Skip to main content

Advertisement

SpringerLink
Log in

Mechanisms of TGFβ3 Action as a Therapeutic Agent for Promoting the Synthesis of Extracellular Matrix Proteins in Hyaline Cartilage

  • Review
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

Hyaline cartilage is a nonvascular connective tissue covering the joint surface. It consists mostly of the extracellular matrix proteins and a small number of highly differentiated chondrocytes. At present, various techniques for repairing joint surfaces damage, for example, the use of modified cell cultures and biodegradable scaffolds, are under investigation. Molecular mechanisms of cartilage tissue proliferation have been also actively studied in recent years. TGFβ3, which plays a critical role in the proliferation of normal cartilage tissue, is one of the most important protein among cytokines and growth factors affecting chondrogenesis. By interacting directly with receptors on the cell membrane surface, TGFβ3 triggers a cascade of molecular interactions involving transcription factor Sox9. In this review, we describe the effects of TGFβ3 on the receptor complex activation and subsequent intracellular trafficking of Smad proteins and analyze the relation between these processes and upregulation of expression of major extracellular matrix genes, such as col2a1 and acan.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Figure.

Similar content being viewed by others

Abbreviations

BMP:

bone morphogenetic protein

CTEC:

cell-based tissue engineered construct

FSH:

follicle-stimulating hormone

GDF:

growth differentiation factor

MIF:

Müllerian inhibiting factor

MMSC:

mesenchymal multipotent stromal cell

SARA:

Smad anchor for receptor activation

SBE:

Smad-binding element

Sp1:

special protein

SUM:

small ubiquitin-like modifier

TGFβ:

transforming growth factor

REFERENCES

  1. Bozhokin, M. S., Bozhkova, S. A., and Netyl’ko G. I. (2016) Opportunities of contemporary cell technologies for recovery of damaged articular cartilage (analytical review) [in Russian], Travmatol. Ortoped. Ross., 22, 122-134, doi: 10.21823/2311-2905-2016-22-3-122-134.

    Article  Google Scholar 

  2. Sophia Fox, A. J., Bedi, A., and Rodeo, S. A. (2009) The basic science of articular cartilage: structure, composition, and function, Sports Health, 1, 461-468, doi: 10.1177/1941738109350438.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Bozhokin, M. S., Bozhkova, S. A., Netyl’ko, G. I., Rumakin, V. P., Nakonechnyy, D. G., and Chepurnenko, M. N. (2017) Morphofunctional characteristics of chondroregenerative process in experimental local superficial defect of articular cartilage [in Russian], Mezhdunarod. Zhurn. Prikl. Fundamental. Issled., 8, 302-306.

    Google Scholar 

  4. Maglio, M., Brogini, S., Pagani, S., Giavaresi, G., and Tschon, M. (2019) Current trends in the evaluation of osteochondral lesion treatments: histology, histomorphometry, and biomechanics in preclinical models, Bio. Med. Res. Intern., 2019, 4040236, doi: 10.1155/2019/4040236.

    Article  CAS  Google Scholar 

  5. Kurtz, S., Ong, K., Lau, E., Mowat, F., and Halpern, M. (2007) Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030, J. Bone Joint Surg. Am., 89, 780-785, doi: 10.2106/JBJS.F.00222.

    Article  PubMed  Google Scholar 

  6. Brittberg, M., Lindahl, A., Nilsson, A., Ohlsson, C., Isaksson, O., and Peterson, L. (1994) Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation, N. Engl. J. Med., 6, 889-895, doi: 10.1056/NEJM199410063311401.

    Article  Google Scholar 

  7. Xiang, Y., Bunpetch, V., Zhou, W., and Ouyang, H. (2019) Optimization strategies for ACI: a step-chronicle review, J. Orthop. Translat., 17, 3-14, doi: 10.1016/j.jot.2018.12.005.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Elmallah, R., Cherian, J., Jauregui, J., Pierce, T., Beaver, W., and Mont, M. (2015) Genetically modified chondrocytes expressing TGF-β1: a revolutionary treatment for articular cartilage damage? Expert Opin. Biol. Ther., 15, 455-464, doi: 10.1517/14712598.2015.1009886.

    Article  CAS  PubMed  Google Scholar 

  9. Finnson, K., Chi, Y., Bou-Gharios, G., Leask, A., and Philip, A. (2012) TGF-beta signaling in cartilage homeostasis and osteoarthritis, Front. Biosci. (Schol. Ed.), 1, 251-268, doi: 10.2741/s266.

    Article  Google Scholar 

  10. Jeuken, R., Roth, A., Peters, R., Van Donkelaar, C., Thies, J., Van Rhijn, L., and Emans, P. J. (2016) Polymers in cartilage defect repair of the knee: current status and future prospects, Polymers, 4, 8, doi: 10.3390/polym8060219.

    Article  CAS  Google Scholar 

  11. Plánka, L., Starý, D., Srnec, R., Necas, A., and Gál, P. (2008) New options for management of posttraumatic articular cartilage defects, Rozhledy v Chirurgii : Měsíčník Československé Chirurgické Společnosti, 87, 1, 42-45.

    Google Scholar 

  12. Diederichs, S., Gabler, J., Autenrieth, J., Kynast, K., Merle, C., Walles, H., Utikal, J., and Richter, W. (2016) Differential regulation of SOX9 protein during chondrogenesis of induced pluripotent stem cells versus mesenchymal stromal cells: a shortcoming for cartilage formation, Stem Cells Dev., 25, 598-609, doi: 10.1089/scd.2015.0312.

    Article  CAS  PubMed  Google Scholar 

  13. Skuse, G., and Lamkin-Kennard, K. (2013) Reverse engineering life: physical and chemical mimetics for controlled stem cell differentiation into cardiomyocytes, Methods Mol. Biol., 1001, 99-114, doi: 10.1007/978-1-62703-363-3_9.

    Article  CAS  PubMed  Google Scholar 

  14. Tokuda, S., and Yu, A. (2019) Regulation of epithelial cell functions by the osmolality and hydrostatic pressure gradients: a possible role of the tight junction as a sensor, Intern. J. Mol. Sci., 20, doi: 10.3390/ijms20143513.

    Article  Google Scholar 

  15. Vieira, H., Alves, P., and Vercelli, A. (2011) Modulation of neuronal stem cell differentiation by hypoxia and reactive oxygen species, Prog. Neurobiol., 93, 444-455, doi: 10.1016/j.pneurobio.2011.01.007.

    Article  CAS  PubMed  Google Scholar 

  16. Khamo, J., Krishnamurthy, V., Sharum, S., Mondal, P., and Zhang, K. (2017) Applications of optobiology in intact cells and multicellular organisms, J. Mol. Biol., 429, 2999-3017, doi: 10.1016/j.jmb.2017.08.015.

    Article  CAS  PubMed  Google Scholar 

  17. Bozhokin, M. S., Bozhkova, S. A., Netyl’ko, G. I., Nakonechnyy, D. G., Blinova, M. I., and Nashchekina, Yu. A. (2018) Results of replacing superficial defect in rat hyaline cartilage by experimental cell engineering construct [in Russian], Trudy Karel’skogo NTs RAN, 4, 13-22, doi: 10.17076/them815.

    Article  Google Scholar 

  18. Kuroda, Y., Kawai, T., Goto, K., and Matsuda, S. (2019) Clinical application of injectable growth factor for bone regeneration: a systematic review, Inflamm. Regen., 39, 1-10, doi: 10.1186/s41232-019-0109-x.

    Article  CAS  Google Scholar 

  19. Hamann, A., Nguyen, A., and Pannier, A. (2019) Nucleic acid delivery to mesenchymal stem cells: a review of nonviral methods and applications, J. Biol. Engin., 13, 7, doi: 10.1186/s13036-019-0140-0.

    Article  Google Scholar 

  20. Oggu, G., Sasikumar, S., Reddy, N., Ella, K., Rao, C., and Bokara, K. (2017) Gene delivery approaches for mesenchymal stem cell therapy: strategies to increase efficiency and specificity, Stem Cell Rev., 13, 725-740, doi: 10.1007/s12015-017-9760-2.

    Article  CAS  Google Scholar 

  21. Hata, A., and Chen, Y. (2016) TGF-β signaling from receptors to Smads, Cold Spring Harb. Perspect. Biol., 8, doi: 10.1101/cshperspect.a022061.

    Article  Google Scholar 

  22. Yang, X., Chen, L., Xu, X., Li, C., Huang, C., and Deng, C. (2001) TGF-β/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage, J. Cell Biol., 153, 35-46.

    Article  CAS  Google Scholar 

  23. Moses, H., Roberts, A., and Derynck, R. (2016) The discovery and early days of TGF-b: a historical perspective, Cold Spring Harb. Perspect. Biol., 8, doi: 10.1101/cshperspect.a021865.

    Article  Google Scholar 

  24. Derynck, R., and Budi, E. (2019) Specificity, versatility, and control of TGF-β family signaling, Sci. Signal., 12, 570, doi: 10.1126/scisignal.aav5183.

    Article  CAS  Google Scholar 

  25. De Larco, J., and Todaro, G. (1978) Growth factors from murine sarcoma virus-transformed cells, Proc. Natl. Acad. Sci. USA, 75, 4001-4005.

    Article  CAS  Google Scholar 

  26. Todaro, G., De Larco, J., and Fryling, C. (1982) Sarcoma growth factor and other transforming peptides produced by human cells: interactions with membrane receptors, Fed. Proc., 41, 2996-3003.

    CAS  PubMed  Google Scholar 

  27. Kastin, A. (2013) Handbook of Biologically Active Peptides, Chapter 225, doi: 10.1016/C2010-0-66490-X.

  28. Assoian, R., Komoriya, A., Meyers, C., Miller, D., and Sporn, M. (1983) Transforming growth factor-β in human platelets. Identification of a major storage site, purification, and characterization, J. Biol. Chem., 258, 7155-7160.

    CAS  PubMed  Google Scholar 

  29. Frenkel, S., Saadeh, P., Mehrara, B., Chin, G., Steinbrech, D., Brent, B., Gittes, G., and Longaker, M. (2000) Transforming growth factor beta superfamily members: role in cartilage modeling, Plast. Reconstr. Surg., 105, 980-990, doi: 10.1097/00006534-200003000-00022.

    Article  CAS  PubMed  Google Scholar 

  30. Reddi, A., and Cunningham, N. (1990) Bone induction by osteogenin and bone morphogenetic proteins, Biomaterials, 11, 33-34.

    CAS  PubMed  Google Scholar 

  31. Glick, A., Weinberg, W., Wu, I., Quan, W., and Yuspa, S. (1996) Transforming growth factor beta 1 suppresses genomic instability independent of a G1 arrest, p53, and Rb, Cancer Res., 56, 3645-3650.

    CAS  PubMed  Google Scholar 

  32. Massagué, J. (1999) Wounding Smad, Nat. Cell Biol., 1, 117-119, doi: 10.1038/12944.

    Article  Google Scholar 

  33. Herpin, A., Lelong, C., and Favrel, P. (2004) Transforming growth factor-β-related proteins: an ancestral and widespread superfamily of cytokines in metazoans, Dev. Comp. Immunol., 28, 461-485, doi: 10.1016/j. dci. 2003.09.007.

    Article  CAS  PubMed  Google Scholar 

  34. Kwiatkowski, W., Gray, P., and Choe, S. (2014) Engineering TGF-β superfamily ligands for clinical applications, Trends Pharmacol. Sci., 35, 648-657, doi: 10.1016/j.tips.2014.10.006.

    Article  CAS  PubMed  Google Scholar 

  35. Lu, Y., Boer, J., Barsova, R., Favorova, O., Goel, A., Müller, M., and Feskens, E. (2012) TGFB1 genetic polymorphisms and coronary heart disease risk: a meta-analysis, BMC Med. Genet., 13, 39, doi: 10.1186/1471-2350-13-39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rao, K., Nagireddy, S., and Chakrabarti, S. (2011) Complex genetic mechanisms in glaucoma: an overview, Ind. J. Ophthalm., 59, 31-42, doi: 10.4103/0301-4738.73685.

    Article  Google Scholar 

  37. Leutermann, R., Sheikhzadeh, S., Brockstädt, L., Rybczynski, M., van Rahden, V., Kutsche, K., von Kodolitsch, Y., and Rosenberger, G. (2014) A 1-bp duplication in TGFB2 in three family members with a syndromic form of thoracic aortic aneurysm, Eur. J. Hum. Genet., 22, 944-948, doi: 10.1038/ejhg.2013.252.

    Article  CAS  PubMed  Google Scholar 

  38. Occleston, N., Laverty, H., O’Kane, S., and Ferguson, M. (2008) Prevention and reduction of scarring in the skin by transforming growth factor beta 3 (TGFβ3): from laboratory discovery to clinical pharmaceutical, J. Biomater. Sci., Polymer Edition, 19, 1047-1063, doi: 10.1163/156856208784909345.

    Article  CAS  Google Scholar 

  39. Gilbert, R., Vickaryous, M., and Viloria-Petit, A. (2016) Signalling by transforming growth factor beta isoforms in wound healing and tissue regeneration, J. Dev. Biol., 22, 4, doi: 10.3390/jdb4020021.

    Article  CAS  Google Scholar 

  40. Furumatsu, T., Tsuda, M., Taniguchi, N., Tajima, Y., and Asahara, H. (2005) Smad3 induces chondrogenesis through the activation of SOX9 via CREB-binding protein/p300 recruitment, J. Biol. Chem., 280, 8343-8350, doi: 10.1074/jbc.M413913200.

    Article  CAS  PubMed  Google Scholar 

  41. Yu, J., Shao, L., Lemas, V., Yu, A., Vaughan, J., Rivier, J., and Vale, W. (1987) Importance of FSH-releasing protein and inhibin in erythrodifferentiation, Nature, 330, 765-767, doi: 10.1038/330765a0.

    Article  CAS  PubMed  Google Scholar 

  42. Bloise, E., Ciarmela, P., Cruz, C., Luisi, S., Petraglia, F., and Reis, F. (2019) Activin A in mammalian physiology, Physiol. Rev., 99, 739-780, doi: 10.1152/physrev.00002.2018.

    Article  CAS  PubMed  Google Scholar 

  43. Ling, N., Ying, S., Ueno, N., Shimasaki, S., Esch, F., Hotta, M., and Guillemin, R. (1986) Pituitary FSH is released by a heterodimer of the β-subunits from the two forms of inhibin, Nature, 321, 779-782, doi: 10.1038/321779a0.

    Article  CAS  PubMed  Google Scholar 

  44. Namwanje, M., and Brown, C. (2016) Activins and inhibins: roles in development, physiology, and disease, Cold Spring Harb. Perspect. Biol., 8, doi: 10.1101/cshperspect.a021881.

    Article  Google Scholar 

  45. Chin, D., Boyl, G., Parsons, P., and Coman, W. (2004) What is transforming growth factor-beta (TGF-β)? Brit. J. Plastic Surg., 57, 215-221, doi: 10.1016/j.bjps.2003.12.012.

    Article  Google Scholar 

  46. Kushnir, V., Seifer, D., Barad, D., Sen, A., and Gleicher, N. (2017) Potential therapeutic applications of human anti-Müllerian hormone (AMH) analogues in reproductive medicine, J. Assist. Reprod. Genet., 34, 1105-1113, doi: 10.1007/s10815-017-0977-4.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Tabibzadeh, S., and Hemmati-Brivanlou, A. (2006) Lefty at the crossroads of “stemness” and differentiative events, Stem Cells, 24, 1998-2006, doi: 10.1634/stemcells.2006-0075.

    Article  CAS  PubMed  Google Scholar 

  48. Jones, C., Kuehn, M., Hogan, B., Smith, J., and Wright, C. (1995) Nodal-related signals induce axial mesoderm and dorsalize mesoderm during gastrulation, Development, 121, 3651-3662.

    CAS  PubMed  Google Scholar 

  49. Morikawa, M., Derynck, R., and Miyazono, K. (2016) TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology, Cold Spring Harb. Perspect. Biol., 2, 8, doi: 10.1101/cshperspect.a021873.

    Article  CAS  Google Scholar 

  50. Papageorgis, P., and Stylianopoulos, T. (2015) Role of TGFβ in regulation of the tumor microenvironment and drug delivery (review), Int. J. Oncol., 46, 933-943, doi: 10.3892/ijo.2015.2816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gatza, C., Oh, S., and Blobe, G. (2010) Roles for the type III TGF-β receptor in human cancer, Cell. Signal., 22, 1163-1174, doi: 10.1016/j.cellsig.2010.01.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lawler, S., Feng, X., Chen, R., Maruoka, E., Turck, C., Griswold-Prenner, I., and Derynck, R. (1997) The type II transforming growth factor-β receptor autophosphorylates not only on serine and threonine but also on tyrosine residues, J. Biol. Chem., 272, 14850-14859, doi: 10.1074/jbc.272.23.14850.

    Article  CAS  PubMed  Google Scholar 

  53. Heldin, C., and Moustakas, A. (2016) Signaling receptors for TGF-β family members, Cold Spring Harb. Perspect. Biol., 8, 8, doi: 10.1101/cshperspect.a022053.

    Article  CAS  Google Scholar 

  54. Ahmadi, A., Najafi, M., Farhood, B., and Mortezaee, K. (2019) Transforming growth factor-β signaling: tumorigenesis and targeting for cancer therapy, J. Cell. Physiol., 234, 12173-12187, doi: 10.1002/jcp.27955.

    Article  CAS  PubMed  Google Scholar 

  55. Wrana, J., Attisano, L., Cárcamo, J., Zentella, A., Doody, J., Laiho, M., Wang, X., and Massagué, J. (1992) TGFβ signals through a heteromeric protein kinase receptor complex, Cell, 71, 1003-1014, doi: 10.1016/0092-8674(92)90395-S.

    Article  CAS  PubMed  Google Scholar 

  56. Yamashita, H., ten Dijke, P., Franzén, P., Miyazono, K., and Heldin, C. (1994) Formation of hetero-oligomeric complexes of type I and type II receptors for transforming growth factor-β, J. Biol. Chem., 269, 20172-20178.

    CAS  PubMed  Google Scholar 

  57. Massagué, J. (1998) TGF-beta signal transduction, Annu. Rev. Biochem., 67, 753-791, doi: 10.1146/annurev.biochem.67.1.753.

    Article  PubMed  Google Scholar 

  58. Massagué, J., and Chen, Y. (2000) Controlling TGF-beta signaling, Genes Dev., 14, 627-644.

    PubMed  Google Scholar 

  59. Feng, X., and Derynck, R. (2005) Specificity and versatility in TGF-beta signaling through Smads, Annu. Rev. Cell Dev. Biol., 21, 659-693, doi: 10.1146/annurev.cellbio.21.022404.142018.

    Article  CAS  PubMed  Google Scholar 

  60. Huang, T., David, L., Mendoza, V., Yang, Y., Villarreal, M., De, K., Sun, L., Fang, X., López-Casillas, F., Wrana, J., and Hinck, A. (2011) TGF-β signalling is mediated by two autonomously functioning TβRI:TβRII pairs, EMBO J., 30, 1263-1276, doi: 10.1038/emboj.2011.54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Atfi, A., Dumont, E., Colland, F., Bonnier, D., L’helgoualc’h, A., Prunier, C., Ferrand, N., Clément, B., Wewer, U., and Théret, N. (2007) The disintegrin and metalloproteinase ADAM12 contributes to TGF-β signaling through interaction with the type II receptor, J. Cell Biol., 16, 201-208, doi: 10.1083/jcb.200612046.

    Article  CAS  Google Scholar 

  62. Kang, J., Liu, C., and Derynck, R. (2009) New regulatory mechanisms of TGF-β receptor function, Trends Cell Biol., 19, 385-394, doi: 10.1016/j.tcb.2009.05.008.

    Article  CAS  PubMed  Google Scholar 

  63. Imamura, T., Oshima, Y., and Hikita, A. (2013) Regulation of TGF-β family signalling by ubiquitination and deubiquitination, J. Biochem., 154, 481-489, doi: 10.1093/jb/mvt097.

    Article  CAS  PubMed  Google Scholar 

  64. Zuo, W., Huang, F., Chiang, Y., Li, M., Du, J., Ding, Y., Zhang, T., Lee, H., Jeong, L., Chen, Y., Deng, H., Feng, X., Luo, S., Gao, C., and Chen, Y. (2013) c-Cbl-mediated neddylation antagonizes ubiquitination and degradation of the TGF-β type II receptor, Mol. Cell, 49, 499-510, doi: 10.1016/j.molcel.2012.12.002.

    Article  CAS  PubMed  Google Scholar 

  65. Zhang, L., Zhou, F., Drabsch, Y., Gao, R., Snaar-Jagalska, B., Mickanin, C., Huang, H., Sheppard, K., Porter, J., Lu, C., and Dijke, P. (2012) USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-β type I receptor, Nat. Cell Biol., 14, 717-726, doi: 10.1038/ncb2522.

    Article  CAS  PubMed  Google Scholar 

  66. Flotho, A., and Melchior, F. (2013) Sumoylation: a regulatory protein modification in health and disease, Annu. Rev. Biochem., 82, 357-385, doi: 10.1146/annurev-biochem-061909-093311.

    Article  CAS  PubMed  Google Scholar 

  67. Mu, Y., Sundar, R., Thakur, N., Ekman, M., Gudey, S., Yakymovych, M., Hermansson, A., Dimitriou, H., Bengoechea-Alonso, M., Ericsson, J., Heldin, C., and Landström, M. (2011) TRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer, Nat. Commun., 2, 330, doi: 10.1038/ncomms1332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Li, S. B., and Wu, J. F. (2020) TGF-β/SMAD Signaling regulation of mesenchymal stem cells in adipocyte commitment, Rev. Stem Cell Res. Therl., 11, 41, doi: 10.1186/s13287-020-1552-y.

    Article  CAS  Google Scholar 

  69. Nishita, M., Ueno, N., and Shibuya, H. (1999) Smad8B, a Smad8 splice variant lacking the SSXS site that inhibits Smad8-mediated signaling, Genes Cells, 4, 583-591, doi: 10.1046/j.1365-2443.1999.00285.x.

    Article  CAS  PubMed  Google Scholar 

  70. Hill, C. (2009) Nucleocytoplasmic shuttling of Smad proteins, Cell Res., 19, 36-46, doi: 10.1038/cr.2008.325.

    Article  CAS  PubMed  Google Scholar 

  71. Wu, M., Chen, G., and Li, Y. (2016) TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease, Bone Res., 4, 16009, doi: 10.1038/boneres.2016.9.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Kang, J., Alliston, T., Delston, R., and Derynck, R. (2014) Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3, EMBO J., 24, 2543-2555.

    Article  Google Scholar 

  73. Massagué, J. (2014) TGFbeta signalling in context, Nat. Rev. Mol. Cell Biol., 13, 616-630, doi: 10.1038/nrm3434.

    Article  CAS  Google Scholar 

  74. Zhang, S., Fei, T., Zhang, L., Zhang, R., Chen, F., Ning, Y., Han, Y., Feng, X., Meng, A., and Chen, Y. (2007) Smad7 antagonizes transforming growth factor signaling in the nucleus by interfering with functional Smad–DNA complex formation, Mol. Cell. Biol., 27, 4488-4499, doi: 10.1128/mcb.01636-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Gu, W., Monteiro, R., Zuo, J., Simões, F., Martella, A., Andrieu-Soler, C., Grosveld, F., Sauka-Spengler, T., and Patient, R. (2015) A novel TGFβ modulator that uncouples R-Smad/I-Smad-mediated negative feedback from R-Smad/ligand-driven positive feedback, PLoS Biol., 13, doi: 10.1371/journal.pbio.1002051.

    Article  Google Scholar 

  76. Thielen, N., van der Kraan, P., and van Caam, A. (2019) TGFβ/BMP signaling pathway in cartilage homeostasis, Cells, 8, 9, doi: 10.3390/cells8090969.

    Article  CAS  Google Scholar 

  77. Li, Y., Luo, W., and Yang, W. (2018) Nuclear transport and accumulation of Smad proteins studied by single-molecule microscopy, Biophys. J., 114, 2243-2251, doi: 10.1016/j.bpj.2018.03.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Jin, Q., Gao, G., and Mulder, K. (2009) Requirement of a dynein light chain in TGFβ/Smad3 signaling, J. Cell. Physiol., 221, 707-715, doi: 10.1002/jcp.21910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Batut, J., Howell, M., and Hill, C. (2007) Kinesin-mediated transport of Smad2 is required for signaling in response to TGF-β ligands, Dev. Cell., 12, 261-274, doi: 10.1016/j.devcel.2007.01.010.

    Article  CAS  PubMed  Google Scholar 

  80. Massagué, J., Seoane, J., and Wotton, D. (2005) Smad transcription factors, Genes Dev., 19, 2783-2810, doi: 10.1101/gad.1350705.

    Article  CAS  PubMed  Google Scholar 

  81. Hill, C. (2016) Transcriptional control by the SMADs, Cold Spring Harb. Perspect. Biol., 8, doi: 10.1101/cshperspect.a022079.

    Article  Google Scholar 

  82. Qiao, B., Padilla, S., and Benya, P. (2005) Transforming growth factor (TGF)-β-activated kinase 1 mimics and mediates TGF-β-induced stimulation of type II collagen synthesis in chondrocytes independent of Col2a1 transcription and Smad3 signaling, J. Biol. Chem., 280, 17562-17571, doi: 10.1074/jbc.M500646200.

    Article  CAS  PubMed  Google Scholar 

  83. Bhogal, R., Stoica, C., McGaha, T., and Bona, C. (2005) Molecular aspects of regulation of collagen gene expression in fibrosis, J. Clin. Immun., 25, 592-603, doi: 10.1007/s10875-005-7827-3.

    Article  CAS  PubMed  Google Scholar 

  84. Bell, D., Leung, K., Wheatley, S., Ng, L., Zhou, S., Ling, K., Sham, M., Koopman, P., Tam, P., and Cheah, K. (1997) SOX9 directly regulates the type-II collagen gene, Nat. Genet., 16, 174-178, doi: 10.1038/ng0697-174.

    Article  CAS  PubMed  Google Scholar 

  85. Sen, R., Pezoa, S., Carpio, Shull, L., Hernandez-Lagunas, L., Niswander, L., and Artinger, K. (2018) Kat2a and Kat2b acetyltransferase activity regulates craniofacial cartilage and bone differentiation in Zebrafish and mice, J. Dev. Biol., 12, doi: 10.3390/jdb6040027.

    Google Scholar 

  86. Chen, X., Huang, H., Wang, H., Guo, F., Du, X., Ma, L., Zhao, L., Pan, Z., Gui, H., Yuan, T., Liu, X., Song, L., Wang, Y., He, J., Lei, H., and Gao, R. (2014) Characterization of zebrafish pax1b and pax9 in fin bud development, Biomed. Res. Int., 2014, 309385, doi: 10.1155/2014/309385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Seoane, J., Le, H., Shen, L., Anderson, S., and Massagué, J. (2004) Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation, Cell, 117, 211-223, doi: 10.1016/S0092-8674(04)00298-3.

    Article  CAS  PubMed  Google Scholar 

  88. Naka, K., Hoshii, T., Muraguchi, T., Tadokoro, Y., Ooshio, T., Kondo, Y., Nakao, S., Motoyama, N., and Hirao, A. (2010) TGF-β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia, Nature, 463, 676-680, doi: 10.1038/nature08734.

    Article  CAS  PubMed  Google Scholar 

  89. Kang, Y., Chen, C., and Massagué, J. (2003) A self-enabling TGFβ response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells, Mol. Cell, 11, 915-926, doi: 10.1016/S1097-2765(03)00109-6.

    Article  CAS  PubMed  Google Scholar 

  90. Vincent, T., Neve, E., Johnson, J., Kukalev, A., Rojo, F., Albanell, J., Pietras, K., Virtanen, I., Philipson, L., Leopold, P., Crystal, R., de Herreros, A., Moustakas, A., Pettersson, R., and Fuxe, J. (2009) A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial-mesenchymal transition, Nat. Cell Biol., 11, 943-950, doi: 10.1038/ncb1905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Pardali, K., Kurisaki, A., Morén, A., ten Dijke, P., Kardassis, D., and Moustakas, A. (2000) Role of Smad proteins and transcription factor Sp1 in p21Waf1/Cip1 regulation by transforming growth factor-β, J. Biol. Chem., 275, 29244-29256, doi: 10.1074/jbc.M909467199.

    Article  CAS  PubMed  Google Scholar 

  92. Baugé, C., Cauvard, O., Leclercq, S., Galéra, P., and Boumédiene, K. (2011) Modulation of transforming growth factor beta signalling pathway genes by transforming growth factor beta in human osteoarthritic chondrocytes: Involvement of Sp1 in both early and late response cells to transforming growth factor beta, Arthritis Res. Ther., 13, 23, doi: 10.1186/ar3247.

    Article  Google Scholar 

  93. Blaney Davidson, E., Remst, D. F., Vitters, E., van Beuningen, H., Blom, A., Goumans, M., van den Berg, W., and van der Kraan, P. (2009) Increase in ALK1/ALK5 ratio as a cause for elevated MMP-13 expression in osteoarthritis in humans and mice, J. Immunol., 182, 7937-7945, doi: 10.4049/jimmunol.0803991.

    Article  CAS  PubMed  Google Scholar 

  94. Siomi, H., and Siomi, M. (2010) Posttranscriptional regulation of microRNA biogenesis in animals, Mol. Cell, 38, 323-332, doi: 10.1016/j.molcel.2010.03.013.

    Article  CAS  PubMed  Google Scholar 

  95. Ha, M., and Kim, V. (2014) Regulation of microRNA biogenesis, Nat. Rev. Mol. Cell Biol., 15, 509-524, doi: 10.1038/nrm3838.

    Article  CAS  PubMed  Google Scholar 

  96. Blahna, M., and Hata, A. (2012) Smad-mediated regulation of microRNA biosynthesis, FEBS Lett., 586, 1906-1912, doi: 10.1016/j.febslet.2012.01.041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhang, Y., Huang, X., and Yuan, Y. (2017) MicroRNA-410 promotes chondrogenic differentiation of human bone marrow mesenchymal stem cells through down-regulating Wnt3a, Am. J. Transl. Res., 9, 136-145.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Lee, S., Yoon, D., Paik, S., Lee, K., Jang, Y., and Lee, J. (2014) MicroRNA-495 Inhibits chondrogenic differentiation in human mesenchymal stem cells by targeting Sox9, Stem Cells Dev., 23, 1798-1808, doi: 10.1089/scd.2013.0609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Crecente-Campo, J., Borrajo, E., Vidal, A., and Garcia-Fuentes, M. (2017) New scaffolds encapsulating TGF-β3/BMP-7 combinations driving strong chondrogenic differentiation, Eur. J. Pharm. Biopharm., 114, 69-78, doi: 10.1016/j.ejpb.2016.12.021.

    Article  CAS  PubMed  Google Scholar 

  100. Wang, J., Sun, B., Tian, L., He, X., Gao, Q., Wu, T., Ramakrishna, S., Zheng, J., and Mo, X. (2017) Evaluation of the potential of rhTGF-β3 encapsulated P(LLA-CL)/collagen nanofibers for tracheal cartilage regeneration using mesenchymal stems cells derived from Wharton’s jelly of human umbilical cord, Mater. Sci. Eng., 70, 637-645, doi: 10.1016/j.msec.2016.09.044.

    Article  CAS  Google Scholar 

  101. Yanagawa, Y., Hiraide, S., and Iizuka, K. (2016) Isoform-specific regulation of transforming growth factor-β mRNA expression in macrophages in response to adrenoceptor stimulation, Microbiol. Immunol., 60, 56-63, doi: 10.1111/1348-0421.12344.

    Article  CAS  PubMed  Google Scholar 

  102. Frangogiannis, N. G. (2017) The role of transforming growth factor (TGF)-β in the infarcted myocardium, J. Thor. Dis., 9, 52-63, doi: 10.21037/jtd.2016.11.19.

    Article  Google Scholar 

  103. Luo, Z., Jiang, L., Xu, Y., Li, H., Xu, W., Wu, S., Wang, Y., Tang, Z., Lv, Y., and Yang, L. (2015) Mechano growth factor (MGF) and transforming growth factor (TGF)-β3 functionalized silk scaffolds enhance articular hyaline cartilage regeneration in rabbit model, Biomaterials, 52, 463-475, doi: 10.1016/j.biomaterials.2015.01.001.

    Article  CAS  PubMed  Google Scholar 

  104. Yang, S. S., Jin, L. H., Park, S. H., Kim, M. S., Kim, Y. J., Choi, B. H., Lee, C. T., Park, S. R., and Min, B. H. (2016) Extracellular matrix (ECM) multilayer membrane as a sustained releasing growth factor delivery system for rhTGF-β3 in articular cartilage repair, PLoS One, 11, e0156292, doi: 10.1371/journal.pone.0156292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Yang, Q., Teng, B. H., Wang, L. N., Li, K., Xu, C., Ma, X. L., Zhang, Y., Kong, D. L., Wang, L. Y., and Zhao, Y. H. (2017) Silk fibroin/cartilage extracellular matrix scaffolds with sequential delivery of TGF-β3 for chondrogenic differentiation of adipose-derived stem cells, Int. J. Nanomed., 12, 6721-6733, doi: 10.2147/IJN.S141888.

    Article  CAS  Google Scholar 

  106. Wang, X., Li, Y., Han, R., He, C., Wang, G., Wang, J., Zheng, J., Pei, M., and Wei, L. (2014) Demineralized bone matrix combined bone marrow mesenchymal stem cells, bone morphogenetic protein-2 and transforming growth factor-β3 gene promoted pig cartilage defect repair, PLoS One, 9, e116061, doi: 10.1371/journal.pone.0116061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sun, Q., Zhang, L., Xu, T., Ying, J., Xia, B., Jing, H., and Tong, P. (2018) Combined use of adipose derived stem cells and TGF-β3 microspheres promotes articular cartilage regeneration in vivo, Biotech. Histochem., 93, 168-176, doi: 10.1080/10520295.2017.1401663.

    Article  CAS  PubMed  Google Scholar 

  108. Zhou, M., Lozano, N., Wychowaniec, J. K., Hodgkinson, T., Richardson, S. M., Kostarelos, K., and Hoyland, J. A. (2019) Graphene oxide: a growth factor delivery carrier to enhance chondrogenic differentiation of human mesenchymal stem cells in 3D hydrogels, Acta Biomater., 96, 271-280, doi: 10.1016/j.actbio.2019.07.027.

    Article  CAS  PubMed  Google Scholar 

  109. Rothrauff, B., Sasaki, H., Kihara, S., Overholt, K., Gottardi, R., Lin, H., Fu, F., Tuan, R., and Alexander, P. (2019) Point-of-care procedure for enhancement of meniscal healing in a goat model utilizing infrapatellar fat pad-derived stromal vascular fraction cells seeded in photocrosslinkable hydrogel, Am. J. Sports Med., 47, 3396-3405, doi: 10.1177/0363546519880468.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the Chromas Shared Use Center, Biobank, Center for Molecular and Cell Technologies, and Research Park of Saint Petersburg State University for collaboration.

Funding

This study was performed within the framework of the Russian Academic State Task for the Institute of Cytology with financial support from the Ministry of Education and Science of the Russian Federation and the Saint-Petersburg State University (grant ID 51140332).

Author information

Authors and Affiliations

  1. Vreden Russian Scientific Research Institute of Traumatology and Orthopedics, 195427, St. Petersburg, Russia

    M. S. Bozhokin

  2. Institute of Cytology, Russian Academy of Science, 194064, St. Petersburg, Russia

    M. S. Bozhokin & M. G. Khotin

  3. Vavilov Institute of General Genetics, Russian Academy of Science, St. Petersburg Branch, 199034, St. Petersburg, Russia

    Y. V. Sopova

  4. St. Petersburg State University, Faculty of Biology, 199034, St. Petersburg, Russia

    Y. V. Sopova, D. V. Kachkin & A. A. Rubel

  5. St. Petersburg State University, Laboratory of Amyloid Biology, 199034, St. Petersburg, Russia

    Y. V. Sopova, D. V. Kachkin & A. A. Rubel

Authors
  1. M. S. Bozhokin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y. V. Sopova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. V. Kachkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. A. Rubel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. G. Khotin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. S. Bozhokin.

Ethics declarations

This article does not contain any studies involving animals or human participants performed by any of the authors. The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bozhokin, M., Sopova, Y., Kachkin, D. et al. Mechanisms of TGFβ3 Action as a Therapeutic Agent for Promoting the Synthesis of Extracellular Matrix Proteins in Hyaline Cartilage. Biochemistry Moscow 85, 436–447 (2020). https://doi.org/10.1134/S0006297920040045

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297920040045

Keywords

Search

Navigation