{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T04:20:16Z","timestamp":1772252416681,"version":"3.50.1"},"reference-count":132,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,10,9]],"date-time":"2020-10-09T00:00:00Z","timestamp":1602201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>This review article focuses on the current state-of-the-art cellular and molecular biotechnology for the over-production of clinically relevant therapeutic and anabolic growth factors. We discuss how the currently available tools and emerging technologies can be used for the regenerative treatment of osteoarthritis (OA). Transfected protein packaging cell lines such as GP-293 cells may be used as \u201ccellular factories\u201d for large-scale production of therapeutic proteins and pro-anabolic growth factors, particularly in the context of cartilage regeneration. However, when irradiated with gamma or x-rays, these cells lose their capacity for replication, which makes them safe for use as a live cell component of intra-articular injections. This innovation is already here, in the form of TissueGene-C, a new biological drug that consists of normal allogeneic primary chondrocytes combined with transduced GP2-293 cells that overexpress the growth factor transforming growth factor \u03b21 (TGF-\u03b21). TissueGene-C has revolutionized the concept of cell therapy, allowing drug companies to develop live cells as biological drug delivery systems for direct intra-articular injection of growth factors whose half-lives are in the order of minutes. Therefore, in this paper, we discuss the potential for new innovations in regenerative medicine for degenerative diseases of synovial joints using mammalian protein production platforms, specifically protein packaging cell lines, for over-producing growth factors for cartilage tissue regeneration and give recent examples. Mammalian protein production platforms that incorporate protein packaging eukaryotic cell lines are superior to prokaryotic bacterial expression systems and are likely to have a significant impact on the development of new humanized biological growth factor therapies for treating focal cartilage defects and more generally for the treatment of degenerative joint diseases such as OA, especially when injected directly into the joint.<\/jats:p>","DOI":"10.3390\/biology9100330","type":"journal-article","created":{"date-parts":[[2020,10,12]],"date-time":"2020-10-12T10:18:00Z","timestamp":1602497880000},"page":"330","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Over-Production of Therapeutic Growth Factors for Articular Cartilage Regeneration by Protein Production Platforms and Protein Packaging Cell Lines"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6261-1286","authenticated-orcid":false,"given":"Ali","family":"Mobasheri","sequence":"first","affiliation":[{"name":"Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, University of Oulu, FI-90014 Oulu, Finland"},{"name":"Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, LT-08406 Vilnius, Lithuania"},{"name":"Departments of Orthopedics, Rheumatology and Clinical Immunology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands"},{"name":"Versus Arthritis Centre for Sport, Exercise and Osteoarthritis Research, Queen\u2019s Medical Centre, Nottingham NG7 2UH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0489-2662","authenticated-orcid":false,"given":"Heonsik","family":"Choi","sequence":"additional","affiliation":[{"name":"Kolon TissueGene, Inc., Rockville, MD 20850, USA"},{"name":"Healthcare Research Institute, Kolon Advanced Research Center, Kolon Industries, Inc., Magok-dong, Gangseo-gu, Seoul 07793, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2220-5774","authenticated-orcid":false,"given":"Pablo","family":"Mart\u00edn-Vasallo","sequence":"additional","affiliation":[{"name":"UD of Biochemistry and Molecular Biology, Instituto de Tecnolog\u00edas Biom\u00e9dicas de Canarias, Universidad de La Laguna, San Crist\u00f3bal de La Laguna, 38071 Tenerife, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1038\/347762a0","article-title":"Proliferation and differentiation of neuronal stem cells regulated by nerve growth factor","volume":"347","author":"Cattaneo","year":"1990","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"543","DOI":"10.2106\/00004623-199504000-00007","article-title":"Regulation of proliferation and osteochondrogenic differentiation of periosteum-derived cells by transforming growth factor-beta and basic fibroblast growth factor","volume":"77","author":"Iwasaki","year":"1995","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1046\/j.1524-475x.2000.00192.x","article-title":"Epidermal growth factor and keratinocyte growth factor differentially regulate epidermal migration, growth, and differentiation","volume":"8","author":"Gibbs","year":"2000","journal-title":"Wound Repair Regen."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1002\/stem.720","article-title":"Effects on proliferation and differentiation of multipotent bone marrow stromal cells engineered to express growth factors for combined cell and gene therapy","volume":"29","author":"Fierro","year":"2011","journal-title":"Stem Cells"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1002\/jnr.490250404","article-title":"Fibroblast growth factor stimulates the proliferation and differentiation of neural precursor cells in vitro","volume":"25","author":"Murphy","year":"1990","journal-title":"J. Neurosci. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1872","DOI":"10.1681\/ASN.V5111872","article-title":"Signal transduction by the hepatocyte growth factor receptor, c-met. Activation of the phosphatidylinositol 3-kinase","volume":"5","author":"Cantley","year":"1995","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1038\/313756a0","article-title":"Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes","volume":"313","author":"Ullrich","year":"1985","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4715","DOI":"10.1073\/pnas.85.13.4715","article-title":"Identification of another member of the transforming growth factor type beta gene family","volume":"85","author":"Hansen","year":"1988","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/0006-2952(90)90175-K","article-title":"Structure-function relationships in epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha)","volume":"40","author":"Campbell","year":"1990","journal-title":"Biochem. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1111\/j.1524-475X.2008.00410.x","article-title":"Growth factors and cytokines in wound healing","volume":"16","author":"Barrientos","year":"2008","journal-title":"Wound Repair Regen."},{"key":"ref_11","unstructured":"Brenner, S., and Miller, J.H. (2014). Brenner\u2019s Encyclopedia of Genetics, Elsevier Science."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1146\/annurev.cb.03.110187.002303","article-title":"Polypeptide growth factors: Roles in normal and abnormal cell growth","volume":"3","author":"Deuel","year":"1987","journal-title":"Annu. Rev. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1096\/fasebj.11.1.9034166","article-title":"Growth factors in the extracellular matrix","volume":"11","author":"Taipale","year":"1997","journal-title":"FASEB J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1002\/bies.950160210","article-title":"Growth factors as survival factors: Regulation of apoptosis","volume":"16","author":"Collins","year":"1994","journal-title":"Bioessays"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1210\/er.2003-0040","article-title":"Fibroblast growth factor signaling during early vertebrate development","volume":"26","author":"Niehrs","year":"2005","journal-title":"Endocr. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4589","DOI":"10.1182\/blood-2005-10-4169","article-title":"Role of transforming growth factor-beta in hematologic malignancies","volume":"107","author":"Dong","year":"2006","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"25476","DOI":"10.3390\/ijms161025476","article-title":"Stem cells in skin regeneration, wound healing, and their clinical applications","volume":"16","author":"Ojeh","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_18","first-page":"129","article-title":"Growth factor actions on articular cartilage","volume":"43","author":"Trippel","year":"1995","journal-title":"J. Rheumatol. Suppl."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/S0959-437X(96)80064-5","article-title":"Bone morphogenetic proteins in development","volume":"6","author":"Hogan","year":"1996","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.imlet.2006.12.010","article-title":"The role of TGF-beta superfamily during T cell development: New insights","volume":"109","author":"Soldevila","year":"2007","journal-title":"Immunol. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1S","DOI":"10.1016\/S8756-3282(96)00138-X","article-title":"Growth factors for bone growth and repair: IGF, TGF beta and BMP","volume":"19","author":"Linkhart","year":"1996","journal-title":"Bone"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2207","DOI":"10.1046\/j.1523-1755.2000.00081.x","article-title":"The family of bone morphogenetic proteins","volume":"57","author":"Ducy","year":"2000","journal-title":"Kidney Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.mce.2004.07.010","article-title":"Activin A and follistatin in systemic inflammation","volume":"225","author":"Jones","year":"2004","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/icb.2011.32","article-title":"When versatility matters: Activins\/inhibins as key regulators of immunity","volume":"90","author":"Soldevila","year":"2012","journal-title":"Immunol. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/nri.2016.112","article-title":"Immunoregulation by members of the TGF\u03b2 superfamily","volume":"16","author":"Chen","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Morikawa, M., Derynck, R., and Miyazono, K. (2016). TGF-\u03b2 and the TGF-\u03b2 Family: Context-Dependent Roles in Cell and Tissue Physiology. Cold Spring Harb. Perspect. Biol., 8.","DOI":"10.1101\/cshperspect.a021873"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2575","DOI":"10.3389\/fimmu.2018.02575","article-title":"Extracellular vesicles in joint disease and therapy","volume":"9","author":"Boere","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/nrrheum.2015.170","article-title":"Extracellular vesicles\u2014New tool for joint repair and regeneration","volume":"12","author":"Malda","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Tominaga, K., and Suzuki, H.I. (2019). TGF-\u03b2 Signaling in Cellular Senescence and Aging-Related Pathology. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20205002"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/nrrheum.2016.219","article-title":"The changing role of TGF\u03b2 in healthy, ageing and osteoarthritic joints","volume":"13","year":"2017","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.tips.2014.03.005","article-title":"Targeting TGF\u03b2 signaling in subchondral bone and articular cartilage homeostasis","volume":"35","author":"Zhen","year":"2014","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Vishwakarma, A., Sharpe, P., Shi, S., and Ramalingam, M. (2014). Stem Cell Biology and Tissue Engineering in Dental Sciences, Academic Press.","DOI":"10.1016\/B978-0-12-397157-9.00001-1"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Wingard, J.R., and Demetri, G.D. (1999). Clinical Applications of Cytokines and Growth Factors, Springer US.","DOI":"10.1007\/978-1-4615-5013-6"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/d41586-019-00490-6","article-title":"Medicinal signalling cells: They work, so use them","volume":"566","author":"Caplan","year":"2019","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e54","DOI":"10.1038\/emm.2013.94","article-title":"Mesenchymal stem cells: Environmentally responsive therapeutics for regenerative medicine","volume":"45","author":"Murphy","year":"2013","journal-title":"Exp. Mol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1002\/sctm.17-0051","article-title":"Mesenchymal stem cells: Time to change the name!","volume":"6","author":"Caplan","year":"2017","journal-title":"Stem Cells Transl. Med."},{"key":"ref_37","first-page":"12","article-title":"Osteoarthritis 1: Physiology, risk factors and causes of pain","volume":"108","author":"Swift","year":"2012","journal-title":"Nurs. Times"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"430S","DOI":"10.1093\/ajcn\/63.3.430","article-title":"Weight and osteoarthritis","volume":"63","author":"Felson","year":"1996","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/s41574-019-0176-8","article-title":"Obesity: Global epidemiology and pathogenesis","volume":"15","year":"2019","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1002\/cphy.c110025","article-title":"Lack of exercise is a major cause of chronic diseases","volume":"2","author":"Booth","year":"2012","journal-title":"Compr. Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1016\/j.joca.2015.03.036","article-title":"Call for standardized definitions of osteoarthritis and risk stratification for clinical trials and clinical use","volume":"23","author":"Kraus","year":"2015","journal-title":"Osteoarthr. Cartil."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Felson, D.T. (2004). Risk factors for osteoarthritis: Understanding joint vulnerability. Clin. Orthop. Relat. Res., S16\u2013S21.","DOI":"10.1097\/01.blo.0000144971.12731.a2"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.berh.2009.08.008","article-title":"The role of biomechanics in the initiation and progression of OA of the knee","volume":"24","author":"Englund","year":"2010","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.joca.2012.11.012","article-title":"Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!)","volume":"21","author":"Berenbaum","year":"2013","journal-title":"Osteoarthr. Cartil."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/nrrheum.2017.50","article-title":"The role of metabolism in the pathogenesis of osteoarthritis","volume":"13","author":"Mobasheri","year":"2017","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/jor.1100070106","article-title":"Growth factor stimulation of adult articular cartilage","volume":"7","author":"Osborn","year":"1989","journal-title":"J. Orthop. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1016\/j.biomaterials.2012.09.076","article-title":"In vitro growth factor-induced bio engineering of mature articular cartilage","volume":"34","author":"Khan","year":"2013","journal-title":"Biomaterials"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.injury.2011.05.035","article-title":"Chondrocytes or adult stem cells for cartilage repair: The indisputable role of growth factors","volume":"43","author":"Freyria","year":"2012","journal-title":"Injury"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1136\/bjsm.2007.040071","article-title":"Growth factor delivery methods in the management of sports injuries: The state of play","volume":"42","author":"Creaney","year":"2008","journal-title":"Br. J. Sports Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2706","DOI":"10.1007\/s11999-011-1857-3","article-title":"The role of growth factors in cartilage repair","volume":"469","author":"Fortier","year":"2011","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1016\/j.joca.2013.07.017","article-title":"Basic science and clinical application of platelet-rich plasma for cartilage defects and osteoarthritis: A review","volume":"21","author":"Zhu","year":"2013","journal-title":"Osteoarthr. Cartil."},{"key":"ref_52","first-page":"70","article-title":"Clinical applications of growth factors for articular cartilage repair","volume":"32","author":"Hickey","year":"2003","journal-title":"Am. J. Orthop."},{"key":"ref_53","first-page":"419","article-title":"Growth factors for skeletal reconstruction and fracture repair","volume":"5","author":"Oreffo","year":"2004","journal-title":"Curr. Opin. Investig. Drugs"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/scrt32","article-title":"Growth factor regulation of proliferation and survival of multipotential stromal cells","volume":"1","author":"Rodrigues","year":"2010","journal-title":"Stem Cell Res. Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.cytogfr.2013.03.008","article-title":"Angiogenic factors in bone local environment","volume":"24","author":"Chim","year":"2013","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_56","first-page":"217","article-title":"Targeting VEGF-A in cartilage repair and regeneration: State of the art and perspectives","volume":"32","author":"Russo","year":"2018","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.berh.2007.12.001","article-title":"Joint homeostasis, restoration, and remodeling in osteoarthritis","volume":"22","author":"Lories","year":"2008","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.gene.2008.04.019","article-title":"Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis","volume":"420","author":"Ellman","year":"2008","journal-title":"Gene"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1002\/jcb.24418","article-title":"Fibroblast growth factor control of cartilage homeostasis","volume":"114","author":"Ellman","year":"2013","journal-title":"J. Cell Biochem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1615\/CritRevEukarGeneExpr.v21.i1.40","article-title":"The role of connective tissue growth factor (CTGF\/CCN2) in skeletogenesis","volume":"21","author":"Arnott","year":"2011","journal-title":"Crit. Rev. Eukaryot. Gene Expr."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1042\/CS20140264","article-title":"Cellular and molecular actions of CCN2\/CTGF and its role under physiological and pathological conditions","volume":"128","author":"Kubota","year":"2015","journal-title":"Clin. Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3686","DOI":"10.1002\/art.27709","article-title":"Intraarticular injection of heparin-binding insulin-like growth factor 1 sustains delivery of insulin-like growth factor 1 to cartilage through binding to chondroitin sulfate","volume":"62","author":"Miller","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/0003-9861(88)90047-1","article-title":"Insulin-like growth factors maintain steady-state metabolism of proteoglycans in bovine articular cartilage explants","volume":"267","author":"Luyten","year":"1988","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1042\/bj2600543","article-title":"Insulin-like growth factor 1 can decrease degradation and promote synthesis of proteoglycan in cartilage exposed to cytokines","volume":"260","author":"Tyler","year":"1989","journal-title":"Biochem. J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.joca.2005.10.011","article-title":"A review of the effects of insulin-like growth factor and platelet derived growth factor on in vivo cartilage healing and repair","volume":"14","author":"Schmidt","year":"2006","journal-title":"Osteoarthr. Cartil."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1038\/sj.gt.3302515","article-title":"Enhanced repair of articular cartilage defects in vivo by transplanted chondrocytes overexpressing insulin-like growth factor I (IGF-I)","volume":"12","author":"Madry","year":"2005","journal-title":"Gene Ther."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/S0958-1669(02)00300-2","article-title":"Recombinant protein expression for therapeutic applications","volume":"13","author":"Andersen","year":"2002","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/978-1-61779-352-3_16","article-title":"Optimizing transient recombinant protein expression in mammalian cells","volume":"801","author":"Hopkins","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"579","DOI":"10.3390\/ph6050579","article-title":"Advances in Mammalian cell line development technologies for recombinant protein production","volume":"6","author":"Lai","year":"2013","journal-title":"Pharmaceuticals"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.2174\/092986652012131112130322","article-title":"Production of recombinant therapeutic proteins in human cells: Current achievements and future perspectives","volume":"20","author":"Biaggio","year":"2013","journal-title":"Protein Pept. Lett."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/S0958-1669(99)80027-5","article-title":"Large-scale transient expression in mammalian cells for recombinant protein production","volume":"10","author":"Wurm","year":"1999","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1007\/s10529-006-9297-y","article-title":"Recombinant protein production by large-scale transient gene expression in mammalian cells: State of the art and future perspectives","volume":"29","author":"Baldi","year":"2007","journal-title":"Biotechnol. Lett."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.pep.2012.04.023","article-title":"Human cells: New platform for recombinant therapeutic protein production","volume":"84","author":"Swiech","year":"2012","journal-title":"Protein Expr. Purif."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1007\/s00253-013-5427-3","article-title":"Proteins improving recombinant antibody production in mammalian cells","volume":"98","author":"Nishimiya","year":"2014","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e77","DOI":"10.1002\/cpps.77","article-title":"Optimization of protein expression in mammalian cells","volume":"95","author":"Hunter","year":"2019","journal-title":"Curr. Protoc. Protein Sci."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Sharker, S.M., and Rahman, M.A. (2020). Review of the current methods of Chinese Hamster Ovary (CHO) cells cultivation for production of therapeutic protein. Curr. Drug Discov. Technol.","DOI":"10.2174\/1570163817666200312102137"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"233","DOI":"10.2174\/138920110791111960","article-title":"Cell engineering and cultivation of chinese hamster ovary (CHO) cells","volume":"11","author":"Omasa","year":"2010","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/978-3-319-27216-0_14","article-title":"Fundamentals of expression in mammalian cells","volume":"896","author":"Dyson","year":"2016","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/978-1-4939-2205-5_11","article-title":"Transient expression in HEK 293 cells: An alternative to E. coli for the production of secreted and intracellular mammalian proteins","volume":"1258","author":"Nettleship","year":"2015","journal-title":"Methods Mol. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1021\/bp049830x","article-title":"Transient gene expression in suspension HEK-293 cells: Application to large-scale protein production","volume":"21","author":"Baldi","year":"2005","journal-title":"Biotechnol. Prog."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"4767","DOI":"10.1038\/ncomms5767","article-title":"Genome dynamics of the human embryonic kidney 293 lineage in response to cell biology manipulations","volume":"5","author":"Lin","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e1700234","DOI":"10.1002\/biot.201700234","article-title":"Glycoengineering in CHO cells: Advances in systems biology","volume":"13","author":"Tejwani","year":"2018","journal-title":"Biotechnol. J."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.sbi.2013.03.008","article-title":"Advances in recombinant protein expression for use in pharmaceutical research","volume":"23","author":"Assenberg","year":"2013","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Orlova, N.A., Kovnir, S.V., Hodak, J.A., Vorobiev, I.I., Gabibov, A.G., and Skryabin, K.G. (2014). Improved elongation factor-1 alpha-based vectors for stable high-level expression of heterologous proteins in Chinese hamster ovary cells. BMC Biotechnol., 14.","DOI":"10.1186\/1472-6750-14-56"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.ymben.2007.01.001","article-title":"Application of destabilizing sequences on selection marker for improved recombinant protein productivity in CHO-DG44","volume":"9","author":"Ng","year":"2007","journal-title":"Metab. Eng."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1186\/s40064-016-3213-2","article-title":"Design of a stable cell line producing a recombinant monoclonal anti-TNF\u03b1 antibody based on a CHO cell line","volume":"5","author":"Voronina","year":"2016","journal-title":"Springerplus"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.csbj.2016.10.004","article-title":"Engineering Translation in Mammalian Cell Factories to Increase Protein Yield: The Unexpected Use of Long Non-Coding SINEUP RNAs","volume":"14","author":"Zucchelli","year":"2016","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.sbi.2013.04.003","article-title":"Expression of recombinant glycoproteins in mammalian cells: Towards an integrative approach to structural biology","volume":"23","author":"Aricescu","year":"2013","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.febslet.2013.11.035","article-title":"Recent advances in mammalian protein production","volume":"588","author":"Bandaranayake","year":"2014","journal-title":"FEBS Lett."},{"key":"ref_90","first-page":"11","article-title":"Mammalian cell line developments in speed and efficiency","volume":"139","author":"Estes","year":"2014","journal-title":"Adv. Biochem. Eng. Biotechnol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.jbiotec.2017.04.028","article-title":"Therapeutic glycoprotein production in mammalian cells","volume":"251","author":"Lalonde","year":"2017","journal-title":"J. Biotechnol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/sj.gt.3302196","article-title":"Osteoarthritis gene therapy","volume":"11","author":"Evans","year":"2004","journal-title":"Gene Ther."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s13075-017-1229-9","article-title":"Synovitis in osteoarthritis: Current understanding with therapeutic implications","volume":"19","author":"Mathiessen","year":"2017","journal-title":"Arthritis Res. Ther."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.addr.2006.01.009","article-title":"Gene therapeutic approaches-transfer in vivo","volume":"58","author":"Evans","year":"2006","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.trsl.2013.01.002","article-title":"Arthritis gene therapy and its tortuous path into the clinic","volume":"161","author":"Evans","year":"2013","journal-title":"Transl. Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.bone.2012.02.012","article-title":"The role of synovitis in osteoarthritis pathogenesis","volume":"51","author":"Scanzello","year":"2012","journal-title":"Bone"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Goomer, R.S., Maris, T.M., Gelberman, R., Boyer, M., Silva, M., and Amiel, D. (2000). Nonviral in vivo gene therapy for tissue engineering of articular cartilage and tendon repair. Clin. Orthop. Relat. Res., S189\u2013S200.","DOI":"10.1097\/00003086-200010001-00025"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1002\/jgm.368","article-title":"Sustained transgene expression in cartilage defects in vivo after transplantation of articular chondrocytes modified by lipid-mediated gene transfer in a gel suspension delivery system","volume":"5","author":"Madry","year":"2003","journal-title":"J. Gene Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1002\/jgm.819","article-title":"Local stimulation of articular cartilage repair by transplantation of encapsulated chondrocytes overexpressing human fibroblast growth factor 2 (FGF-2) in vivo","volume":"8","author":"Kaul","year":"2006","journal-title":"J. Gene Med."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1007\/s00167-011-1448-6","article-title":"Transplanted articular chondrocytes co-overexpressing IGF-I and FGF-2 stimulate cartilage repair in vivo","volume":"19","author":"Orth","year":"2011","journal-title":"Knee Surg. Sports Traumatol. Arthrosc."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/S0749-0739(17)30059-7","article-title":"Gene therapy: Future therapies in osteoarthritis","volume":"17","author":"Frisbie","year":"2001","journal-title":"Vet Clin. North Am. Equine Pract."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1517\/14712598.2016.1124084","article-title":"Gene therapy for human osteoarthritis: Principles and clinical translation","volume":"16","author":"Madry","year":"2016","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1097\/BOR.0000000000000567","article-title":"Molecular taxonomy of osteoarthritis for patient stratification, disease management and drug development: Biochemical markers associated with emerging clinical phenotypes and molecular endotypes","volume":"31","author":"Mobasheri","year":"2019","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"3464","DOI":"10.1002\/art.11365","article-title":"Stem cell therapy in a caprine model of osteoarthritis","volume":"48","author":"Murphy","year":"2003","journal-title":"Arthritis Rheum."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Freitag, J., Bates, D., Boyd, R., Shah, K., Barnard, A., Huguenin, L., and Tenen, A. (2016). Mesenchymal stem cell therapy in the treatment of osteoarthritis: Reparative pathways, safety and efficacy\u2014A review. BMC Musculoskelet. Disord., 17.","DOI":"10.1186\/s12891-016-1085-9"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Kalamegam, G., Memic, A., Budd, E., Abbas, M., and Mobasheri, A. (2018). A comprehensive review of stem cells for cartilage regeneration in osteoarthritis. Adv. Exp. Med. Biol., 22\u201336.","DOI":"10.1007\/5584_2018_205"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.maturitas.2014.04.017","article-title":"Chondrocyte and mesenchymal stem cell-based therapies for cartilage repair in osteoarthritis and related orthopaedic conditions","volume":"78","author":"Mobasheri","year":"2014","journal-title":"Maturitas"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.ymeth.2015.09.015","article-title":"Mesenchymal stem cells in regenerative medicine: Focus on articular cartilage and intervertebral disc regeneration","volume":"99","author":"Richardson","year":"2016","journal-title":"Methods"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"213","DOI":"10.3389\/fgene.2016.00213","article-title":"Adipose, Bone Marrow and Synovial Joint-Derived Mesenchymal Stem Cells for Cartilage Repair","volume":"7","author":"Fellows","year":"2016","journal-title":"Front. Genet."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.ymeth.2015.09.016","article-title":"Mesenchymal stem cells: Identification, phenotypic characterization, biological properties and potential for regenerative medicine through biomaterial micro-engineering of their niche","volume":"99","author":"Kobolak","year":"2016","journal-title":"Methods"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"5748126","DOI":"10.1155\/2018\/5748126","article-title":"The Potential of Menstrual Blood-Derived Mesenchymal Stem Cells for Cartilage Repair and Regeneration: Novel Aspects","volume":"2018","author":"Uzieliene","year":"2018","journal-title":"Stem Cells Int."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Murphy, C., Mobasheri, A., T\u00e1ncos, Z., Kobol\u00e1k, J., and Dinny\u00e9s, A. (2017). The potency of induced pluripotent stem cells in cartilage regeneration and osteoarthritis treatment. Adv. Exp. Med. Biol., 55\u201368.","DOI":"10.1007\/5584_2017_141"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1002\/art.10118","article-title":"Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis","volume":"46","author":"Murphy","year":"2002","journal-title":"Arthritis Rheum."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/s11926-013-0385-4","article-title":"The future of osteoarthritis therapeutics: Emerging biological therapy","volume":"15","author":"Mobasheri","year":"2013","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.ymthe.2005.03.012","article-title":"Improved tissue repair in articular cartilage defects in vivo by rAAV-mediated overexpression of human fibroblast growth factor 2","volume":"12","author":"Cucchiarini","year":"2005","journal-title":"Mol. Ther."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1177\/1947603510392914","article-title":"Gene therapy for cartilage repair","volume":"2","author":"Madry","year":"2011","journal-title":"Cartilage"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"S97","DOI":"10.1016\/j.injury.2008.01.034","article-title":"Concepts in gene therapy for cartilage repair","volume":"39","author":"Steinert","year":"2008","journal-title":"Injury"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.coph.2018.03.005","article-title":"Gene therapy for repair and regeneration of bone and cartilage","volume":"40","author":"Grol","year":"2018","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1089\/ten.teb.2015.0347","article-title":"Gene transfer strategies to promote chondrogenesis and cartilage regeneration","volume":"22","author":"Im","year":"2016","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_120","first-page":"279","article-title":"Transforming growth factor-beta 1 stimulates articular chondrocyte proteoglycan synthesis and induces osteophyte formation in the murine knee joint","volume":"71","author":"Arntz","year":"1994","journal-title":"Lab. Invest."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1053\/joca.2000.0368","article-title":"Overexpression of active TGF-beta-1 in the murine knee joint: Evidence for synovial-layer-dependent chondro-osteophyte formation","volume":"9","author":"Bakker","year":"2001","journal-title":"Osteoarthr. Cartil."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.joca.2004.03.003","article-title":"Synovial lining macrophages mediate osteophyte formation during experimental osteoarthritis","volume":"12","author":"Blom","year":"2004","journal-title":"Osteoarthr. Cartil."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"4065","DOI":"10.1002\/art.23034","article-title":"Resemblance of osteophytes in experimental osteoarthritis to transforming growth factor beta-induced osteophytes: Limited role of bone morphogenetic protein in early osteoarthritic osteophyte formation","volume":"56","author":"Vitters","year":"2007","journal-title":"Arthritis Rheum."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"3442","DOI":"10.1002\/art.11328","article-title":"Reduction of osteophyte formation and synovial thickening by adenoviral overexpression of transforming growth factor beta\/bone morphogenetic protein inhibitors during experimental osteoarthritis","volume":"48","author":"Scharstuhl","year":"2003","journal-title":"Arthritis Rheum."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"R1338","DOI":"10.1186\/ar1833","article-title":"Reduced transforming growth factor-beta signaling in cartilage of old mice: Role in impaired repair capacity","volume":"7","author":"Scharstuhl","year":"2005","journal-title":"Arthritis Res. Ther."},{"key":"ref_126","first-page":"75","article-title":"Age-related alterations in TGF beta signaling as a causal factor of cartilage degeneration in osteoarthritis","volume":"24","year":"2014","journal-title":"Biomed. Mater. Eng."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/s41584-018-0009-5","article-title":"Arthritis gene therapy is becoming a reality","volume":"14","author":"Evans","year":"2018","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/s13770-019-00179-x","article-title":"Current trends in viral gene therapy for human orthopaedic regenerative medicine","volume":"16","author":"Venkatesan","year":"2019","journal-title":"Tissue Eng. Regen. Med."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/5584_2019_457","article-title":"Future Cell and Gene Therapy for Osteoarthritis (OA): Potential for Using Mammalian Protein Production Platforms, Irradiated and Transfected Protein Packaging Cell Lines for Over-Production of Therapeutic Proteins and Growth Factors","volume":"1247","author":"Mobasheri","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.nec.2019.08.015","article-title":"Cell and gene therapy for spine regeneration: Mammalian protein production platforms for overproduction of therapeutic proteins and growth factors","volume":"31","author":"Mobasheri","year":"2020","journal-title":"Neurosurg. Clin. N. Am."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/978-1-4939-9624-7_5","article-title":"A High-Throughput System for Transient and Stable Protein Production in Mammalian Cells","volume":"2025","author":"Rue","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1007\/s10787-020-00738-y","article-title":"TissueGene-C promotes an anti-inflammatory micro-environment in a rat monoiodoacetate model of osteoarthritis via polarization of M2 macrophages leading to pain relief and structural improvement","volume":"28","author":"Lee","year":"2020","journal-title":"Inflammopharmacology"}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/9\/10\/330\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:18:04Z","timestamp":1760177884000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/9\/10\/330"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,9]]},"references-count":132,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["biology9100330"],"URL":"https:\/\/doi.org\/10.3390\/biology9100330","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202007.0674.v1","asserted-by":"object"}]},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,9]]}}}