{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T15:25:21Z","timestamp":1790781921805,"version":"4.1.0"},"reference-count":93,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2020,12,16]],"date-time":"2020-12-16T00:00:00Z","timestamp":1608076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006360","name":"Bundesministerium f\u00fcr Wirtschaft und Energie","doi-asserted-by":"publisher","award":["50WB1924"],"award-info":[{"award-number":["50WB1924"]}],"id":[{"id":"10.13039\/501100006360","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000844","name":"European Space Agency","doi-asserted-by":"publisher","award":["CORA-GBF-2013-004"],"award-info":[{"award-number":["CORA-GBF-2013-004"]}],"id":[{"id":"10.13039\/501100000844","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Articular cartilage is a skeletal tissue of avascular nature and limited self-repair capacity. Cartilage-degenerative diseases, such as osteoarthritis (OA), are difficult to treat and often necessitate joint replacement surgery. Cartilage is a tough but flexible material and relatively easy to damage. It is, therefore, of high interest to develop methods allowing chondrocytes to recolonize, to rebuild the cartilage and to restore joint functionality. Here we studied the in vitro production of cartilage-like tissue using human articular chondrocytes exposed to the Random Positioning Machine (RPM), a device to simulate certain aspects of microgravity on Earth. To screen early adoption reactions of chondrocytes exposed to the RPM, we performed quantitative real-time PCR analyses after 24 h on chondrocytes cultured in DMEM\/F-12. A significant up-regulation in the gene expression of IL6, RUNX2, RUNX3, SPP1, SOX6, SOX9, and MMP13 was detected, while the levels of IL8, ACAN, PRG4, ITGB1, TGFB1, COL1A1, COL2A1, COL10A1, SOD3, SOX5, MMP1, and MMP2 mRNAs remained unchanged. The STRING (Search Tool for the Retrieval of Interacting Genes\/Proteins) analysis demonstrated among others the importance of these differentially regulated genes for cartilage formation. Chondrocytes grown in DMEM\/F-12 medium produced three-dimensional (3D) spheroids after five days without the addition of scaffolds. On day 28, the produced tissue constructs reached up to 2 mm in diameter. Using specific chondrocyte growth medium, similar results were achieved within 14 days. Spheroids from both types of culture media showed the typical cartilage morphology with aggrecan positivity. Intermediate filaments form clusters under RPM conditions as detected by vimentin staining after 7 d and 14 d. Larger meshes appear in the network in 28-day samples. Furthermore, they were able to form a confluent chondrocyte monolayer after being transferred back into cell culture flasks in 1 g conditions showing their suitability for transplantation into joints. Our results demonstrate that the cultivation medium has a direct influence on the velocity of tissue formation and tissue composition. The spheroids show properties that make them interesting candidates for cellular cartilage regeneration approaches in trauma and OA therapy.<\/jats:p>","DOI":"10.3390\/ijms21249596","type":"journal-article","created":{"date-parts":[[2020,12,16]],"date-time":"2020-12-16T22:12:06Z","timestamp":1608156726000},"page":"9596","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Tissue Engineering of Cartilage Using a Random Positioning Machine"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8160-859X","authenticated-orcid":false,"given":"Markus","family":"Wehland","sequence":"first","affiliation":[{"name":"Department of Microgravity and Translational Regenerative Medicine, Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, 39106 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Steinwerth","sequence":"additional","affiliation":[{"name":"Department of Microgravity and Translational Regenerative Medicine, Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, 39106 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganna","family":"Aleshcheva","sequence":"additional","affiliation":[{"name":"Department of Microgravity and Translational Regenerative Medicine, Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, 39106 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayashree","family":"Sahana","sequence":"additional","affiliation":[{"name":"Department for Biomedicine, Aarhus University, 8000 Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Hemmersbach","sequence":"additional","affiliation":[{"name":"Gravitational Biology, Institute of Aerospace Medicine, German Aerospace Center, 51147 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald","family":"L\u00fctzenberg","sequence":"additional","affiliation":[{"name":"Department of Microgravity and Translational Regenerative Medicine, Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, 39106 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5829-6455","authenticated-orcid":false,"given":"Sascha","family":"Kopp","sequence":"additional","affiliation":[{"name":"Department of Microgravity and Translational Regenerative Medicine, Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, 39106 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Infanger","sequence":"additional","affiliation":[{"name":"Department of Microgravity and Translational Regenerative Medicine, Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, 39106 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Grimm","sequence":"additional","affiliation":[{"name":"Department of Microgravity and Translational Regenerative Medicine, Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, 39106 Magdeburg, Germany"},{"name":"Department for Biomedicine, Aarhus University, 8000 Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"61","DOI":"10.4015\/S101623720500010X","article-title":"Cartilage Tissue Engineering","volume":"17","author":"Chang","year":"2005","journal-title":"Biomed. Eng. Appl. Basis Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1177\/003335490512000310","article-title":"Trends in total knee replacement surgeries and implications for public health, 1990\u20132000","volume":"120","author":"Mehrotra","year":"2005","journal-title":"Public Health Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/s00441-011-1243-1","article-title":"Tissue engineering of functional articular cartilage: The current status","volume":"347","author":"Kock","year":"2012","journal-title":"Cell Tissue Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Eberli, D. (2011). Cartilage Regeneration from Bone Marrow Cells Using RWV Bioreactor and Its Automation System for Clinical Application. Tissue Engineering for Tissue and Organ Regeneration, IntechOpen.","DOI":"10.5772\/1146"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.2741\/1914","article-title":"Hydrostatic pressure increases apoptosis in cartilage-constructs produced from human osteoarthritic chondrocytes","volume":"11","author":"Wenger","year":"2006","journal-title":"Front. Biosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1089\/10763270360728125","article-title":"Chondrogenesis of aged human articular cartilage in a scaffold-free bioreactor","volume":"9","author":"Marlovits","year":"2003","journal-title":"Tissue Eng."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.joca.2005.02.015","article-title":"Autologous chondrocyte implantation (ACI) for aged patients: Development of the proper cell expansion conditions for possible therapeutic applications","volume":"13","author":"Giannoni","year":"2005","journal-title":"Osteoarthr. Cartil."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"234","DOI":"10.3109\/17453674.2011.566135","article-title":"Combined 3D and hypoxic culture improves cartilage-specific gene expression in human chondrocytes","volume":"82","author":"Foldager","year":"2011","journal-title":"Acta Orthopeadica"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.joca.2004.02.010","article-title":"Age related changes in human articular chondrocyte yield, proliferation and post-expansion chondrogenic capacity","volume":"12","author":"Barbero","year":"2004","journal-title":"Osteoarthr. Cartil."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8771","DOI":"10.1016\/j.biomaterials.2011.08.073","article-title":"Hydrogel design for cartilage tissue engineering: A case study with hyaluronic acid","volume":"32","author":"Kim","year":"2011","journal-title":"Biomaterials"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.orthres.2004.08.008","article-title":"Rapid phenotypic changes in passaged articular chondrocyte subpopulations","volume":"23","author":"Darling","year":"2005","journal-title":"J. Orthop. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"13380","DOI":"10.1073\/pnas.94.25.13380","article-title":"Weaving cartilage at zero g: The reality of tissue engineering in space","volume":"94","author":"Saltzman","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1089\/ten.tea.2008.0624","article-title":"Neocartilage formation in 1 g, simulated, and microgravity environments: Implications for tissue engineering","volume":"16","author":"Stamenkovic","year":"2010","journal-title":"Tissue Eng. Part A"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/s12217-008-9043-2","article-title":"Technology and Developments for the Random Positioning Machine, RPM","volume":"21","author":"Borst","year":"2008","journal-title":"Microgravity Sci. Technol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Kruger, M., Melnik, D., Kopp, S., Buken, C., Sahana, J., Bauer, J., Wehland, M., Hemmersbach, R., Corydon, T.J., and Infanger, M. (2019). Fighting Thyroid Cancer with Microgravity Research. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20102553"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"16691","DOI":"10.1038\/srep16691","article-title":"Mechanisms of three-dimensional growth of thyroid cells during long-term simulated microgravity","volume":"5","author":"Kopp","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"26887","DOI":"10.1038\/srep26887","article-title":"Identifications of novel mechanisms in breast cancer cells involving duct-like multicellular spheroid formation after exposure to the Random Positioning Machine","volume":"6","author":"Kopp","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1159\/000303059","article-title":"Characterization of human chondrocytes exposed to simulated microgravity","volume":"25","author":"Ulbrich","year":"2010","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2267","DOI":"10.1089\/ten.tea.2008.0576","article-title":"A delayed type of three-dimensional growth of human endothelial cells under simulated weightlessness","volume":"15","author":"Grimm","year":"2009","journal-title":"Tissue Eng. Part A"},{"key":"ref_20","unstructured":"Freeman, M.A.R. (1973). The chondrocytes. Adult Articular Cartilage, Pitman Medical."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1098\/rstb.1975.0055","article-title":"The secretion of enzymes into the pericellular environment","volume":"271","author":"Dingle","year":"1975","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1136\/jcp.31.Suppl_12.7","article-title":"Chondrocytes","volume":"12","author":"Stockwell","year":"1978","journal-title":"Suppl. (R. Coll. Pathol.)"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1136\/ard.26.1.50","article-title":"Intracytoplasmic filaments in the cells of adult human articular cartilage","volume":"26","author":"Meachim","year":"1967","journal-title":"Ann. Rheum. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1083\/jcb.43.2.312","article-title":"Formation of arrowhead complexes with heavy meromyosin in a variety of cell types","volume":"43","author":"Ishikawa","year":"1969","journal-title":"J. Cell Biol."},{"key":"ref_25","unstructured":"Bush, P.G., Hoemann, C.D., and Hall, A.C. (2001, January 25\u201328). A Similarity between Morphology of Chondrocytes within Degenerate Cartilage and Those Cultured in a Weak 3D Matrix. Proceedings of the 47th Annual Meeting of the Orthopaedic Research Society, San Francisco, CA, USA."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1242\/jcs.01731","article-title":"Procollagen trafficking, processing and fibrillogenesis","volume":"118","author":"Canty","year":"2005","journal-title":"J. Cell Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/0955-0674(91)90059-8","article-title":"Transmembrane molecular assemblies in cell-extracellular matrix interactions","volume":"3","author":"Turner","year":"1991","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1242\/jcs.103.4.1215","article-title":"Altering the cellular mechanical force balance results in integrated changes in cell, cytoskeletal and nuclear shape","volume":"103","author":"Sims","year":"1992","journal-title":"J. Cell Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1083\/jcb.120.3.577","article-title":"Signal transduction from the extracellular matrix","volume":"120","author":"Juliano","year":"1993","journal-title":"J. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1007\/BF01952110","article-title":"Actin-based organelle movement","volume":"52","author":"Simon","year":"1996","journal-title":"Experientia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1007\/BF01952099","article-title":"Actin-, myosin- and ubiquitin-dependent endocytosis","volume":"52","author":"Riezman","year":"1996","journal-title":"Experientia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1096\/fj.13-236356","article-title":"The role of the cytoskeleton in sensing changes in gravity by nonspecialized cells","volume":"28","author":"Vorselen","year":"2014","journal-title":"FASEB J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1146\/annurev.cb.03.110187.002023","article-title":"Intracellular transport using microtubule-based motors","volume":"3","author":"Vale","year":"1987","journal-title":"Annu. Rev. Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/0092-8674(86)90283-7","article-title":"Sites of microtubule assembly and disassembly in the mitotic spindle","volume":"45","author":"Mitchison","year":"1986","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"107s","DOI":"10.1083\/jcb.91.3.107s","article-title":"Cilia and flagella of eukaryotes","volume":"91","author":"Gibbons","year":"1981","journal-title":"J. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/S8756-3282(99)00187-8","article-title":"Microtubules are potential regulators of growth-plate chondrocyte differentiation and hypertrophy","volume":"25","author":"Farquharson","year":"1999","journal-title":"Bone"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/283249a0","article-title":"Intermediate filaments as mechanical integrators of cellular space","volume":"283","author":"Lazarides","year":"1980","journal-title":"Nature"},{"key":"ref_38","first-page":"377","article-title":"Intermediate filaments and gene regulation","volume":"27","author":"Traub","year":"1995","journal-title":"Physiol. Chem. Phys. Med. NMR"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"77s","DOI":"10.1016\/8756-3282(95)00183-E","article-title":"Osteoblast and chondroblast differentiation","volume":"17","author":"Aubin","year":"1995","journal-title":"Bone"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1006\/excr.1997.3858","article-title":"In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells","volume":"238","author":"Johnstone","year":"1998","journal-title":"Exp. Cell Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/S0142-9612(99)00213-6","article-title":"Review: Tissue engineering for regeneration of articular cartilage","volume":"21","author":"Temenoff","year":"2000","journal-title":"Biomaterials"},{"key":"ref_42","first-page":"753","article-title":"The cell density of human articular and costal cartilage","volume":"101","author":"Stockwell","year":"1967","journal-title":"J. Anat."},{"key":"ref_43","first-page":"477","article-title":"Articular cartilage: Tissue design and chondrocyte-matrix interactions","volume":"47","author":"Buckwalter","year":"1998","journal-title":"Instr. Course Lect."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1002\/jor.20077","article-title":"Hydrostatic pressure induces apoptosis of chondrocytes cultured in alginate beads","volume":"24","author":"Nakamura","year":"2006","journal-title":"J. Orthop. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1302\/0301-620X.88B4.16498","article-title":"The culture of articular chondrocytes in hydrogel constructs within a bioreactor enhances cell proliferation and matrix synthesis","volume":"88","author":"Akmal","year":"2006","journal-title":"J. Bone Jt. Surg. Br."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.actaastro.2005.03.012","article-title":"Cell-to-cell interactions in changed gravity: Ground-based and flight experiments","volume":"57","author":"Buravkova","year":"2005","journal-title":"Acta Astronaut."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/2045-9769-1-2","article-title":"Differentiation of human mesenchymal stem cell spheroids under microgravity conditions","volume":"1","author":"Cerwinka","year":"2012","journal-title":"Cell Regen."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"13885","DOI":"10.1073\/pnas.94.25.13885","article-title":"Tissue engineering of cartilage in space","volume":"94","author":"Freed","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1080\/13684730050515796","article-title":"Interleukin-6 and interleukin-8 levels in serum and synovial fluid of patients with osteoarthritis","volume":"6","author":"Kaneko","year":"2000","journal-title":"Cytokines Cell. Mol. Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.joca.2018.10.010","article-title":"IL6 receptor blockade preserves articular cartilage and increases bone volume following ischemic osteonecrosis in immature mice","volume":"27","author":"Kamiya","year":"2019","journal-title":"Osteoarthr. Cartil."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1042\/CBI20110150","article-title":"IL-6 and soluble IL-6 receptor stimulate the production of MMPs and their inhibitors via JAK-STAT and ERK-MAPK signalling in human chondrocytes","volume":"36","author":"Aida","year":"2012","journal-title":"Cell Biol. Int."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1002\/1529-0131(200003)43:3<673::AID-ANR25>3.0.CO;2-8","article-title":"Selective enhancement of collagenase-mediated cleavage of resident type II collagen in cultured osteoarthritic cartilage and arrest with a synthetic inhibitor that spares collagenase 1 (matrix metalloproteinase 1)","volume":"43","author":"Dahlberg","year":"2000","journal-title":"Arthritis Rheum."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.joca.2009.07.009","article-title":"Elevated osteopontin level of synovial fluid and articular cartilage is associated with disease severity in knee osteoarthritis patients","volume":"18","author":"Gao","year":"2010","journal-title":"Osteoarthr. Cartil."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/j.clinbiochem.2009.02.002","article-title":"Correlation of plasma and synovial fluid osteopontin with disease severity in knee osteoarthritis","volume":"42","author":"Honsawek","year":"2009","journal-title":"Clin. Biochem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1007\/s00296-012-2548-4","article-title":"Phosphorylation of osteopontin in osteoarthritis degenerative cartilage and its effect on matrix metalloprotease 13","volume":"33","author":"Xu","year":"2013","journal-title":"Rheumatol. Int."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/S0945-053X(00)00068-8","article-title":"Osteopontin is expressed by adult human osteoarthritic chondrocytes: Protein and mRNA analysis of normal and osteoarthritic cartilage","volume":"19","author":"Pullig","year":"2000","journal-title":"Matrix Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2362","DOI":"10.1002\/art.24705","article-title":"Accelerated development of aging-associated and instability-induced osteoarthritis in osteopontin-deficient mice","volume":"60","author":"Matsui","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1007\/s00774-011-0273-9","article-title":"Unraveling the transcriptional regulatory machinery in chondrogenesis","volume":"29","author":"Akiyama","year":"2011","journal-title":"J. Bone Miner. Metab."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1242\/dev.105536","article-title":"A pathway to bone: Signaling molecules and transcription factors involved in chondrocyte development and maturation","volume":"142","author":"Kozhemyakina","year":"2015","journal-title":"Development"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Oh, C.D., Lu, Y., Liang, S., Mori-Akiyama, Y., Chen, D., de Crombrugghe, B., and Yasuda, H. (2014). SOX9 regulates multiple genes in chondrocytes, including genes encoding ECM proteins, ECM modification enzymes, receptors, and transporters. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0107577"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.celrep.2015.06.013","article-title":"Distinct Transcriptional Programs Underlie Sox9 Regulation of the Mammalian Chondrocyte","volume":"12","author":"Ohba","year":"2015","journal-title":"Cell Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"8183","DOI":"10.1093\/nar\/gkv688","article-title":"The transcription factors SOX9 and SOX5\/SOX6 cooperate genome-wide through super-enhancers to drive chondrogenesis","volume":"43","author":"Liu","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1002\/jcb.25099","article-title":"Role of sox9 in growth factor regulation of articular chondrocytes","volume":"116","author":"Shi","year":"2015","journal-title":"J. Cell. Biochem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"19004","DOI":"10.1073\/pnas.0605170103","article-title":"Dominance of SOX9 function over RUNX2 during skeletogenesis","volume":"103","author":"Zhou","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1242\/dev.057802","article-title":"Sox9 sustains chondrocyte survival and hypertrophy in part through Pik3ca-Akt pathways","volume":"138","author":"Ikegami","year":"2011","journal-title":"Development"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"8695","DOI":"10.1074\/jbc.275.12.8695","article-title":"Cbfa1 is a positive regulatory factor in chondrocyte maturation","volume":"275","author":"Enomoto","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1101\/gad.845101","article-title":"Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice","volume":"15","author":"Takeda","year":"2001","journal-title":"Genes Dev."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1083\/jcb.153.1.87","article-title":"Skeletal malformations caused by overexpression of Cbfa1 or its dominant negative form in chondrocytes","volume":"153","author":"Ueta","year":"2001","journal-title":"J. Cell Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4431","DOI":"10.1128\/MCB.19.6.4431","article-title":"Collagenase 3 is a target of Cbfa1, a transcription factor of the runt gene family involved in bone formation","volume":"19","author":"Alvarez","year":"1999","journal-title":"Mol. Cell. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"20029","DOI":"10.1074\/jbc.M010601200","article-title":"AP-1 and Cbfa\/runt physically interact and regulate parathyroid hormone-dependent MMP13 expression in osteoblasts through a new osteoblast-specific element 2\/AP-1 composite element","volume":"276","author":"Hess","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s00441-009-0832-8","article-title":"Regulation of bone development and extracellular matrix protein genes by RUNX2","volume":"339","author":"Komori","year":"2010","journal-title":"Cell Tissue Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1038\/sj.onc.1202064","article-title":"Transcriptional regulation of osteopontin gene in vivo by PEBP2alphaA\/CBFA1 and ETS1 in the skeletal tissues","volume":"17","author":"Sato","year":"1998","journal-title":"Oncogene"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2462","DOI":"10.1002\/art.22041","article-title":"Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability","volume":"54","author":"Kamekura","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1038\/s41598-017-02490-w","article-title":"Deletion of Runx2 in Articular Chondrocytes Decelerates the Progression of DMM-Induced Osteoarthritis in Adult Mice","volume":"7","author":"Liao","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1177\/039139880302600407","article-title":"Collagen expression in tissue engineered cartilage of aged human articular chondrocytes in a rotating bioreactor","volume":"26","author":"Marlovits","year":"2003","journal-title":"Int. J. Artif. Organs"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/s12217-015-9479-0","article-title":"Tissue Engineering of Cartilage on Ground-Based Facilities","volume":"28","author":"Aleshcheva","year":"2016","journal-title":"Microgravity Sci. Technol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1002\/sctm.20-0084","article-title":"The effects of microgravity on differentiation and cell growth in stem cells and cancer stem cells","volume":"9","author":"Grimm","year":"2020","journal-title":"Stem Cells Transl. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1002\/bit.20892","article-title":"Cartilaginous tissue formation from bone marrow cells using rotating wall vessel (RWV) bioreactor","volume":"95","author":"Ohyabu","year":"2006","journal-title":"Biotechnol. Bioeng."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/s11596-011-0252-3","article-title":"Differentiation of mesenchymal stem cells towards a nucleus pulposus-like phenotype utilizing simulated microgravity In vitro","volume":"31","author":"Luo","year":"2011","journal-title":"J. Huazhong Univ. Sci. Technol. Med. Sci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1089\/scd.2006.15.921","article-title":"Microgravity potentiates stem cell proliferation while sustaining the capability of differentiation","volume":"15","author":"Yuge","year":"2006","journal-title":"Stem Cells Dev."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1007\/s12033-012-9568-x","article-title":"The effect of the microgravity rotating culture system on the chondrogenic differentiation of bone marrow mesenchymal stem cells","volume":"54","author":"Wu","year":"2013","journal-title":"Mol. Biotechnol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2615","DOI":"10.1007\/s00264-014-2454-3","article-title":"Simulated microgravity affects chondrogenesis and hypertrophy of human mesenchymal stem cells","volume":"38","author":"Hammerschmid","year":"2014","journal-title":"Int. Orthop."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1089\/ten.teb.2013.0704","article-title":"Growing tissues in real and simulated microgravity: New methods for tissue engineering","volume":"20","author":"Grimm","year":"2014","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.33594\/000000071","article-title":"Growth of Endothelial Cells in Space and in Simulated Microgravity\u2014A Comparison on the Secretory Level","volume":"52","author":"Pietsch","year":"2019","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Mann, V., Grimm, D., Corydon, T.J., Kr\u00fcger, M., Wehland, M., Riwaldt, S., Sahana, J., Kopp, S., Bauer, J., and Reseland, J.E. (2019). Changes in Human Foetal Osteoblasts Exposed to the Random Positioning Machine and Bone Construct Tissue Engineering. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20061357"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.biomaterials.2017.02.005","article-title":"Three-dimensional growth of human endothelial cells in an automated cell culture experiment container during the SpaceX CRS-8 ISS space mission\u2014The SPHEROIDS project","volume":"124","author":"Pietsch","year":"2017","journal-title":"Biomaterials"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/ast.2012.0876","article-title":"Ground-Based Facilities for Simulation of Microgravity: Organism-Specific Recommendations for Their Use, and Recommended Terminology","volume":"13","author":"Herranz","year":"2012","journal-title":"Astrobiology"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"971474","DOI":"10.1155\/2015\/971474","article-title":"Simulated Microgravity: Critical Review on the Use of Random Positioning Machines for Mammalian Cell Culture","volume":"2015","author":"Wuest","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1002\/jcb.21261","article-title":"Modeled gravitational unloading induced downregulation of endothelin-1 in human endothelial cells","volume":"101","author":"Infanger","year":"2007","journal-title":"J. Cell. Biochem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1007\/s00204-002-0338-6","article-title":"Low doses of 2,3,7,8-tetrachlorodibenzo- p-dioxin increase transforming growth factor beta and cause myocardial fibrosis in marmosets (Callithrix jacchus)","volume":"76","author":"Riecke","year":"2002","journal-title":"Arch. Toxicol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/S0895-7061(02)02956-4","article-title":"Early onset of chondroitin sulfate and osteopontin expression in angiotensin II-dependent left ventricular hypertrophy","volume":"15","author":"Rothermund","year":"2002","journal-title":"Am. J. Hypertens."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1089\/ten.tea.2009.0524","article-title":"Different responsiveness of endothelial cells to vascular endothelial growth factor and basic fibroblast growth factor added to culture media under gravity and simulated microgravity","volume":"16","author":"Grimm","year":"2010","journal-title":"Tissue Eng. Part A"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/24\/9596\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:46:03Z","timestamp":1760179563000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/24\/9596"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,16]]},"references-count":93,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["ijms21249596"],"URL":"https:\/\/doi.org\/10.3390\/ijms21249596","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,16]]}}}