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The essential anti-angiogenic strategies in cartilage engineering and osteoarthritic cartilage repair

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Abstract

In the cartilage matrix, complex interactions occur between angiogenic and anti-angiogenic components, growth factors, and environmental stressors to maintain a proper cartilage phenotype that allows for effective load bearing and force distribution. However, as seen in both degenerative disease and tissue engineering, cartilage can lose its vascular resistance. This vascularization then leads to matrix breakdown, chondrocyte apoptosis, and ossification. Research has shown that articular cartilage inflammation leads to compromised joint function and decreased clinical potential for regeneration. Unfortunately, few articles comprehensively summarize what we have learned from previous investigations. In this review, we summarize our current understanding of the factors that stabilize chondrocytes to prevent terminal differentiation and applications of these factors to rescue the cartilage phenotype during cartilage engineering and osteoarthritis treatment. Inhibiting vascularization will allow for enhanced phenotypic stability so that we are able to develop more stable implants for cartilage repair and regeneration.

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References

  1. Kozhemyakina E, Lassar AB, Zelzer E (2015) A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation. Development 142(5):817–831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ulrich-Vinther M, Maloney MD, Schwarz EM, Rosier R, O’Keefe RJ (2003) Articular cartilage biology. J Am Acad Orthop Surg 11:421–430

    Article  PubMed  Google Scholar 

  3. Zhang Y, Chen S, Pei M (2016) Biomechanical signals guiding stem cell cartilage engineering: from molecular adaption to tissue functionality. Eur Cells Mater 31:59–78

    Article  CAS  Google Scholar 

  4. Singh P, Marcu KB, Goldring MB, Otero M (2019) Phenotypic instability of chondrocytes in osteoarthritis: on a path to hypertrophy. Ann N Y Acad Sci 1442:17–34

    Article  CAS  PubMed  Google Scholar 

  5. Fenwick SA, Gregg PJ, Rooney P (1999) Osteoarthritic cartilage loses its ability to remain avascular. Osteoarthr Cartil 7:441–452

    Article  CAS  Google Scholar 

  6. Walsh DA, Haywood L (2001) Angiogenesis: a therapeutic target in arthritis. Curr Opin Investig Drugs 2:1054–1063

    CAS  PubMed  Google Scholar 

  7. Suri S, Gill SE, Massena de Camin S, Wilson D, McWilliams DF, Walsh DA (2007) Neurovascular invasion at the osteochondral junction and in osteophytes in osteoarthritis. Ann Rheum Dis 66:1423–1428

    Article  PubMed  PubMed Central  Google Scholar 

  8. Goldring SR, Goldring MB (2016) Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage-bone crosstalk. Nat Rev Rheumatol 12:632–644

    Article  PubMed  Google Scholar 

  9. Tesche F, Miosge N (2005) New aspects of the pathogenesis of osteoarthritis: the role of fibroblast-like chondrocytes in late stages of the disease. Histol Histopathol 20:329–337

    CAS  PubMed  Google Scholar 

  10. Sun MM, Beier F (2014) Chondrocyte hypertrophy in skeletal development, growth, and disease. Birth Defects Res C Embryo Today 102:74–82

    Article  CAS  PubMed  Google Scholar 

  11. Minas T, Gomoll AH, Rosenberger R, Royce RO, Bryant T (2009) Increased failure rate of autologous chondrocyte implantation after previous treatment with marrow stimulation techniques. Am J Sports Med 37:902–908

    Article  PubMed  Google Scholar 

  12. Patra D, Sandell LJ (2012) Antiangiogenic and anticancer molecules in cartilage. Expert Rev Mol Med 14:e10

    Article  CAS  PubMed  Google Scholar 

  13. Rouwkema J, Khademhosseini A (2016) Vascularization and angiogenesis in tissue engineering: beyond creating static networks. Trends Biotechnol 34:733–745

    Article  CAS  PubMed  Google Scholar 

  14. Sun Y, Chen S, Zhang X, Pei M (2019) Significance of cellular cross-talk in stromal vascular fraction of adipose tissue in neovascularization. Arterioscler Thromb Vasc Biol 39:1034–1044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Provot S, Schipani E (2005) Molecular mechanisms of endochondral bone development. Biochem Biophys Res Commun 328:658–665

    Article  CAS  PubMed  Google Scholar 

  16. Cohen-Zinder M, Karasik D, Onn I (2013) Structural maintenance of chromosome complexes and bone development: the beginning of a wonderful relationship? BoneKEy Rep 2:388

    Article  PubMed  Google Scholar 

  17. Goldring MB, Otero M, Plumb DA, Dragomir C, Favero M, El Hachem K, Hashimoto K, Roach HI, Olivotto E, Borzi RM, Marcu KB (2011) Roles of inflammatory and anabolic cytokines in cartilage metabolism: signals and multiple effectors converge upon MMP-13 regulation in osteoarthritis. Eur Cells Mater 21:2022–2120

    Google Scholar 

  18. Goldring MB, Otero M (2011) Inflammation in osteoarthritis. Curr Opin Rheumatol 23:471–478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Marcu KB, Otero M, Olivotto E, Borzi RM, Goldring MB (2010) NF-kappaB signaling: multiple angles to target OA. Curr Drug Targets 11:599–613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Houard X, Goldring MB, Berenbaum F (2013) Homeostatic mechanisms in articular cartilage and role of inflammation in osteoarthritis. Curr Rheumatol Rep 15:375

    Article  PubMed  PubMed Central  Google Scholar 

  21. Reuther MS, Briggs KK, Schumacher BL, Masuda K, Sah RL, Watson D (2012) In vivo oxygen tension in human septal cartilage increases with age. Laryngoscope 122:2407–2410

    Article  PubMed  PubMed Central  Google Scholar 

  22. Shukunami C, Oshima Y, Hiraki Y (2005) Chondromodulin-I and tenomodulin: a new class of tissue-specific angiogenesis inhibitors found in hypovascular connective tissues. Biochem Biophys Res Commun 333:299–307

    Article  CAS  PubMed  Google Scholar 

  23. Shibakawa A, Yudoh K, Masuko-Hongo K, Kato T, Nishioka K, Nakamura H (2005) The role of subchondral bone resorption pits in osteoarthritis: MMP production by cells derived from bone marrow. Osteoarthr Cartil 13:679–687

    Article  CAS  Google Scholar 

  24. Binette F, McQuaid DP, Haudenschild DR, Yaeger PC, McPherson JM, Tubo R (1998) Expression of a stable articular cartilage phenotype without evidence of hypertrophy by adult human articular chondrocytes in vitro. J Orthop Res 16:207–216

    Article  CAS  PubMed  Google Scholar 

  25. Ludin A, Sela JJ, Schroeder A, Samuni Y, Nitzan DW, Amir G (2013) Injection of vascular endothelial growth factor into knee joints induces osteoarthritis in mice. Osteoarthr Cartil 21:491–497

    Article  CAS  Google Scholar 

  26. Smith JO, Oreffo RO, Clarke NM, Roach HI (2003) Changes in the antiangiogenic properties of articular cartilage in osteoarthritis. J Orthop Sci 8:849–857

    Article  PubMed  Google Scholar 

  27. Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9:653–660

    Article  CAS  PubMed  Google Scholar 

  28. Street J, Bao M, de Guzman L, Bunting S, Peale FV Jr, Ferrara N, Steinmetz H, Hoeffel J, Cleland JL, Daugherty A, van Bruggen N, Redmond HP, Carano RA, Filvaroff EH (2002) Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci USA 99:9656–9661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Franses RE, McWilliams DF, Mapp PI, Walsh DA (2010) Osteochondral angiogenesis and increased protease inhibitor expression in OA. Osteoarthr Cartil 18:563–571

    Article  CAS  Google Scholar 

  30. Giatromanolaki A, Sivridis E, Athanassou N, Zois E, Thorpe PE, Brekken RA, Gatter KC, Harris AL, Koukourakis IM, Koukourakis MI (2001) The angiogenic pathway “vascular endothelial growth factor/flk-1(KDR)-receptor” in rheumatoid arthritis and osteoarthritis. J Pathol 194:101–108

    Article  CAS  PubMed  Google Scholar 

  31. Pufe T, Lemke A, Kurz B, Petersen W, Tillmann B, Grodzinsky AJ, Mentlein R (2004) Mechanical overload induces VEGF in cartilage discs via hypoxia-inducible factor. J Am Pathol 164:185–192

    Article  CAS  Google Scholar 

  32. Murata M, Yudoh K, Nakamura H, Kato T, Inoue K, Chiba J, Nishioka K, Masuko-Hongo K (2006) Distinct signaling pathways are involved in hypoxia- and IL-1-induced VEGF expression in human articular chondrocytes. J Orthop Res 24:1544–1554

    Article  CAS  PubMed  Google Scholar 

  33. Mould AW, Tonks ID, Cahill MM, Pettit AR, Thomas R, Hayward NK, Kay GF (2003) Vegfb gene knockout mice display reduced pathology and synovial angiogenesis in both antigen-induced and collagen-induced models of arthritis. Arthritis Rheum 48:2660–2669

    Article  CAS  PubMed  Google Scholar 

  34. Charlier E, Relic B, Deroyer C, Malaise O, Neuville S, Collee J, Malaise MG, De Seny D (2016) Insights on molecular mechanisms of chondrocytes death in osteoarthritis. Int J Mol Sci 17:2146

    Article  PubMed Central  Google Scholar 

  35. Takada K, Hirose J, Yamabe S, Uehara Y, Mizuta H (2013) Endoplasmic reticulum stress mediates nitric oxide-induced chondrocyte apoptosis. Biomed Rep 1:315–319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Murrell GA, Jang D, Williams RJ (1995) Nitric oxide activates metalloprotease enzymes in articular cartilage. Biochem Biophys Res Commun 206:15–21

    Article  CAS  PubMed  Google Scholar 

  37. Taskiran D, Stefanovic-Racic M, Georgescu H, Evans C (1994) Nitric oxide mediates suppression of cartilage proteoglycan synthesis by interleukin-1. Biochem Biophys Res Commun 200:142–148

    Article  CAS  PubMed  Google Scholar 

  38. Berenbaum F (2004) Signaling transduction: target in osteoarthritis. Curr Opin Rheumatol 16:616–622

    Article  PubMed  Google Scholar 

  39. Kim J, Xu M, Xo R, Mates A, Wilson GL, Pearsall AW, Grishko V (2010) Mitochondrial DNA damage is involved in apoptosis caused by pro-inflammatory cytokines in human OA chondrocytes. Osteoarthr Cartil 18:424–432

    Article  CAS  Google Scholar 

  40. Lotz M, Moats T, Villiger PM (1992) Leukemia inhibitory factor is expressed in cartilage and synovium and can contribute to the pathogenesis of arthritis. J Clin Invest 90:888–896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhao W, Wang T, Luo Q, Chen Y, Leung VY, Wen C, Shah MF, Pan H, Chiu K, Cao X, Lu WW (2016) Cartilage degeneration and excessive subchondral bone formation in spontaneous osteoarthritis involves altered TGF-beta signaling. J Orthop Res 34:763–770

    Article  CAS  PubMed  Google Scholar 

  42. Zhen G, Wen C, Jia X, Li Y, Crane JL, Mears SC, Askin FB, Frassica FJ, Chang W, Yao J, Carrino JA, Cosgarea A, Artemov D, Chen Q, Zhao Z, Zhou X, Riley L, Sponseller P, Wan M, Lu WW, Cao X (2013) Inhibition of TGF-beta signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med 19:704–712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Holmbeck K, Szabova L (2006) Aspects of extracellular matrix remodeling in development and disease. Birth Defects Res C Embryo Today 78:11–23

    Article  CAS  PubMed  Google Scholar 

  44. Yang CY, Chanalaris A, Troeberg L (2017) ADAMTS and ADAM metalloproteinases in osteoarthritis—looking beyond the “usual suspects.” Osteoarthr Cartil 25:1000–1009

    Article  CAS  Google Scholar 

  45. Sharma N, Drobinski P, Kayed A, Chen Z, Kjelgaard-Petersen CF, Gantzel T, Karsdal MA, Michaelis M, Ladel C, Bay-Jensen AC, Lindemann S, Thudium CS (2020) Inflammation and joint destruction may be linked to the generation of cartilage metabolites of ADAMTS-5 through activation of toll-like receptors. Osteoarthr Cartil 28:658–668

    Article  CAS  Google Scholar 

  46. Malfait AM, Liu RQ, Ijiri K, Komiya S, Tortorella MD (2002) Inhibition of ADAM-TS4 and ADAM-TS5 prevents aggrecan degradation in osteoarthritic cartilage. J Biol Chem 277:22201–22208

    Article  CAS  PubMed  Google Scholar 

  47. Larkin J, Lohr TA, Elefante L, Shearin J, Matico R, Su JL, Xue Y, Liu F, Genell C, Miller RE, Tran PB, Malfait AM, Maier CC, Matheny CJ (2015) Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification. Osteoarthr Cartil 23:1254–1266

    Article  CAS  Google Scholar 

  48. Krane SM, Inada M (2008) Matrix metalloproteinases and bone. Bone 43:7–18

    Article  CAS  PubMed  Google Scholar 

  49. Knauper V, Lopez-Otin C, Smith B, Knight G, Murphy G (1996) Biochemical characterization of human collagenase-3. J Biol Chem 271:1544–1550

    Article  CAS  PubMed  Google Scholar 

  50. Stickens D, Behonick DJ, Ortega N, Heyer B, Hartenstein B, Yu Y, Fosang AJ, Schorpp-Kistner M, Angel P, Werb Z (2004) Altered endochondral bone development in matrix metalloproteinase 13-deficient mice. Development 131:5883–5895

    Article  CAS  PubMed  Google Scholar 

  51. Yamamoto K, Okano H, Miyagawa W, Visse R, Shitomi Y, Santamaria S, Dudhia J, Troeberg L, Strickland DK, Hirohata S, Nagase H (2016) MMP-13 is constitutively produced in human chondrocytes and co-endocytosed with ADAMTS-5 and TIMP-3 by the endocytic receptor LRP1. Matrix Biol 56:57–73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Smith GN Jr (2006) The role of collagenolytic matrix metalloproteinases in the loss of articular cartilage in osteoarthritis. Front Biosci 11:3081–3095

    Article  CAS  PubMed  Google Scholar 

  53. Baragi VM, Becher G, Bendele AM, Biesinger R, Bluhm H, Boer J, Deng H, Dodd R, Essers M, Feuerstein T, Gallagher BM Jr, Gege C, Hochgurtel M, Hofmann M, Jaworski A, Jin L, Kiely A, Korniski B, Kroth H, Nix D, Nolte B, Piecha D, Powers TS, Richter F, Schneider M, Steeneck C, Sucholeiki I, Taveras A, Timmermann A, Van Veldhuizen J, Weik J, Wu X, Xia B (2009) A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models. Arthritis Rheum 60:2008–2018

    Article  CAS  PubMed  Google Scholar 

  54. Johnson AR, Pavlovsky AG, Ortwine DF, Prior F, Man CF, Bornemeier DA, Banotai CA, Mueller WT, McConnell P, Yan C, Baragi V, Lesch C, Roark WH, Wilson M, Datta K, Guzman R, Han HK, Dyer RD (2007) Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 that reduces cartilage damage in vivo without joint fibroplasia side effects. J Biol Chem 282:27781–27791

    Article  CAS  PubMed  Google Scholar 

  55. Vu TH, Shipley JM, Bergers G, Berger JE, Helms JA, Hanahan D, Shapiro SD, Senior RM, Werb Z (1998) MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93:411–422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Engsig MT, Chen QJ, Vu TH, Pedersen AC, Therkidsen B, Lund LR, Henriksen K, Lenhard T, Foged NT, Werb Z, Delaisse JM (2000) Matrix metalloproteinase 9 and vascular endothelial growth factor are essential for osteoclast recruitment into developing long bones. J Cell Biol 151:879–889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Holmbeck K, Bianco P, Caterina J, Yamada S, Kromer M, Kuznetsov SA, Mankani M, Robey PG, Poole AR, Pidoux I, Ward JM, Birkedal-Hansen H (1999) MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 99:81–92

    Article  CAS  PubMed  Google Scholar 

  58. Amar S, Smith L, Fields GB (1864) Matrix metalloproteinase collagenolysis in health and disease. Biochim Biophys Acta Mol Cell Res 2017:1940–1951

    Google Scholar 

  59. Hwang IY, Youm YS, Cho SD, Choi SW, Bae MH, Park SJ, Kim HW (2018) Synovial fluid levels of TWEAK and matrix metalloproteinase 1 in patients with osteoarthritis, and associations with disease severity. J Orthop Surg 26:2309499018760112

    Article  Google Scholar 

  60. Karsdal MA, Madsen SH, Christiansen C, Henriksen K, Fosang AJ, Sondergaard BC (2008) Cartilage degradation is fully reversible in the presence of aggrecanase but not matrix metalloproteinase activity. Arthritis Res Ther 10:R63

    Article  PubMed  PubMed Central  Google Scholar 

  61. Bank RA, Krikken M, Beekman B, Stoop R, Maroudas A, Lafeber FP, te Koppele JM (1997) A simplified measurement of degraded collagen in tissues: application in healthy, fibrillated and osteoarthritic cartilage. Matrix Biol 16:233–243

    Article  CAS  PubMed  Google Scholar 

  62. Melrose J, Fuller ES, Roughley PJ, Smith MM, Kerr B, Hughes CE, Caterson B, Little CB (2008) Fragmentation of decorin, biglycan, lumican and keratocan is elevated in degenerate human meniscus, knee and hip articular cartilages compared with age-matched macroscopically normal and control tissues. Arthritis Res Ther 10:R79

    Article  PubMed  PubMed Central  Google Scholar 

  63. Zack MD, Arner EC, Anglin CP, Alston JT, Malfait AM, Tortorella MD (2006) Identification of fibronectin neoepitopes present in human osteoarthritic cartilage. Arthritis Rheum 54:2912–2922

    Article  CAS  PubMed  Google Scholar 

  64. Liu-Bryan R, Terkeltaub R (2010) Chondrocyte innate immune myeloid differentiation factor 88-dependent signaling drives procatabolic effects of the endogenous Toll-like receptor 2/Toll-like receptor 4 ligands low molecular weight hyaluronan and high mobility group box chromosomal protein 1 in mice. Arthritis Rheum 62:2004–2012

    PubMed  PubMed Central  Google Scholar 

  65. Fichter M, Korner U, Schomburg J, Jennings L, Cole AA, Mollenhauer J (2006) Collagen degradation products modulate matrix metalloproteinase expression in cultured articular chondrocytes. J Orthop Res 24:63–70

    Article  CAS  PubMed  Google Scholar 

  66. Pulai JI, Chen H, Im HJ, Kumar S, Hanning C, Hegde PS, Loeser RF (2005) NF-kappa B mediates the stimulation of cytokine and chemokine expression by human articular chondrocytes in response to fibronectin fragments. J Immunol 174:5781–5788

    Article  CAS  PubMed  Google Scholar 

  67. Lees S, Golub SB, Last K, Zeng W, Jackson DC, Sutton P, Fosang AJ (2015) Bioactivity in an Aggrecan 32-mer fragment is mediated via toll-like receptor 2. Arthritis Rheum 67:1240–1249

    Article  CAS  Google Scholar 

  68. Miller RE, Ishihara S, Tran PB, Golub SB, Last K, Miller RJ, Fosang AJ, Malfait AM (2018) An aggrecan fragment drives osteoarthritis pain through Toll-like receptor 2. JCI Insight 3:e95704

    Article  PubMed Central  Google Scholar 

  69. Sellam J, Berenbaum F (2010) The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis, Nature reviews. Rheumatology 6:625–635

    CAS  PubMed  Google Scholar 

  70. Mapp PI, Walsh DA (2012) Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis, Nature reviews. Rheumatology 8:390–398

    CAS  PubMed  Google Scholar 

  71. Atri C, Guerfali FZ, Laouini D (2018) Role of human macrophage polarization in inflammation during infectious diseases. Int J Mol Sci 19:1801

    Article  PubMed Central  Google Scholar 

  72. McInnes IB, Leung BP, Field M, Wei XQ, Huang FP, Sturrock RD, Kinninmonth A, Weidner J, Mumford R, Liew FY (1996) Production of nitric oxide in the synovial membrane of rheumatoid and osteoarthritis patients. J Exp Med 184:1519–1524

    Article  CAS  PubMed  Google Scholar 

  73. Wu WK, Llewellyn OP, Bates DO, Nicholson LB, Dick AD (2010) IL-10 regulation of macrophage VEGF production is dependent on macrophage polarisation and hypoxia. Immunobiology 215:796–803

    Article  CAS  PubMed  Google Scholar 

  74. Tsuchida AI, Beekhuizen M, t’Hart MC, Radstake TR, Dhert WJ, Saris DB, van Osch GJ, Creemers LB (2014) Cytokine profiles in the joint depend on pathology, but are different between synovial fluid, cartilage tissue and cultured chondrocytes. Arthritis Res Ther 16:441

    Article  PubMed  PubMed Central  Google Scholar 

  75. Filardo G, Vannini F, Marcacci M, Andriolo L, Ferruzzi A, Giannini S, Kon E (2013) Matrix-assisted autologous chondrocyte transplantation for cartilage regeneration in osteoarthritic knees: results and failures at midterm follow-up. Am J Sports Med 41:95–100

    Article  PubMed  Google Scholar 

  76. Xiaoshi J, Maoquan L, Jiwei W, Jinqiu N, Ke Z (2021) SETD7 mediates the vascular invasion in articular cartilage and chondrocytes apoptosis in osteoarthriis. FASEB J 35:e21283

    Article  PubMed  Google Scholar 

  77. Wojdasiewicz P, Poniatowski LA, Szukiewicz D (2014) The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediators Inflamm 2014:561459

    Article  PubMed  PubMed Central  Google Scholar 

  78. Choy EH, Panayi GS (2001) Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 344:907–916

    Article  CAS  PubMed  Google Scholar 

  79. Hirata M, Kugimiya F, Fukai A, Saito T, Yano F, Ikeda T, Mabuchi A, Sapkota BR, Akune T, Nishida N, Yoshimura N, Nakagawa T, Tokunaga K, Nakamura K, Chung UI, Kawaguchi H (2012) C/EBPbeta and RUNX2 cooperate to degrade cartilage with MMP-13 as the target and HIF-2alpha as the inducer in chondrocytes. Hum Mol Genet 21:1111–1123

    Article  CAS  PubMed  Google Scholar 

  80. Saito T, Fukai A, Mabuchi A, Ikeda T, Yano F, Ohba S, Nishida N, Akune T, Yoshimura N, Nakagawa T, Nakamura K, Tokunaga K, Chung UI, Kawaguchi H (2010) Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development. Nat Med 16:678–686

    Article  CAS  PubMed  Google Scholar 

  81. Wondimu EB, Culley KL, Quinn J, Chang J, Dragomir CL, Plumb DA, Goldring MB, Otero M (2018) Elf3 contributes to cartilage degradation in vivo in a surgical model of post-traumatic osteoarthritis. Sci Rep 8:6438

    Article  PubMed  PubMed Central  Google Scholar 

  82. Bui C, Barter MJ, Scott JL, Xu Y, Galler M, Reynard LN, Rowan AD, Young DA (2012) cAMP response element-binding (CREB) recruitment following a specific CpG demethylation leads to the elevated expression of the matrix metalloproteinase 13 in human articular chondrocytes and osteoarthritis. FASEB J 26:3000–3011

    Article  CAS  PubMed  Google Scholar 

  83. Chan CM, Macdonald CD, Litherland GJ, Wilkinson DJ, Skelton A, Europe-Finner GN, Rowan AD (2017) Cytokine-induced MMP13 expression in human chondrocytes is dependent on activating transcription factor 3 (ATF3) regulation. J Biol Chem 292:1625–1636

    Article  CAS  PubMed  Google Scholar 

  84. Fanning PJ, Emkey G, Smith RJ, Grodzinsky AJ, Szasz N, Trippel SB (2003) Mechanical regulation of mitogen-activated protein kinase signaling in articular cartilage. J Biol Chem 278:50940–50948

    Article  CAS  PubMed  Google Scholar 

  85. Sun SC (2017) The non-canonical NF-kappaB pathway in immunity and inflammation. Nat Rev Immunol 17:545–558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Olivotto E, Otero M, Marcu KB, Goldring MB (2015) Pathophysiology of osteoarthritis: canonical NF-kappaB/IKKbeta-dependent and kinase-independent effects of IKKalpha in cartilage degradation and chondrocyte differentiation. RMD Open 1(Suppl 1):e000061

    Article  PubMed  PubMed Central  Google Scholar 

  87. Olivotto E, Otero M, Astolfi A, Platano D, Facchini A, Pagani S, Flamigni F, Facchini A, Goldring MB, Borzi RM, Marcu KB (2013) IKKalpha/CHUK regulates extracellular matrix remodeling independent of its kinase activity to facilitate articular chondrocyte differentiation. PLoS ONE 8:e73024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Chen J, Crawford R, Xiao Y (2013) Vertical inhibition of the PI3K/Akt/mTOR pathway for the treatment of osteoarthritis. J Cell Biochem 114:245–249

    Article  CAS  PubMed  Google Scholar 

  89. Murakami S, Lefebvre V, de Crombrugghe B (2000) Potent inhibition of the master chondrogenic factor Sox9 gene by interleukin-1 and tumor necrosis factor-alpha. J Biol Chem 275:3687–3692

    Article  CAS  PubMed  Google Scholar 

  90. Nakase T, Miyaji T, Tomita T, Kaneko M, Kuriyama K, Myoui A, Sugamoto K, Ochi T, Yoshikawa H (2003) Localization of bone morphogenetic protein-2 in human osteoarthritic cartilage and osteophyte. Osteoarthr Cartil 11:278–284

    Article  CAS  Google Scholar 

  91. Sitcheran R, Cogswell PC, Baldwin AS Jr (2003) NF-kappaB mediates inhibition of mesenchymal cell differentiation through a posttranscriptional gene silencing mechanism. Genes Dev 17:2368–2373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Ijiri K, Zerbini LF, Peng H, Otu HH, Tsuchimochi K, Otero M, Dragomir C, Walsh N, Bierbaum BE, Mattingly D, van Flandern G, Komiya S, Aigner T, Libermann TA, Goldring MB (2008) Differential expression of GADD45beta in normal and osteoarthritic cartilage: potential role in homeostasis of articular chondrocytes. Arthritis Rheum 58:2075–2087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Ijiri K, Zerbini LF, Peng H, Correa RG, Lu B, Walsh N, Zhao Y, Taniguchi N, Huang XL, Otu H, Wang H, Wang JF, Komiya S, Ducy P, Rahman MU, Flavell RA, Gravallese EM, Oettgen P, Libermann TA, Goldring MB (2005) A novel role for GADD45beta as a mediator of MMP-13 gene expression during chondrocyte terminal differentiation. J Biol Chem 280:38544–38555

    Article  CAS  PubMed  Google Scholar 

  94. Fernandez-Torres J, Zamudio-Cuevas Y, Martinez-Nava GA, Lopez-Reyes AG (2017) Hypoxia-inducible factors (HIFs) in the articular cartilage: a systematic review. Eur Rev Med Pharmacol Sci 21:2800–2810

    CAS  PubMed  Google Scholar 

  95. Ryu JH, Shin Y, Huh YH, Yang S, Chun CH, Chun JS (2012) Hypoxia-inducible factor-2alpha regulates Fas-mediated chondrocyte apoptosis during osteoarthritic cartilage destruction. Cell Death Differ 19:440–450

    Article  CAS  PubMed  Google Scholar 

  96. Ryu JH, Yang S, Shin Y, Rhee J, Chun CH, Chun JS (2011) Interleukin-6 plays an essential role in hypoxia-inducible factor 2alpha-induced experimental osteoarthritic cartilage destruction in mice. Arthritis Rheum 63:2732–2743

    Article  CAS  PubMed  Google Scholar 

  97. Lafont JE (2010) Lack of oxygen in articular cartilage: consequences for chondrocyte biology. Int J Exp Pathol 91:99–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Bohensky J, Terkhorn SP, Freeman TA, Adams CS, Garcia JA, Shapiro IM, Srinivas V (2009) Regulation of autophagy in human and murine cartilage: hypoxia-inducible factor 2 suppresses chondrocyte autophagy. Arthritis Rheum 60:1406–1415

    Article  PubMed  PubMed Central  Google Scholar 

  99. Liu Q, Li M, Jiang L, Jiang R, Fu B (2019) METTL3 promotes experimental osteoarthritis development by regulating inflammatory response and apoptosis in chondrocyte. Biochem Biophys Res Commun 516:22–27

    Article  CAS  PubMed  Google Scholar 

  100. Hashimoto K, Otero M, Imagawa K, de Andres MC, Coico JM, Roach HI, Oreffo ROC, Marcu KB, Goldring MB (2013) Regulated transcription of human matrix metalloproteinase 13 (MMP13) and interleukin-1beta (IL1B) genes in chondrocytes depends on methylation of specific proximal promoter CpG sites. J Biol Chem 288:10061–10072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Haseeb A, Makki MS, Haqqi TM (2014) Modulation of ten-eleven translocation 1 (TET1), isocitrate dehydrogenase (IDH) expression, alpha-ketoglutarate (alpha-KG), and DNA hydroxymethylation levels by interleukin-1beta in primary human chondrocytes. J Biol Chem 289:6877–6885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hasei J, Teramura T, Takehara T, Onodera Y, Horii T, Olmer M, Hatada I, Fukuda K, Ozaki T, Lotz MK, Asahara H (2017) TWIST1 induces MMP3 expression through up-regulating DNA hydroxymethylation and promotes catabolic responses in human chondrocytes. Sci Rep 7:42990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Choi MC, Jo J, Park J, Kang HK, Park Y (2019) NF-kappaB signaling pathways in osteoarthritic cartilage destruction. Cells 8:734

    Article  CAS  PubMed Central  Google Scholar 

  104. Yang X, Guan Y, Tian S, Wang Y, Sun K, Chen Q (2016) Mechanical and IL-1beta responsive miR-365 contributes to osteoarthritis development by targeting histone deacetylase 4. Int J Mol Sci 17:436

    Article  PubMed  PubMed Central  Google Scholar 

  105. Hosaka Y, Saito T, Sugita S, Hikata T, Kobayashi H, Fukai A, Taniguchi Y, Hirata M, Akiyama H, Chung UI, Kawaguchi H (2013) Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development. Proc Natl Acad Sci USA 110:1875–1880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Monteagudo S, Lories RJ (2017) Cushioning the cartilage: a canonical Wnt restricting matter. Nat Rev Rheumatol 13:670–681

    Article  CAS  PubMed  Google Scholar 

  107. Ma B, Zhong L, van Blitterswijk CA, Post JN, Karperien M (2013) T cell factor 4 is a pro-catabolic and apoptotic factor in human articular chondrocytes by potentiating nuclear factor kappaB signaling. J Biol Chem 288:17552–17558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kuettner KE, Pauli BU (1983) Vascularity of cartilage. Cartilage 1:281–312

    Article  Google Scholar 

  109. Walsh DA (2004) Angiogenesis in osteoarthritis and spondylosis: successful repair with undesirable outcomes. Curr Opin Rheumatol 16:609–615

    Article  PubMed  Google Scholar 

  110. Ilic MZ, Robinson HC, Handley CJ (1998) Characterization of aggrecan retained and lost from the extracellular matrix of articular cartilage. Involvement of carboxyl-terminal processing in the catabolism of aggrecan. J Biol Chem 273:17451–17458

    Article  CAS  PubMed  Google Scholar 

  111. Kobayashi T, Kakizaki I, Nozaka H, Nakamura T (2017) Chondroitin sulfate proteoglycans from salmon nasal cartilage inhibit angiogenesis. Biochem Biophys Rep 9:72–78

    PubMed  Google Scholar 

  112. Calamia V, Lourido L, Fernandez-Puente P, Mateos J, Rocha B, Montell E, Verges J, Ruiz-Romero C, Blanco FJ (2012) Secretome analysis of chondroitin sulfate-treated chondrocytes reveals anti-angiogenic, anti-inflammatory and anti-catabolic properties. Arthritis Res Ther 14:R202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Lambert C, Mathy-Hartert M, Dubuc JE, Montell E, Verges J, Munaut C, Noel A, Henrotin Y (2012) Characterization of synovial angiogenesis in osteoarthritis patients and its modulation by chondroitin sulfate. Arthritis Res Ther 14:R58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Roughley PJ, Mort JS (2014) The role of aggrecan in normal and osteoarthritic cartilage. J Exp Orthop 1:8

    Article  PubMed  PubMed Central  Google Scholar 

  115. Ji WR, Castellino FJ, Chang Y, Deford ME, Gray H, Villarreal X, Kondri ME, Marti DN, Llinas M, Schaller J, Kramer RA, Trail PA (1998) Characterization of kringle domains of angiostatin as antagonists of endothelial cell migration, an important process in angiogenesis. FASEB J 12:1731–1738

    Article  CAS  PubMed  Google Scholar 

  116. O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79:315–328

    Article  CAS  PubMed  Google Scholar 

  117. Claesson-Welsh L, Welsh M, Ito N, Anand-Apte B, Soker S, Zetter B, O’Reilly M, Folkman J (1998) Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrin-binding motif RGD. Proc Natl Acad Sci 95:5579–5583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Helgeland E, Pedersen TO, Rashad A, Johannessen AC, Mustafa K, Rosen A (2020) Angiostatin-functionalized collagen scaffolds suppress angiogenesis but do not induce chondrogenesis by mesenchymal stromal cells in vivo. J Oral Sci 62:371–376

    Article  CAS  PubMed  Google Scholar 

  119. Paek SY, Kim YS, Choi SG (2010) The orientation-dependent expression of angiostatin-endostatin hybrid proteins and their characterization for the synergistic effects of antiangiogenesis. J Microbiol Biotechnol 20:1430–1435

    Article  CAS  PubMed  Google Scholar 

  120. Gok M, Erdem H, Gogus F, Yilmaz S, Karadag O, Simsek I, Sagkan RI, Saglam M, Musabak U, Dinc A, Pay S (2013) Relationship of ultrasonographic findings with synovial angiogenesis modulators in different forms of knee arthritides. Rheumatol Int 33:879–885

    Article  PubMed  Google Scholar 

  121. Hiraki Y, Tanaka H, Inoue H, Kondo J, Kamizono A, Suzuki F (1991) Molecular cloning of a new class of cartilage-specific matrix, chondromodulin-I, which stimulates growth of cultured chondrocytes. Biochem Biophys Res Commun 175:971–977

    Article  CAS  PubMed  Google Scholar 

  122. Shukunami C, Iyama K, Inoue H, Hiraki Y (1999) Spatiotemporal pattern of the mouse chondromodulin-I gene expression and its regulatory role in vascular invasion into cartilage during endochondral bone formation. Int J Dev Biol 43:39–49

    CAS  PubMed  Google Scholar 

  123. Klinger P, Surmann-Schmitt C, Brem M, Swoboda B, Distler JH, Carl HD, von der Mark K, Hennig FF, Gelse K (2011) Chondromodulin 1 stabilizes the chondrocyte phenotype and inhibits endochondral ossification of porcine cartilage repair tissue. Arthritis Rheum 63:2721–2731

    Article  CAS  PubMed  Google Scholar 

  124. Inoue H, Kondo J, Koike T, Shukunami C, Hiraki Y (1997) Identification of an autocrine chondrocyte colony-stimulating factor: chondromodulin-I stimulates the colony formation of growth plate chondrocytes in agarose culture. Biochem Biophys Res Commun 241:395–400

    Article  CAS  PubMed  Google Scholar 

  125. Hiraki Y, Mitsui K, Endo N, Takahashi K, Hayami T, Inoue H, Shukunami C, Tokunaga K, Kono T, Yamada M, Takahashi HE, Kondo J (1999) Molecular cloning of human chondromodulin-I, a cartilage-derived growth modulating factor, and its expression in Chinese hamster ovary cells. Eur J Biochem 260:869–878

    Article  CAS  PubMed  Google Scholar 

  126. Hiraki Y, Shukunami C (2000) Chondromodulin-I as a novel cartilage-specific growth-modulating factor. Pediatr Nephrol 14:602–605

    Article  CAS  PubMed  Google Scholar 

  127. Hayami T, Funaki H, Yaoeda K, Mitui K, Yamagiwa H, Tokunaga K, Hatano H, Kondo J, Hiraki Y, Yamamoto T, Duong LT, Endo N (2003) Expression of the cartilage derived anti-angiogenic factor chondromodulin-I decreases in the early stage of experimental osteoarthritis. J Rheumatol 30:2207–2217

    CAS  PubMed  Google Scholar 

  128. Walsh DA, Bonnet CS, Turner EL, Wilson D, Situ M, McWilliams DF (2007) Angiogenesis in the synovium and at the osteochondral junction in osteoarthritis. Osteoarthr Cartil 15:743–751

    Article  CAS  Google Scholar 

  129. Zhu Y, Zhang Y, Liu Y, Tao R, Xia H, Zheng R, Shi Y, Tang S, Zhang W, Liu W, Cao Y, Zhou G (2015) The influence of Chm-I knockout on ectopic cartilage regeneration and homeostasis maintenance. Tissue Eng A 21:782–792

    Article  CAS  Google Scholar 

  130. Miura S, Mitsui K, Heishi T, Shukunami C, Sekiguchi K, Kondo J, Sato Y, Hiraki Y (2010) Impairment of VEGF-A-stimulated lamellipodial extensions and motility of vascular endothelial cells by chondromodulin-I, a cartilage-derived angiogenesis inhibitor. Exp Cell Res 316:775–788

    Article  CAS  PubMed  Google Scholar 

  131. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277–285

    Article  CAS  PubMed  Google Scholar 

  132. Pufe T, Kurz B, Petersen W, Varoga D, Mentlein R, Kulow S, Lemke A, Tillmann B (2005) The influence of biomechanical parameters on the expression of VEGF and endostatin in the bone and joint system. Ann Anat 187:461–472

    Article  CAS  PubMed  Google Scholar 

  133. Pufe T, Petersen WJ, Miosge N, Goldring MB, Mentlein R, Varoga DJ, Tillmann BN (2004) Endostatin/collagen XVIII—an inhibitor of angiogenesis—is expressed in cartilage and fibrocartilage. Matrix Biol 23:267–276

    Article  CAS  PubMed  Google Scholar 

  134. Matsumoto G, Hirohata R, Hayashi K, Sugimoto Y, Kotani E, Shimabukuro J, Hirano T, Nakajima Y, Kawamata S, Mori H (2014) Control of angiogenesis by VEGF and endostatin-encapsulated protein microcrystals and inhibition of tumor angiogenesis. Biomaterials 35:1326–1333

    Article  CAS  PubMed  Google Scholar 

  135. Kim YM, Hwang S, Kim YM, Pyun BJ, Kim TY, Lee ST, Gho YS, Kwon YG (2002) Endostatin blocks vascular endothelial growth factor-mediated signaling via direct interaction with KDR/Flk-1. J Biol Chem 277:27872–27879

    Article  CAS  PubMed  Google Scholar 

  136. Dhanabal M, Ramchandran R, Waterman MJ, Lu H, Knebelmann B, Segal M, Sukhatme VP (1999) Endostatin induces endothelial cell apoptosis. J Biol Chem 274:11721–11726

    Article  CAS  PubMed  Google Scholar 

  137. Nguyen TM, Subramanian IV, Xiao X, Ghosh G, Nguyen P, Kelekar A, Ramakrishnan S (2009) Endostatin induces autophagy in endothelial cells by modulating Beclin 1 and beta-catenin levels. J Cell Mol Med 13:3687–3698

    Article  PubMed  PubMed Central  Google Scholar 

  138. Xu X, Mao W, Chen Q, Zhuang Q, Wang L, Dai J, Wang H, Huang Z (2014) Endostar, a modified recombinant human endostatin, suppresses angiogenesis through inhibition of Wnt/beta-catenin signaling pathway. PLoS ONE 9:e107463

    Article  PubMed  PubMed Central  Google Scholar 

  139. Hanai J, Dhanabal M, Karumanchi SA, Albanese C, Waterman M, Chan B, Ramchandran R, Pestell R, Sukhatme VP (2002) Endostatin causes G1 arrest of endothelial cells through inhibition of cyclin D1. J Biol Chem 277:16464–16469

    Article  CAS  PubMed  Google Scholar 

  140. Xu W, Ye P, Li Z, Shi J, Wang W, Yao K (2010) Endostar, a recently introduced recombinant human endostatin, inhibits proliferation and migration through regulating growth factors, adhesion factors and inflammatory mediators in choroid-retinal endothelial cells. Mol Biol (Mosk) 44:664–670

    Article  Google Scholar 

  141. Mao H, Xie L, Pi X (2017) Low-density lipoprotein receptor-related protein-1 signaling in angiogenesis. Front Cardiovasc Med 4:34

    Article  PubMed  PubMed Central  Google Scholar 

  142. Yamamoto K, Santamaria S, Botkjaer KA, Dudhia J, Troeberg L, Itoh Y, Murphy G, Nagase H (2017) Inhibition of shedding of low-density lipoprotein receptor-related protein 1 reverses cartilage matrix degradation in osteoarthritis. Arthritis Rheum 69:1246–1256

    Article  CAS  Google Scholar 

  143. Pi X, Schmitt CE, Xie L, Portbury AL, Wu Y, Lockyer P, Dyer LA, Moser M, Bu G, Flynn EJ 3rd, Jin SW, Patterson C (2012) LRP1-dependent endocytic mechanism governs the signaling output of the bmp system in endothelial cells and in angiogenesis. Circ Res 111:564–574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Mao H, Lockyer P, Townley-Tilson WH, Xie L, Pi X (2016) LRP1 regulates retinal angiogenesis by inhibiting PARP-1 activity and endothelial cell proliferation. Arterioscler Thromb Vasc Biol 36:350–360

    Article  CAS  PubMed  Google Scholar 

  145. Nakajima C, Haffner P, Goerke SM, Zurhove K, Adelmann G, Frotscher M, Herz J, Bock HH, May P (2014) The lipoprotein receptor LRP1 modulates sphingosine-1-phosphate signaling and is essential for vascular development. Development 141:4513–4525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Makarova AM, Lebedeva TV, Nassar T, Higazi AA, Xue J, Carinato ME, Bdeir K, Cines DB, Stepanova V (2011) Urokinase-type plasminogen activator (uPA) induces pulmonary microvascular endothelial permeability through low density lipoprotein receptor-related protein (LRP)-dependent activation of endothelial nitric-oxide synthase. J Biol Chem 286:23044–23053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Herkenne S, Paques C, Nivelles O, Lion M, Bajou K, Pollenus T, Fontaine M, Carmeliet P, Martial JA, Nguyen NQ, Struman I (2015) The interaction of uPAR with VEGFR2 promotes VEGF-induced angiogenesis. Sci Signal 8:117

    Article  Google Scholar 

  148. Chen JS, Chang CM, Wu JC, Wang SM (2000) Shark cartilage extract interferes with cell adhesion and induces reorganization of focal adhesions in cultured endothelial cells. J Cell Biochem 78:417–428

    Article  CAS  PubMed  Google Scholar 

  149. Gingras D, Renaud A, Mousseau N, Beaulieu E, Kachra Z, Beliveau R (2001) Matrix proteinase inhibition by AE-941, a multifunctional antiangiogenic compound. Anticancer Res 21:145–155

    CAS  PubMed  Google Scholar 

  150. Zheng L, Ling P, Wang Z, Niu R, Hu C, Zhang T, Lin X (2007) A novel polypeptide from shark cartilage with potent anti-angiogenic activity. Cancer Biol Ther 6:775–780

    Article  CAS  PubMed  Google Scholar 

  151. Dupont E, Falardeau P, Mousa SA, Dimitriadou V, Pepin MC, Wang T, Alaoui-Jamali MA (2002) Antiangiogenic and antimetastatic properties of Neovastat (AE-941), an orally active extract derived from cartilage tissue. Clin Exp Metastasis 19:145–153

    Article  CAS  PubMed  Google Scholar 

  152. Boivin D, Gendron S, Beaulieu E, Gingras D, Beliveau R (2002) The antiangiogenic agent Neovastat (AE-941) induces endothelial cell apoptosis. Mol Cancer Ther 1:795–802

    CAS  PubMed  Google Scholar 

  153. Gingras D, Nyalendo C, Di Tomasso G, Annabi B, Beliveau R (2004) Activation of tissue plasminogen activator gene transcription by Neovastat, a multifunctional antiangiogenic agent. Biochem Biophys Res Commun 320:205–212

    Article  CAS  PubMed  Google Scholar 

  154. Simard B, Ratel D, Dupre I, Pautre V, Berger F (2013) Shark cartilage extract induces cytokines expression and release in endothelial cells and induces E-selectin, plasminogen and t-PA genes expression through an antioxidant-sensitive mechanism. Cytokine 61:104–111

    Article  CAS  PubMed  Google Scholar 

  155. Merly L, Smith SL (2013) Collagen type II, alpha 1 protein: a bioactive component of shark cartilage. Int Immunopharmacol 15:309–315

    Article  CAS  PubMed  Google Scholar 

  156. Jeevithan E, Bao B, Zhang J, Hong S, Wu W (2015) Purification, characterization and antioxidant properties of low molecular weight collagenous polypeptide (37 kDa) prepared from whale shark cartilage (Rhincodon typus). J Food Sci Technol 52:6312–6322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Safari E, Hassan Z (2020) Immunomodulatory effects of shark cartilage: stimulatory or anti-inflammatory. Process Biochem 92:417–425

    Article  Google Scholar 

  158. Nah HD, Upholt WB (1991) Type II collagen mRNA containing an alternatively spliced exon predominates in the chick limb prior to chondrogenesis. J Biol Chem 266:23446–23452

    Article  CAS  PubMed  Google Scholar 

  159. Ryan MC, Sandell LJ (1990) Differential expression of a cysteine-rich domain in the amino-terminal propeptide of type II (cartilage) procollagen by alternative splicing of mRNA. J Biol Chem 265:10334–10339

    Article  CAS  PubMed  Google Scholar 

  160. Aigner T, Zhu Y, Chansky HH, Matsen FA 3rd, Maloney WJ, Sandell LJ (1999) Reexpression of type IIA procollagen by adult articular chondrocytes in osteoarthritic cartilage. Arthritis Rheum 42:1443–1450

    Article  CAS  PubMed  Google Scholar 

  161. Sandell LJ, Morris N, Robbins JR, Goldring MB (1991) Alternatively spliced type II procollagen mRNAs define distinct populations of cells during vertebral development: differential expression of the amino-propeptide. J Cell Biol 114:1307–1319

    Article  CAS  PubMed  Google Scholar 

  162. Wang Z, Bryan J, Franz C, Havlioglu N, Sandell LJ (2010) Type IIB procollagen NH(2)-propeptide induces death of tumor cells via interaction with integrins alpha(V)beta(3) and alpha(V)beta(5). J Biol Chem 285:20806–20817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Hayashi S, Wang Z, Bryan J, Kobayashi C, Faccio R, Sandell LJ (2011) The type II collagen N-propeptide, PIIBNP, inhibits cell survival and bone resorption of osteoclasts via integrin-mediated signaling. Bone 49:644–652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Chandrasekhar S, Harvey AK, Johnson MG, Becker GW (1994) Osteonectin/SPARC is a product of articular chondrocytes/cartilage and is regulated by cytokines and growth factors. Biochim Biophys Acta 1221:7–14

    Article  CAS  PubMed  Google Scholar 

  165. Brekken RA, Sage EH (2001) SPARC, a matricellular protein: at the crossroads of cell-matrix communication. Matrix Biol 19:816–827

    Article  CAS  PubMed  Google Scholar 

  166. Martinek N, Shahab J, Sodek J, Ringuette M (2007) Is SPARC an evolutionarily conserved collagen chaperone? J Dent Res 86:296–305

    Article  CAS  PubMed  Google Scholar 

  167. Nakamura S, Kamihagi K, Satakeda H, Katayama M, Pan H, Okamoto H, Noshiro M, Takahashi K, Yoshihara Y, Shimmei M, Okada Y, Kato Y (1996) Enhancement of SPARC (osteonectin) synthesis in arthritic cartilage. Increased levels in synovial fluids from patients with rheumatoid arthritis and regulation by growth factors and cytokines in chondrocyte cultures. Arthritis Rheum 39:539–551

    Article  CAS  PubMed  Google Scholar 

  168. Rivera LB, Bradshaw AD, Brekken RA (2011) The regulatory function of SPARC in vascular biology. Cell Mol Life Sci 68:3165–3173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Nozaki M, Sakurai E, Raisler BJ, Baffi JZ, Witta J, Ogura Y, Brekken RA, Sage EH, Ambati BK, Ambati J (2006) Loss of SPARC-mediated VEGFR-1 suppression after injury reveals a novel antiangiogenic activity of VEGF-A. J Clin Invest 116:422–429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Motamed K, Blake DJ, Angello JC, Allen BL, Rapraeger AC, Hauschka SD, Sage EH (2003) Fibroblast growth factor receptor-1 mediates the inhibition of endothelial cell proliferation and the promotion of skeletal myoblast differentiation by SPARC: a role for protein kinase A. J Cell Biochem 90:408–423

    Article  CAS  PubMed  Google Scholar 

  171. Fujita T, Shiba H, Van Dyke TE, Kurihara H (2004) Differential effects of growth factors and cytokines on the synthesis of SPARC, DNA, fibronectin and alkaline phosphatase activity in human periodontal ligament cells. Cell Biol Int 28:281–286

    Article  CAS  PubMed  Google Scholar 

  172. Sage EH, Reed M, Funk SE, Truong T, Steadele M, Puolakkainen P, Maurice DH, Bassuk JA (2003) Cleavage of the matricellular protein SPARC by matrix metalloproteinase 3 produces polypeptides that influence angiogenesis. J Biol Chem 278:37849–37857

    Article  CAS  PubMed  Google Scholar 

  173. Shiba H, Fujita T, Doi N, Nakamura S, Nakanishi K, Takemoto T, Hino T, Noshiro M, Kawamoto T, Kurihara H, Kato Y (1998) Differential effects of various growth factors and cytokines on the syntheses of DNA, type I collagen, laminin, fibronectin, osteonectin/secreted protein, acidic and rich in cysteine (SPARC), and alkaline phosphatase by human pulp cells in culture. J Cell Physiol 174:194–205

    Article  CAS  PubMed  Google Scholar 

  174. Good DJ, Polverini PJ, Rastinejad F, Le Beau MM, Lemons RS, Frazier WA, Bouck NP (1990) A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc Natl Acad Sci USA 87:6624–6628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Lawler PR, Lawler J (2012) Molecular basis for the regulation of angiogenesis by thrombospondin-1 and -2. Cold Spring Harb Perspect Med 2:a006627

    Article  PubMed  PubMed Central  Google Scholar 

  176. Xie A, Xue J, Shen G, Nie L (2017) Thrombospondin-1 inhibits ossification of tissue engineered cartilage constructed by ADSCs. Am J Transl Res 9:3487–3498

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Taylor DK, Meganck JA, Terkhorn S, Rajani R, Naik A, O’Keefe RJ, Goldstein SA, Hankenson KD (2009) Thrombospondin-2 influences the proportion of cartilage and bone during fracture healing. J Bone Miner Res 24:1043–1054

    Article  PubMed  PubMed Central  Google Scholar 

  178. Docheva D, Hunziker EB, Fassler R, Brandau O (2005) Tenomodulin is necessary for tenocyte proliferation and tendon maturation. Mol Cell Biol 25:699–705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Nakamichi Y, Shukunami C, Yamada T, Aihara K, Kawano H, Sato T, Nishizaki Y, Yamamoto Y, Shindo M, Yoshimura K, Nakamura T, Takahashi N, Kawaguchi H, Hiraki Y, Kato S (2003) Chondromodulin I is a bone remodeling factor. Mol Cell Biol 23:636–644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Figg W, Folkman J (2008) Angiogenesis: An integrative approach from science to medicine. Springer, New York

    Book  Google Scholar 

  181. Bornstein P (2009) Thrombospondins function as regulators of angiogenesis. J Cell Commun Signal 3:189–200

    Article  PubMed  PubMed Central  Google Scholar 

  182. Moses MA, Wiederschain D, Wu I, Fernandez CA, Ghazizadeh V, Lane WS, Flynn E, Sytkowski A, Tao T, Langer R (1999) Troponin I is present in human cartilage and inhibits angiogenesis. Proc Natl Acad Sci USA 96:2645–2650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Feldman L, Rouleau C (2002) Troponin I inhibits capillary endothelial cell proliferation by interaction with the cell’s bFGF receptor. Microvasc Res 63:41–49

    Article  CAS  PubMed  Google Scholar 

  184. Kern BE, Balcom JH, Antoniu BA, Warshaw AL, Fernandez-del Castillo C (2003) Troponin I peptide (Glu94-Leu123), a cartilage-derived angiogenesis inhibitor: in vitro and in vivo effects on human endothelial cells and on pancreatic cancer. J Gastrointest Surg 7:961–968 (discussion 969)

    Article  PubMed  Google Scholar 

  185. Schmidt K, Hoffend J, Altmann A, Kiessling F, Strauss L, Koczan D, Mier W, Eisenhut M, Kinscherf R, Haberkorn U (2006) Troponin I overexpression inhibits tumor growth, perfusion, and vascularization of morris hepatoma. J Nucl Med 47:1506–1514

    CAS  PubMed  Google Scholar 

  186. Tan KB, Harrop J, Reddy M, Young P, Terrett J, Emery J, Moore G, Truneh A (1997) Characterization of a novel TNF-like ligand and recently described TNF ligand and TNF receptor superfamily genes and their constitutive and inducible expression in hematopoietic and non-hematopoietic cells. Gene 204:35–46

    Article  CAS  PubMed  Google Scholar 

  187. Chew LJ, Pan H, Yu J, Tian S, Huang WQ, Zhang JY, Pang S, Li LY (2002) A novel secreted splice variant of vascular endothelial cell growth inhibitor. FASEB J 16:742–744

    Article  CAS  PubMed  Google Scholar 

  188. Metheny-Barlow LJ, Li LY (2006) Vascular endothelial growth inhibitor (VEGI), an endogenous negative regulator of angiogenesis. Semin Ophthalmol 21:49–58

    Article  PubMed  Google Scholar 

  189. Zhang N, Sanders AJ, Ye L, Jiang WG (2009) Vascular endothelial growth inhibitor in human cancer (review). Int J Mol Med 24:3–8

    CAS  PubMed  Google Scholar 

  190. Zhang Z, Li LY (2012) TNFSF15 modulates neovascularization and inflammation. Cancer Microenviron 5:237–247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Tian F, Liang PH, Li LY (2009) Inhibition of endothelial progenitor cell differentiation by VEGI. Blood 113:5352–5360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Duan L, Yang G, Zhang R, Feng L, Xu C (2012) Advancement in the research on vascular endothelial growth inhibitor (VEGI). Target Oncol 7:87–90

    Article  PubMed  Google Scholar 

  193. Huang Z, Ding C, Li T, Yu SP (2018) Current status and future prospects for disease modification in osteoarthritis. Rheumatology 57:iv108–iv123

    Article  CAS  PubMed  Google Scholar 

  194. Ahmad R, El Mabrouk M, Sylvester J, Zafarullah M (2009) Human osteoarthritic chondrocytes are impaired in matrix metalloproteinase-13 inhibition by IFN-gamma due to reduced IFN-gamma receptor levels. Osteoarthr Cartil 17:1049–1055

    Article  CAS  Google Scholar 

  195. Ahmad R, Qureshi HY, El Mabrouk M, Sylvester J, Ahmad M, Zafarullah M (2007) Inhibition of interleukin 1-induced matrix metalloproteinase 13 expression in human chondrocytes by interferon gamma. Ann Rheum Dis 66:782–789

    Article  CAS  PubMed  Google Scholar 

  196. Szekanecz Z, Besenyei T, Paragh G, Koch AE (2009) Angiogenesis in rheumatoid arthritis. Autoimmunity 42:563–573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Tsuchida AI, Beekhuizen M, Rutgers M, van Osch GJ, Bekkers JE, Bot AG, Geurts B, Dhert WJ, Saris DB, Creemers LB (2012) Interleukin-6 is elevated in synovial fluid of patients with focal cartilage defects and stimulates cartilage matrix production in an in vitro regeneration model. Arthritis Res Ther 14:R262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Elshabrawy HA, Chen Z, Volin MV, Ravella S, Virupannavar S, Shahrara S (2015) The pathogenic role of angiogenesis in rheumatoid arthritis. Angiogenesis 18(4):433–448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Davidson RK, Waters JG, Kevorkian L, Darrah C, Cooper A, Donell ST, Clark IM (2006) Expression profiling of metalloproteinases and their inhibitors in synovium and cartilage. Arthritis Res Ther 8:R124

    Article  PubMed  PubMed Central  Google Scholar 

  200. Jacoby AS, Melrose J, Robinson BG, Hyland VJ, Ghosh P (1993) Secretory leucocyte proteinase inhibitor is produced by human articular cartilage chondrocytes and intervertebral disc fibrochondrocytes. Eur J Biochem 218:951–957

    Article  CAS  PubMed  Google Scholar 

  201. Treadwell BV, Pavia M, Towle CA, Cooley VJ, Mankin HJ (1991) Cartilage synthesizes the serine protease inhibitor PAI-1: support for the involvement of serine proteases in cartilage remodeling. J Orthop Res 9:309–316

    Article  CAS  PubMed  Google Scholar 

  202. Wilkinson DJ, Arques MDC, Huesa C, Rowan AD (2019) Serine proteinases in the turnover of the cartilage extracellular matrix in the joint: implications for therapeutics. Br J Pharmacol 176:38–51

    Article  CAS  PubMed  Google Scholar 

  203. Sugino T, Yamaguchi T, Ogura G, Kusakabe T, Goodison S, Homma Y, Suzuki T (2007) The secretory leukocyte protease inhibitor (SLPI) suppresses cancer cell invasion but promotes blood-borne metastasis via an invasion-independent pathway. J Pathol 212:152–160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Milner JM, Elliott SF, Cawston TE (2001) Activation of procollagenases is a key control point in cartilage collagen degradation: interaction of serine and metalloproteinase pathways. Arthritis Rheum 44:2084–2096

    Article  CAS  PubMed  Google Scholar 

  205. Martel-Pelletier J, McCollum R, Fujimoto N, Obata K, Cloutier JM, Pelletier JP (1994) Excess of metalloproteases over tissue inhibitor of metalloprotease may contribute to cartilage degradation in osteoarthritis and rheumatoid arthritis. Lab Invest 70:807–815

    CAS  PubMed  Google Scholar 

  206. Moses MA, Sudhalter J, Langer R (1990) Identification of an inhibitor of neovascularization from cartilage. Science 248:1408–1410

    Article  CAS  PubMed  Google Scholar 

  207. Stetler-Stevenson WG, Seo DW (2005) TIMP-2: an endogenous inhibitor of angiogenesis. Trends Mol Med 11:97–103

    Article  CAS  PubMed  Google Scholar 

  208. Yamamoto K, Murphy G, Troeberg L (2015) Extracellular regulation of metalloproteinases. Matrix Biol 44–46:255–263

    Article  PubMed  Google Scholar 

  209. Kevorkian L, Young DA, Darrah C, Donell ST, Shepstone L, Porter S, Brockbank SM, Edwards DR, Parker AE, Clark IM (2004) Expression profiling of metalloproteinases and their inhibitors in cartilage. Arthritis Rheum 50:131–141

    Article  CAS  PubMed  Google Scholar 

  210. Ohba Y, Goto Y, Kimura Y, Suzuki F, Hisa T, Takahashi K, Takigawa M (1995) Purification of an angiogenesis inhibitor from culture medium conditioned by a human chondrosarcoma-derived chondrocytic cell line, HCS-2/8. Biochim Biophys Acta 1245:1–8

    Article  PubMed  Google Scholar 

  211. Kashiwagi M, Tortorella M, Nagase H, Brew K (2001) TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5). J Biol Chem 276:12501–12504

    Article  CAS  PubMed  Google Scholar 

  212. Qi JH, Ebrahem Q, Moore N, Murphy G, Claesson-Welsh L, Bond M, Baker A, Anand-Apte B (2003) A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med 9:407–415

    Article  CAS  PubMed  Google Scholar 

  213. Sahebjam S, Khokha R, Mort JS (2007) Increased collagen and aggrecan degradation with age in the joints of Timp3(-/-) mice. Arthritis Rheum 56:905–909

    Article  CAS  PubMed  Google Scholar 

  214. Pizzute T, Lynch K, Pei M (2015) Impact of tissue-specific stem cells on lineage-specific differentiation: a focus on the musculoskeletal system. Stem Cell Rev Rep 11:119–132

    Article  CAS  PubMed  Google Scholar 

  215. Sakaguchi Y, Sekiya I, Yagishita K, Muneta T (2005) Comparison of human stem cells derived from various mesenchymal tissues: superiority of synovium as a cell source. Arthritis Rheum 52:2521–2529

    Article  PubMed  Google Scholar 

  216. Wang T, Hill RC, Dzieciatkowska M, Zhu L, Infante AM, Hu G, Hansen KC, Pei M (2020) Site-dependent lineage preference of adipose stem cells. Front Cell Dev Biol 8:237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Vinardell T, Sheehy EJ, Buckley CT, Kelly DJ (2012) A comparison of the functionality and in vivo phenotypic stability of cartilaginous tissues engineered from different stem cell sources. Tissue Eng A 18:1161–1170

    Article  CAS  Google Scholar 

  218. Du WJ, Chi Y, Yang ZX, Li ZJ, Cui JJ, Song BQ, Li X, Yang SG, Han ZB, Han ZC (2016) Heterogeneity of proangiogenic features in mesenchymal stem cells derived from bone marrow, adipose tissue, umbilical cord, and placenta. Stem Cell Res Ther 7:163

    Article  PubMed  PubMed Central  Google Scholar 

  219. Krebsbach PH, Kuznetsov SA, Bianco P, Robey PG (1999) Bone marrow stromal cells: characterization and clinical application. Crit Rev Oral Biol Med 10:165–181

    Article  CAS  PubMed  Google Scholar 

  220. Jones BA, Pei M (2012) Synovium-derived stem cells: a tissue-specific stem cell for cartilage engineering and regeneration. Tissue Eng Part B Rev 18:301–311

    Article  CAS  PubMed  Google Scholar 

  221. Garcia-Fernandez L (2018) Osteochondral angiogenesis and promoted vascularization: new therapeutic target. Adv Exp Med Biol 1059:315–330

    Article  CAS  PubMed  Google Scholar 

  222. Xing SC, Liu Y, Feng Y, Jiang C, Hu YQ, Sun W, Wang XH, Wei ZY, Qi M, Liu J, Zhai LJ, Wang ZQ (2015) Chondrogenic differentiation of ChM-I gene transfected rat bone marrow-derived mesenchymal stem cells on 3-dimensional poly (L-lactic acid) scaffold for cartilage engineering. Cell Biol Int 39:300–309

    Article  CAS  PubMed  Google Scholar 

  223. Zhang X, Prasadam I, Fang W, Crawford R, Xiao Y (2016) Chondromodulin-1 ameliorates osteoarthritis progression by inhibiting HIF-2alpha activity. Osteoarthr Cartil 24:1970–1980

    Article  CAS  Google Scholar 

  224. Kubo S, Cooper GM, Matsumoto T, Phillippi JA, Corsi KA, Usas A, Li G, Fu FH, Huard J (2009) Blocking vascular endothelial growth factor with soluble Flt-1 improves the chondrogenic potential of mouse skeletal muscle-derived stem cells. Arthritis Rheum 60:155–165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Marsano A, Medeiros da Cunha CM, Ghanaati S, Gueven S, Centola M, Tsaryk R, Barbeck M, Stuedle C, Barbero A, Helmrich U, Schaeren S, Kirkpatrick JC, Banfi A, Martin I (2016) Spontaneous in vivo chondrogenesis of bone marrow-derived mesenchymal progenitor cells by blocking vascular endothelial growth factor signaling. Stem cells Transl Med 5:1730–1738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Matsumoto T, Cooper GM, Gharaibeh B, Meszaros LB, Li G, Usas A, Fu FH, Huard J (2009) Cartilage repair in a rat model of osteoarthritis through intraarticular transplantation of muscle-derived stem cells expressing bone morphogenetic protein 4 and soluble Flt-1. Arthritis Rheum 60:1390–1405

    Article  PubMed  PubMed Central  Google Scholar 

  227. Pei M (2017) Environmental preconditioning rejuvenates adult stem cells’ proliferation and chondrogenic potential. Biomaterials 117:10–23

    Article  CAS  PubMed  Google Scholar 

  228. Hubka KM, Dahlin RL, Meretoja VV, Kasper FK, Mikos AG (2014) Enhancing chondrogenic phenotype for cartilage tissue engineering: monoculture and coculture of articular chondrocytes and mesenchymal stem cells. Tissue Eng B Rev 20:641–654

    Article  Google Scholar 

  229. Nazempour A, Van Wie BJ (2016) Chondrocytes, mesenchymal stem cells, and their combination in articular cartilage regenerative medicine. Ann Biomed Eng 44:1325–1354

    Article  CAS  PubMed  Google Scholar 

  230. Hunziker EB, Driesang IM, Saager C (2001) Structural barrier principle for growth factor-based articular cartilage repair. Clin Orthop Relat Res 391(Suppl):S182–S189

    Article  Google Scholar 

  231. Levingstone TJ, Matsiko A, Dickson GR, O’Brien FJ, Gleeson JP (2014) A biomimetic multi-layered collagen-based scaffold for osteochondral repair. Acta Biomater 10:1996–2004

    Article  CAS  PubMed  Google Scholar 

  232. Levingstone TJ, Ramesh A, Brady RT, Brama PAJ, Kearney C, Gleeson JP, O’Brien FJ (2016) Cell-free multi-layered collagen-based scaffolds demonstrate layer specific regeneration of functional osteochondral tissue in caprine joints. Biomaterials 87:69–81

    Article  CAS  PubMed  Google Scholar 

  233. Levingstone TJ, Thompson E, Matsiko A, Schepens A, Gleeson JP, O’Brien FJ (2016) Multi-layered collagen-based scaffolds for osteochondral defect repair in rabbits. Acta Biomater 32:149–160

    Article  CAS  PubMed  Google Scholar 

  234. Kon E, Delcogliano M, Filardo G, Fini M, Giavaresi G, Francioli S, Martin I, Pressato D, Arcangeli E, Quarto R, Sandri M, Marcacci M (2010) Orderly osteochondral regeneration in a sheep model using a novel nano-composite multilayered biomaterial. J Orthop Res 28:116–124

    PubMed  Google Scholar 

  235. Cao L, Mooney DJ (2007) Spatiotemporal control over growth factor signaling for therapeutic neovascularization. Adv Drug Deliv Rev 59:1340–1350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Mohan N, Dormer NH, Caldwell KL, Key VH, Berkland CJ, Detamore MS (2011) Continuous gradients of material composition and growth factors for effective regeneration of the osteochondral interface. Tissue Eng A 17:2845–2855

    Article  CAS  Google Scholar 

  237. Mohan N, Gupta V, Sridharan BP, Mellott AJ, Easley JT, Palmer RH, Galbraith RA, Key VH, Berkland CJ, Detamore MS (2015) Microsphere-based gradient implants for osteochondral regeneration: a long-term study in sheep. Reg Med 10:709–728

    Article  CAS  Google Scholar 

  238. Wylie RG, Shoichet MS (2011) Three-dimensional spatial patterning of proteins in hydrogels. Biomacromol 12:3789–3796

    Article  CAS  Google Scholar 

  239. Centola M, Abbruzzese F, Scotti C, Barbero A, Vadala G, Denaro V, Martin I, Trombetta M, Rainer A, Marsano A (2013) Scaffold-based delivery of a clinically relevant anti-angiogenic drug promotes the formation of in vivo stable cartilage. Tissue Eng A 19:1960–1971

    Article  CAS  Google Scholar 

  240. Jeng L, Olsen BR, Spector M (2010) Engineering endostatin-producing cartilaginous constructs for cartilage repair using nonviral transfection of chondrocyte-seeded and mesenchymal-stem-cell-seeded collagen scaffolds. Tissue Eng A 16:3011–3021

    Article  CAS  Google Scholar 

  241. Sun XD, Jeng L, Bolliet C, Olsen BR, Spector M (2009) Non-viral endostatin plasmid transfection of mesenchymal stem cells via collagen scaffolds. Biomaterials 30:1222–1231

    Article  CAS  PubMed  Google Scholar 

  242. Ferrari M, Onuoha SC, Pitzalis C (2016) Going with the flow: harnessing the power of the vasculature for targeted therapy in rheumatoid arthritis. Drug Discov Today 21:172–179

    Article  PubMed  Google Scholar 

  243. Hu W, Chen Y, Dou C, Dong S (2020) Microenvironment in subchondral bone: predominant regulator for the treatment of osteoarthritis. Ann Rheum Dis 80:413–422

    Article  Google Scholar 

  244. Lu J, Zhang H, Cai D, Zeng C, Lai P, Shao Y, Fang H, Li D, Ouyang J, Zhao C, Xie D, Huang B, Yang J, Jiang Y, Bai X (2018) Positive-feedback regulation of subchondral H-type vessel formation by chondrocyte promotes osteoarthritis development in mice. J Bone Miner Res 33:909–920

    Article  CAS  PubMed  Google Scholar 

  245. Nagai T, Sato M, Kutsuna T, Kokubo M, Ebihara G, Ohta N, Mochida J (2010) Intravenous administration of anti-vascular endothelial growth factor humanized monoclonal antibody bevacizumab improves articular cartilage repair. Arthritis Res Ther 12:R178

    Article  PubMed  PubMed Central  Google Scholar 

  246. Yu SP, Hunter DJ (2015) Emerging drugs for the treatment of knee osteoarthritis. Expert Opin Emerg Drugs 20:361–378

    Article  CAS  PubMed  Google Scholar 

  247. Zweers MC, de Boer TN, van Roon J, Bijlsma JW, Lafeber FP, Mastbergen SC (2011) Celecoxib: considerations regarding its potential disease-modifying properties in osteoarthritis. Arthritis Res Ther 13:239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Alten R, Gram H, Joosten LA, van den Berg WB, Sieper J, Wassenberg S, Burmester G, van Riel P, Diaz-Lorente M, Bruin GJ, Woodworth TG, Rordorf C, Batard Y, Wright AM, Jung T (2008) The human anti-IL-1 beta monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis. Arthritis Res Ther 10:R67

    Article  PubMed  PubMed Central  Google Scholar 

  249. Cheleschi S, Cantarini L, Pascarelli NA, Collodel G, Lucherini OM, Galeazzi M, Fioravanti A (2015) Possible chondroprotective effect of canakinumab: an in vitro study on human osteoarthritic chondrocytes. Cytokine 71:165–172

    Article  CAS  PubMed  Google Scholar 

  250. Gaur K, Kori ML, Tyagi LK, Singh V, Sharma CS (2009) Licofelone- novel analgesic and anti-inflammatory agent for osteoarthritis: an overview. J Young Pharm 1:67–71

    Article  CAS  Google Scholar 

  251. Pelletier JP, Boileau C, Boily M, Brunet J, Mineau F, Geng C, Reboul P, Laufer S, Lajeunesse D, Martel-Pelletier J (2005) The protective effect of licofelone on experimental osteoarthritis is correlated with the downregulation of gene expression and protein synthesis of several major cartilage catabolic factors: MMP-13, cathepsin K and aggrecanases. Arthritis Res Ther 7:R1091-1102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Yang G, Chang CC, Yang Y, Yuan L, Xu L, Ho CT, Li S (2018) Resveratrol alleviates rheumatoid arthritis via reducing ROS and inflammation, inhibiting MAPK signaling pathways, and suppressing angiogenesis. J Agric Food Chem 66:12953–12960

    Article  CAS  PubMed  Google Scholar 

  253. Jiang L, Xu K, Li J, Zhou X, Xu L, Wu Z, Ma C, Ran J, Hu P, Bao J, Wu L, Xiong Y (2020) Nesfatin-1 suppresses interleukin-1beta-induced inflammation, apoptosis, and cartilage matrix destruction in chondrocytes and ameliorates osteoarthritis in rats. Aging 12:1760–1777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Ma Y, Tu C, Liu W, Xiao Y, Wu H (2019) Isorhapontigenin suppresses interleukin-1beta-induced inflammation and cartilage matrix damage in rat chondrocytes. Inflammation 42:2278–2285

    Article  CAS  PubMed  Google Scholar 

  255. Landman EB, Miclea RL, van Blitterswijk CA, Karperien M (2013) Small molecule inhibitors of WNT/beta-catenin signaling block IL-1beta- and TNFalpha-induced cartilage degradation. Arthritis Res Ther 15:R93

    Article  PubMed  PubMed Central  Google Scholar 

  256. Lietman C, Wu B, Lechner S, Shinar A, Sehgal M, Rossomacha E, Datta P, Sharma A, Gandhi R, Kapoor M, Young PP (2018) Inhibition of Wnt/beta-catenin signaling ameliorates osteoarthritis in a murine model of experimental osteoarthritis. JCI Insight 3:e96308

    Article  PubMed Central  Google Scholar 

  257. Cui Z, Crane J, Xie H, Jin X, Zhen G, Li C, Xie L, Wang L, Bian Q, Qiu T, Wan M, Xie M, Ding S, Yu B, Cao X (2016) Halofuginone attenuates osteoarthritis by inhibition of TGF-beta activity and H-type vessel formation in subchondral bone. Ann Rheum Dis 75:1714–1721

    Article  CAS  PubMed  Google Scholar 

  258. Chen Y, Xue K, Zhang X, Zheng Z, Liu K (2018) Exosomes derived from mature chondrocytes facilitate subcutaneous stable ectopic chondrogenesis of cartilage progenitor cells. Stem Cell Res Ther 9:318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Jászai J, Schmidt JMHH (2019) Trends and challenges in tumor anti-angiogenic therapies. Cells 8:1102

    Article  PubMed Central  Google Scholar 

  260. Kato T, Miyaki S, Ishitobi H, Nakamura Y, Nakasa T, Lotz MK, Ochi M (2014) Exosomes from IL-1beta stimulated synovial fibroblasts induce osteoarthritic changes in articular chondrocytes. Arthritis Res Ther 16:R163

    Article  PubMed  PubMed Central  Google Scholar 

  261. Tu M, Yao Y, Qiao FH, Wang L (2019) The pathogenic role of connective tissue growth factor in osteoarthritis. Biosci Rep 39:BSR20191374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Chien SY, Huang CY, Tsai CH, Wang SW, Lin YM, Tang CH (2016) Interleukin-1beta induces fibroblast growth factor 2 expression and subsequently promotes endothelial progenitor cell angiogenesis in chondrocytes. Clin Sci 130:667–681

    Article  CAS  Google Scholar 

  263. Sasaki K, Hattori T, Fujisawa T, Takahashi K, Inoue H, Takigawa M (1998) Nitric oxide mediates interleukin-1-induced gene expression of matrix metalloproteinases and basic fibroblast growth factor in cultured rabbit articular chondrocytes. J Biochem 123:431–439

    Article  CAS  PubMed  Google Scholar 

  264. Melinte R, Jung I, Georgescu L, Gurzu S (2012) VEGF and CD31 expression in arthritic synovium and cartilage of human knee joints. Rom J Morphol Embryol 53:911–915

    CAS  PubMed  Google Scholar 

  265. Ben-Av P, Crofford LJ, Wilder RL, Hla T (1995) Induction of vascular endothelial growth factor expression in synovial fibroblasts by prostaglandin E and interleukin-1: a potential mechanism for inflammatory angiogenesis. FEBS Lett 372:83–87

    Article  CAS  PubMed  Google Scholar 

  266. Pufe T, Petersen W, Tillmann B, Mentlein R (2001) The splice variants VEGF121 and VEGF189 of the angiogenic peptide vascular endothelial growth factor are expressed in osteoarthritic cartilage. Arthritis Rheum 44:1082–1108

    Article  CAS  PubMed  Google Scholar 

  267. Fagiani E, Christofori G (2013) Angiopoietins in angiogenesis. Cancer Lett 328:18–26

    Article  CAS  PubMed  Google Scholar 

  268. Koch AE, Friedman J, Burrows JC, Haines GK, Bouck NP (1993) Localization of the angiogenesis inhibitor thrombospondin in human synovial tissues. Pathobiology 61:1–6

    Article  CAS  PubMed  Google Scholar 

  269. Scott BB, Zaratin PF, Gilmartin AG, Hansbury MJ, Colombo A, Belpasso C, Winkler JD, Jackson JR (2005) TNF-alpha modulates angiopoietin-1 expression in rheumatoid synovial fibroblasts via the NF-kappa B signalling pathway. Biochem Biophys Res Commun 328:409–414

    Article  CAS  PubMed  Google Scholar 

  270. Mabey T, Honsawek S, Saetan N, Poovorawan Y, Tanavalee A, Yuktanandana P (2014) Angiogenic cytokine expression profiles in plasma and synovial fluid of primary knee osteoarthritis. Int Orthop 38:1885–1892

    Article  PubMed  Google Scholar 

  271. Dey P, Panga V, Raghunathan S (2016) A cytokine signalling network for the regulation of inducible nitric oxide synthase expression in rheumatoid arthritis. PLoS ONE 11:e0161306

    Article  PubMed  PubMed Central  Google Scholar 

  272. Rico MC, Rough JJ, DelCarpio-Cano FE, Kunapuli SP, De La Cadena RA (2010) The axis of thrombospondin-1, transforming growth factor beta and connective tissue growth factor: an emerging therapeutic target in rheumatoid arthritis. Curr Vasc Pharmacol 8:338–343

    Article  CAS  PubMed  Google Scholar 

  273. Uchida T, Nakashima M, Hirota Y, Miyazaki Y, Tsukazaki T, Shindo H (2000) Immunohistochemical localisation of protein tyrosine kinase receptors Tie-1 and Tie-2 in synovial tissue of rheumatoid arthritis: correlation with angiogenesis and synovial proliferation. Ann Rheum Dis 59:607–614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Pufe T, Petersen W, Tillmann B, Mentlein R (2001) Splice variants VEGF121 and VEGF165 of the angiogenic peptide vascular endothelial cell growth factor are expressed in the synovial tissue of patients with rheumatoid arthritis. J Rheumatol 28:1482–1485

    CAS  PubMed  Google Scholar 

  275. Hunziker EB, Driesang IM (2003) Functional barrier principle for growth-factor-based articular cartilage repair. Osteoarthr Cartil 11:320–327

    Article  CAS  Google Scholar 

  276. Chanalaris A, Doherty C, Marsden BD, Bambridge G, Wren SP, Nagase H, Troeberg L (2017) Suramin inhibits osteoarthritic cartilage degradation by increasing extracellular levels of chondroprotective tissue inhibitor of metalloproteinases 3. Mol Pharmacol 92:459–468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  277. Yahara Y, Takemori H, Okada M, Kosai A, Yamashita A, Kobayashi T, Fujita K, Itoh Y, Nakamura M, Fuchino H, Kawahara N, Fukui N, Watanabe A, Kimura T, Tsumaki N (2016) Pterosin B prevents chondrocyte hypertrophy and osteoarthritis in mice by inhibiting Sik3. Nat Commun 7:10959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Suzanne Danley for editing the manuscript.

Funding

This work was supported by Research Grants from the National Institutes of Health (1R01AR067747) to M.P., and Health Commission of Sichuan Province (18PJ008), General project of The General Hospital of Western Theater Command (2021-XZYG-B07), and Science & Technology Department of Sichuan Province (2019YFS0267) to S.C.

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  1. Song Chen: co-first author.

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  1. Stem Cell and Tissue Engineering Laboratory, Department of Orthopaedics, West Virginia University, 64 Medical Center Drive, PO Box 9196, Morgantown, WV, 26506-9196, USA

    Yixuan Amy Pei & Ming Pei

  2. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Yixuan Amy Pei

  3. Department of Orthopaedics, The General Hospital of Western Theater Command, Chengdu, 610083, Sichuan, China

    Song Chen

  4. WVU Cancer Institute, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV, USA

    Ming Pei

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YAP: collected the data; performed data analysis; wrote the paper; approved the submission. SC: collected the data; performed data analysis; wrote the paper; approved the submission. MP: conceived and designed the analysis; performed data analysis; wrote the paper; approved the submission; supervision; funding acquisition.

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Pei, Y.A., Chen, S. & Pei, M. The essential anti-angiogenic strategies in cartilage engineering and osteoarthritic cartilage repair. Cell. Mol. Life Sci. 79, 71 (2022). https://doi.org/10.1007/s00018-021-04105-0

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