri H, Mendes LF, Luyten FP. Definition of a Critical Size Osteochondral Knee Defect and its Negative Effect on the Surrounding Articular Cartilage in the Rat. Osteoarthr Cartil. 2017;25(9):1531–1540. doi:10.1016/j.joca.2017.05.006
36. Kalfas IH. Principles of bone healing. Neurosurg Focus. 2001;10(4):E1. doi:10.3171/foc.2001.10.4.2
37. Fowlkes JL, Nyman JS, Bunn RC, et al. Effects of long-term doxycycline on bone quality and strength in diabetic male DBA/2J mice. Bone Rep. 2015;1:16–19. doi:10.1016/j.bonr.2014.10.001
38. Alkan A, Erdem E, Günhan O, Karasu C. Histomorphometric evaluation of the effect of doxycycline on the healing of bone defects in experimental diabetes mellitus: a pilot study. J Oral Maxillofac Surg. 2002;60(8):898–904. doi:10.1053/joms.2002.33859
39. Shahabooei M, Razavi SM, Minaiyan M, et al. A histomorphometric study of the effect of doxycycline and erythromycin on bone formation in dental alveolar socket of rat. Adv Biomed Res. 2015;4:71. doi:10.4103/2277-9175.153895
40. Widdowson JP, Picton AJ, Vince V, Wright CJ, Mearns-Spragg A. In vivo comparison of jellyfish and bovine collagen sponges as prototype medical devices. J Biomed Mater Res Part B Appl Biomater. 2018;106(4):1524–1533. doi:10.1002/jbm.b.33959
41. Simkin PA. Consider the tidemark. J Rheumatol. 2012;39(5):890–892. doi:10.3899/jrheum.110942
42. Lyons TJ, McClure SF, Stoddart RW, McClure J. The normal human chondro-osseous junctional region: evidence for contact of uncalcified cartilage with subchondral bone and marrow spaces. BMC Musculoskelet Disord. 2006;7:52. doi:10.1186/1471-2474-7-52
43. Lyons TJ, Stoddart RW, McClure SF, McClure J. The tidemark of the chondro-osseous junction of the normal human knee joint. J Mol Histol. 2005;36(3):207–215. doi:10.1007/s10735-005-3283-x