{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T01:54:12Z","timestamp":1783648452763,"version":"3.55.0"},"reference-count":118,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,6,8]],"date-time":"2022-06-08T00:00:00Z","timestamp":1654646400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Space Agency project \u2018Muscle and cartilage in Antarctic over-winterers [MACIA]\u2019","award":["ESA-HRE-RS-LE-0495"],"award-info":[{"award-number":["ESA-HRE-RS-LE-0495"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomedicines"],"abstract":"<jats:p>This review summarizes the current literature available on joint cartilage alterations in long-duration spaceflight. Evidence from spaceflight participants is currently limited to serum biomarker data in only a few astronauts. Findings from analogue model research, such as bed rest studies, as well as data from animal and cell research in real microgravity indicate that unloading and radiation exposure are associated with joint degeneration in terms of cartilage thinning and changes in cartilage composition. It is currently unknown how much the individual cartilage regions in the different joints of the human body will be affected on long-term missions beyond the Low Earth Orbit. Given the fact that, apart from total joint replacement or joint resurfacing, currently no treatment exists for late-stage osteoarthritis, countermeasures might be needed to avoid cartilage damage during long-duration missions. To plan countermeasures, it is important to know if and how joint cartilage and the adjacent structures, such as the subchondral bone, are affected by long-term unloading, reloading, and radiation. The use of countermeasures that put either load and shear, or other stimuli on the joints, shields them from radiation or helps by supporting cartilage physiology, or by removing oxidative stress possibly help to avoid OA in later life following long-duration space missions. There is a high demand for research on the efficacy of such countermeasures to judge their suitability for their implementation in long-duration missions.<\/jats:p>","DOI":"10.3390\/biomedicines10061356","type":"journal-article","created":{"date-parts":[[2022,6,9]],"date-time":"2022-06-09T10:49:14Z","timestamp":1654771754000},"page":"1356","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Joint Cartilage in Long-Duration Spaceflight"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9512-2910","authenticated-orcid":false,"given":"Bergita","family":"Ganse","sequence":"first","affiliation":[{"name":"Werner Siemens Foundation Endowed Chair of Innovative Implant Development (Fracture Healing), Clinics and Institutes of Surgery, Saarland University, 66421 Homburg, Germany"},{"name":"Department of Trauma, Hand and Reconstructive Surgery, Clinics and Institutes of Surgery, Saarland University Medical Center, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0323-8922","authenticated-orcid":false,"given":"Magali","family":"Cucchiarini","sequence":"additional","affiliation":[{"name":"Center of Experimental Orthopaedics, Saarland University Medical Center, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8612-4842","authenticated-orcid":false,"given":"Henning","family":"Madry","sequence":"additional","affiliation":[{"name":"Center of Experimental Orthopaedics, Saarland University Medical Center, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1007\/s40279-021-01496-9","article-title":"Effects of Spaceflight on Musculoskeletal Health: A Systematic Review and Meta-Analysis, Considerations for Interplanetary Travel","volume":"51","author":"Comfort","year":"2021","journal-title":"Sports Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/s41526-021-00158-4","article-title":"Update on the effects of microgravity on the musculoskeletal system","volume":"7","author":"Juhl","year":"2021","journal-title":"NPJ Microgravity"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Kim, H.N., Richardson, K.K., Krager, K.J., Ling, W., Simmons, P., Allen, A.R., and Aykin-Burns, N. (2021). Simulated Galactic Cosmic Rays Modify Mitochondrial Metabolism in Osteoclasts, Increase Osteoclastogenesis and Cause Trabecular Bone Loss in Mice. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111711"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"342","DOI":"10.3357\/AMHP.5713.2021","article-title":"Microgravity and Radiation Effects on Astronaut Intervertebral Disc Health","volume":"92","author":"Smith","year":"2021","journal-title":"Aerosp. Med. Hum. Perform."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1007\/s00415-017-8427-x","article-title":"The effect of spaceflight and microgravity on the human brain","volume":"264","author":"Demertzi","year":"2017","journal-title":"J. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.neubiorev.2021.04.026","article-title":"The role of nutrition in space exploration: Implications for sensorimotor, cognition, behavior and the cerebral changes due to the exposure to radiation, altered gravity, and isolation\/confinement hazards of spaceflight","volume":"127","author":"Zwart","year":"2021","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"85","DOI":"10.3389\/fphys.2019.00085","article-title":"Stress Related Shift toward Inflammaging in Cosmonauts after Long-Duration Space Flight","volume":"10","author":"Buchheim","year":"2019","journal-title":"Front. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"697435","DOI":"10.3389\/fimmu.2021.697435","article-title":"Immunological Aspects of Isolation and Confinement","volume":"12","author":"Ponomarev","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1152\/japplphysiol.00839.2015","article-title":"Hopping locomotion at different gravity: Metabolism and mechanics in humans","volume":"120","author":"Pavei","year":"2016","journal-title":"J. Appl. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Weber, T., Green, D.A., Attias, J., Sies, W., Frechette, A., Braunstein, B., and Rittweger, J. (2019). Hopping in hypogravity\u2014A rationale for a plyometric exercise countermeasure in planetary exploration missions. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0211263"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11914-019-00540-y","article-title":"Spaceflight-Induced Bone Tissue Changes That Affect Bone Quality and Increase Fracture Risk","volume":"18","author":"Coulombe","year":"2020","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1007\/s00223-021-00836-1","article-title":"Disuse Osteoporosis: Clinical and Mechanistic Insights","volume":"110","author":"Rolvien","year":"2021","journal-title":"Calcif. Tissue Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3201","DOI":"10.1242\/jeb.204.18.3201","article-title":"Functional and structural adaptations of skeletal muscle to microgravity","volume":"204","author":"Fitts","year":"2001","journal-title":"J. Exp. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1152\/japplphysiol.00363.2020","article-title":"Nonuniform loss of muscle strength and atrophy during bed rest: A systematic review","volume":"131","author":"Marusic","year":"2021","journal-title":"J. Appl. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41536-017-0016-1","article-title":"Cartilage breakdown in microgravity\u2014A problem for long-term spaceflight?","volume":"2","author":"Fitzgerald","year":"2017","journal-title":"NPJ Regen. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"106755","DOI":"10.1016\/j.clineuro.2021.106755","article-title":"Neurosurgery and spinal adaptations in spaceflight: A literature review","volume":"207","author":"Lazzari","year":"2021","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"220","DOI":"10.22203\/eCM.v042a16","article-title":"Bone loss recovery in mice following microgravity with concurrent bone-compartment-specific osteocyte characteristics","volume":"42","author":"Buravkova","year":"2021","journal-title":"Eur. Cells Mater."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.jocd.2019.08.005","article-title":"Use of Quantitative Computed Tomography to Assess for Clinically-Relevant Skeletal Effects of Prolonged Spaceflight on Astronaut Hips","volume":"23","author":"Sibonga","year":"2020","journal-title":"J. Clin. Densitom."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2","DOI":"10.3357\/ASEM.2876.2012","article-title":"Space adaptation back pain: A retrospective study","volume":"83","author":"Kerstman","year":"2012","journal-title":"Aviat. Space Environ. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1097\/ALN.0000000000003812","article-title":"Back Pain in Outer Space","volume":"135","author":"Penchev","year":"2021","journal-title":"Anesthesiology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"117","DOI":"10.3357\/ASEM.2270.2009","article-title":"Musculoskeletal injuries and minor trauma in space: Incidence and injury mechanisms in U. S. astronauts","volume":"80","author":"Scheuring","year":"2009","journal-title":"Aviat. Space Environ. Med."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Howle, L.E., Weber, P.W., Hada, E.A., Vann, R.D., and Denoble, P.J. (2017). The probability and severity of decompression sickness. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0172665"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1097\/JSM.0000000000000093","article-title":"Dysbaric osteonecrosis: A literature review of pathophysiology, clinical presentation, and management","volume":"25","author":"Sharareh","year":"2015","journal-title":"Clin. J. Sport Med."},{"key":"ref_24","unstructured":"Johnston, R.S., and Dietlein, L.F. (1977). Biomedical Results from Skylab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41526-020-00124-6","article-title":"Red risks for a journey to the red planet: The highest priority human health risks for a mission to Mars","volume":"6","author":"Patel","year":"2020","journal-title":"NPJ Microgravity"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1097\/00003677-200510000-00008","article-title":"The role of mechanical loading in the onset and progression of osteoarthritis","volume":"33","author":"Griffin","year":"2005","journal-title":"Exerc. Sport Sci. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"10469","DOI":"10.1038\/s41598-021-90010-2","article-title":"Spaceflight and hind limb unloading induces an arthritic phenotype in knee articular cartilage and menisci of rodents","volume":"11","author":"Kwok","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41526-019-0063-6","article-title":"Articular cartilage and sternal fibrocartilage respond differently to extended microgravity","volume":"5","author":"Fitzgerald","year":"2019","journal-title":"NPJ Microgravity"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1113\/JP275451","article-title":"Mechanoadaptation: Articular cartilage through thick and thin","volume":"597","author":"Vincent","year":"2019","journal-title":"J. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1111\/j.1469-7580.2006.00546.x","article-title":"The effects of exercise on human articular cartilage","volume":"208","author":"Eckstein","year":"2006","journal-title":"J. Anat."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1002\/art.20378","article-title":"Cartilage atrophy in the knees of patients after seven weeks of partial load bearing","volume":"50","author":"Hinterwimmer","year":"2004","journal-title":"Arthr. Rheum."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1016\/j.joca.2009.07.007","article-title":"Vibration training intervention to maintain cartilage thickness and serum concentrations of cartilage oligometric matrix protein (COMP) during immobilization","volume":"17","author":"Liphardt","year":"2009","journal-title":"Osteoarthr. Cartil."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1002\/art.10462","article-title":"Knee cartilage of spinal cord-injured patients displays progressive thinning in the absence of normal joint loading and movement","volume":"46","author":"Vanwanseele","year":"2002","journal-title":"Arthr. Rheum."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3377","DOI":"10.1002\/art.11367","article-title":"Longitudinal analysis of cartilage atrophy in the knees of patients with spinal cord injury","volume":"48","author":"Vanwanseele","year":"2003","journal-title":"Arthr. Rheum."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1016\/j.ultrasmedbio.2010.04.018","article-title":"Ultra-sound evaluation of site-specific effect of simulated microgravity on articular cartilage","volume":"36","author":"Wang","year":"2010","journal-title":"Ultrasound Med. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1002\/mrm.1910360504","article-title":"Gd-DTPA2- as a measure of cartilage degradation","volume":"36","author":"Bashir","year":"1996","journal-title":"Magn. Reson. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1002\/(SICI)1522-2594(199905)41:5<857::AID-MRM1>3.0.CO;2-E","article-title":"Nondestructive imaging of human cartilage glycosaminoglycan concentration by MRI","volume":"41","author":"Bashir","year":"1999","journal-title":"Magn. Reson. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1522S","DOI":"10.1177\/1947603520982350","article-title":"Disuse Atrophy of Articular Cartilage Induced by Unloading Condition Accelerates Histological Progression of Osteoarthritis in a Post-Traumatic Rat Model","volume":"13","author":"Takahashi","year":"2020","journal-title":"Cartilage"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Gr\u00e4ssel, S., Zaucke, F., and Madry, H. (2021). Osteoarthritis: Novel Molecular Mechanisms Increase Our Understanding of the Disease Pathology. J. Clin. Med., 10.","DOI":"10.3390\/jcm10091938"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.bone.2017.09.018","article-title":"Bone replaces articular cartilage in the rat knee joint after prolonged immobilization","volume":"106","author":"Campbell","year":"2018","journal-title":"Bone"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"115694","DOI":"10.1016\/j.bone.2020.115694","article-title":"Bone replaces unloaded articular cartilage during knee immobilization. A longitudinal study in the rat","volume":"142","author":"Watanabe","year":"2021","journal-title":"Bone"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/s00167-010-1054-z","article-title":"The basic science of the subchondral bone","volume":"18","author":"Madry","year":"2010","journal-title":"Knee Surg. Sports Traumatol. Arthrosc."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.joca.2020.11.003","article-title":"Osteoarthritis year in review: Genetics, genomics, epigenetics","volume":"29","author":"Ratneswaran","year":"2021","journal-title":"Osteoarthr. Cartil."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1007\/s00421-019-04232-4","article-title":"The time course and mechanisms of change in biomarkers of joint metabolism in response to acute exercise and chronic training in physiologic and pathological conditions","volume":"119","author":"Roberts","year":"2019","journal-title":"Eur. J. Appl. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2373","DOI":"10.1002\/jor.24753","article-title":"Locomotion replacement exercise cannot counteract cartilage biomarker response to 5 days of immobilization in healthy adults","volume":"38","author":"Liphardt","year":"2020","journal-title":"J. Orthop. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"869","DOI":"10.2174\/138945008785909293","article-title":"The role of cartilage oligomeric matrix protein (COMP) in skeletal disease","volume":"9","author":"Posey","year":"2008","journal-title":"Curr. Drug Targets"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"33","DOI":"10.4137\/BMI.S645","article-title":"Cartilage Oligomeric Matrix Protein (COMP): A Biomarker of Arthritis","volume":"4","author":"Tseng","year":"2009","journal-title":"Biomark. Insights"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Andersson, M.L., Thorstensson, C.A., Roos, E.M., Petersson, I.F., Heinegard, D., and Saxne, T. (2006). Serum levels of cartilage oligomeric matrix protein (COMP) increase temporarily after physical exercise in patients with knee osteoarthritis. BMC Musculoskelet. Disord., 7.","DOI":"10.1186\/1471-2474-7-98"},{"key":"ref_49","first-page":"e18607","article-title":"Association of Matrix Metalloproteinase (MMP) Gene Polymorphisms with Knee Osteoarthritis: A Review of the Literature","volume":"13","author":"Milaras","year":"2021","journal-title":"Cureus"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1080\/10409230701340019","article-title":"The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinases","volume":"42","author":"Cauwe","year":"2007","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1177\/1947603518798884","article-title":"C-Terminal Cross-Linked Telopeptides of Type II Collagen as Biomarker for Radiological Knee Osteoarthritis: A Meta-Analysis","volume":"11","author":"Cheng","year":"2020","journal-title":"Cartilage"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1007\/s10067-021-05885-3","article-title":"Biomarkers of joint metabolism and bone mineral density are associated with early knee osteoarthritis in premenopausal females","volume":"41","author":"Hu","year":"2022","journal-title":"Clin. Rheumatol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1007\/s00223-009-9302-2","article-title":"Association between ultrasonographic findings and bone\/cartilage biomarkers in patients with early-stage knee osteoarthritis","volume":"85","author":"Kumm","year":"2009","journal-title":"Calcif. Tissue Int."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/j.joca.2021.10.016","article-title":"The relation between the biochemical composition of knee articular cartilage and quantitative MRI: A systematic review and meta-analysis","volume":"30","author":"Emanuel","year":"2021","journal-title":"Osteoarthr. Cartil."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1007\/s11547-019-01003-1","article-title":"New advances in MRI diagnosis of degenerative osteoarthropathy of the peripheral joints","volume":"124","author":"Bruno","year":"2019","journal-title":"Radiol. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"388","DOI":"10.3109\/17453674.2014.989382","article-title":"Muscular forces affect the glycosaminoglycan content of joint cartilage: Unloading in human volunteers with the HEPHAISTOS lower leg orthosis","volume":"86","author":"Ganse","year":"2015","journal-title":"Acta Orthop."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"S861","DOI":"10.1007\/s00198-012-2169-5","article-title":"CT imaging for the investigation of subchondral bone in knee osteoarthritis","volume":"23","author":"Bousson","year":"2012","journal-title":"Osteoporos. Int."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e14413","DOI":"10.14814\/phy2.14413","article-title":"The influence of a sustained 10-day hypoxic bed rest on cartilage biomarkers and subchondral bone in females: The FemHab study","volume":"8","author":"McDonnell","year":"2020","journal-title":"Physiol. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1152\/japplphysiol.00935.2015","article-title":"Long-duration bed rest as an analog to microgravity","volume":"120","author":"Hargens","year":"2016","journal-title":"J. Appl. Physiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1002\/jor.23786","article-title":"Sensitivity of serum concentration of cartilage biomarkers to 21-days of bed rest","volume":"36","author":"Liphardt","year":"2018","journal-title":"J. Orthop. Res."},{"key":"ref_61","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":"Keller","year":"2010","journal-title":"Tissue Eng. Part A"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1089\/scd.2017.0242","article-title":"Tissue Engineering under Microgravity Conditions\u2014Use of Stem Cells and Specialized Cells","volume":"27","author":"Grimm","year":"2018","journal-title":"Stem Cells Dev."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1111\/j.1749-6632.2002.tb05927.x","article-title":"Microgravity studies of cells and tissues","volume":"974","author":"Searby","year":"2002","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1007\/s00776-005-0931-7","article-title":"Effect of low loading and joint immobilization for spontaneous repair of osteochondral defect in the knees of weightless (tail suspension) rats","volume":"10","author":"Harada","year":"2005","journal-title":"J. Orthop. Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1530S","DOI":"10.1177\/19476035211063857","article-title":"Physiological Reloading Recovers Histologically Disuse Atrophy of the Articular Cartilage and Bone by Hindlimb Suspension in Rat Knee Joint","volume":"13","author":"Takahashi","year":"2021","journal-title":"Cartilage"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"491","DOI":"10.3390\/life4030491","article-title":"Space Radiation: The Number One Risk to Astronaut Health beyond Low Earth Orbit","volume":"4","author":"Chancellor","year":"2014","journal-title":"Life"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"268","DOI":"10.3109\/09553002.2013.747015","article-title":"Ionizing radiation causes active degradation and reduces matrix synthesis in articular cartilage","volume":"89","author":"Willey","year":"2013","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1667\/RR14400.1","article-title":"Spaceflight-Relevant Challenges of Radiation and\/or Reduced Weight Bearing Cause Arthritic Responses in Knee Articular Cartilage","volume":"186","author":"Willey","year":"2016","journal-title":"Radiat. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1667\/RR15216.1","article-title":"Knee and Hip Joint Cartilage Damage from Combined Spaceflight Hazards of Low-Dose Radiation Less Than 1 Gy and Prolonged Hindlimb Unloading","volume":"191","author":"Kwok","year":"2019","journal-title":"Radiat. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1016\/j.bone.2012.07.001","article-title":"Effect of proton irradiation followed by hindlimb unloading on bone in mature mice: A model of long-duration spaceflight","volume":"51","author":"Lloyd","year":"2012","journal-title":"Bone"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"S144","DOI":"10.1016\/j.joca.2016.01.282","article-title":"Long-duration space flight and cartilage adaptation: First results on changes in tissue metabolism","volume":"24","author":"Niehoff","year":"2016","journal-title":"Osteoarthr. Cartil."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"S169","DOI":"10.1016\/j.joca.2019.02.253","article-title":"The effect of micro- and hypergravity on serum comp levels in healthy adults","volume":"27","author":"Niehoff","year":"2019","journal-title":"Osteoarthr. Cartil."},{"key":"ref_73","unstructured":"Liphardt, A.M., Djalal, N., Smith, S.M., Zwart, S.R., M\u00fcndermann, A., Zaucke, F., Schett, G., and Niehoff, A. Urine Concentration of Cartilage Degradation Marker CTX-II is Sensitive to Microgravity. Abstract. Proceedings of the NASA Human Research Program Investigators\u2019 Workshop, Virtual."},{"key":"ref_74","first-page":"R310","article-title":"Effects of spaceflight on trabecular bone in rats","volume":"244","author":"Jee","year":"1983","journal-title":"Am. J. Physiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1096\/fasebj.4.1.2295377","article-title":"Histomorphometric and electron microscopic analyses of tibial epiphyseal plates from Cosmos 1887 rats","volume":"4","author":"Duke","year":"1990","journal-title":"FASEB J."},{"key":"ref_76","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_77","first-page":"11","article-title":"Studies of Spaceflight Effects on a 3D Model of Chondroblast Culture","volume":"50","author":"Volova","year":"2016","journal-title":"Aviakosm. Ekol. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s12964-015-0095-9","article-title":"Differential gene expression of human chondrocytes cultured under short-term altered gravity conditions during parabolic flight maneuvers","volume":"13","author":"Wehland","year":"2015","journal-title":"Cell Commun. Signal."},{"key":"ref_79","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_80","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.lssr.2019.04.002","article-title":"Research plans in Europe for radiation health hazard assessment in exploratory space missions","volume":"21","author":"Walsh","year":"2019","journal-title":"Life Sci. Space Res."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Restier-Verlet, J., El-Nachef, L., Ferlazzo, M.L., Al-Choboq, J., Granzotto, A., Bouchet, A., and Foray, N. (2021). Radiation on Earth or in Space: What Does It Change?. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073739"},{"key":"ref_82","first-page":"634","article-title":"The effects of cosmic particle radiation on pocket mice aboard Apollo XVII: Appendix II. Evaluation of oral, dental, and skeletal tissues","volume":"46","author":"Person","year":"1975","journal-title":"Aviat. Space Environ. Med."},{"key":"ref_83","first-page":"421","article-title":"The Effects of Space Microgravity on Hip and Knee Cartilage: A New Frontier in Orthopaedics","volume":"35","author":"Ramkumar","year":"2019","journal-title":"Surg. Technol. Int."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e13431","DOI":"10.1111\/apha.13431","article-title":"Muscle unloading: A comparison between spaceflight and ground-based models","volume":"228","author":"Qaisar","year":"2020","journal-title":"Acta Physiol."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Koy, T., Zange, J., Rittweger, J., Pohle-Fr\u00f6hlich, R., Hackenbroch, M., Eysel, P., and Ganse, B. (2014). Assessment of lumbar intervertebral disc glycosaminoglycan content by gadolinium-enhanced MRI before and after 21-days of head-down-tilt bedrest. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0112104"},{"key":"ref_86","first-page":"140","article-title":"T2-relaxation time increases in lumbar intervertebral discs after 21d head-down tilt bed-rest","volume":"17","author":"Koy","year":"2017","journal-title":"J. Musculoskelet. Neuronal Interact."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"433","DOI":"10.21037\/jss.2018.04.07","article-title":"Effects of spaceflight on cartilage: Implications on spinal physiology","volume":"4","author":"Ramachandran","year":"2018","journal-title":"J. Spine Surg."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s13728-016-0050-4","article-title":"Exercise in space: The European Space Agency approach to in-flight exercise countermeasures for long-duration missions on ISS","volume":"5","author":"Petersen","year":"2016","journal-title":"Extreme Physiol. Med."},{"key":"ref_89","first-page":"476","article-title":"Physiologic validation of a short-arm centrifuge for space application","volume":"63","author":"Burton","year":"1992","journal-title":"Aviat. Space Environ. Med."},{"key":"ref_90","first-page":"235","article-title":"Centrifugation as a countermeasure during actual and simulated microgravity: A review","volume":"92","year":"2004","journal-title":"Eur. J. Appl. Physiol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.actaastro.2015.11.030","article-title":"Method to maintain artificial gravity during transfer maneuvers for tethered spacecraft","volume":"120","author":"Martin","year":"2016","journal-title":"Acta Astronaut."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Spilker, T.R. (2020). Engineering Challenges of Artificial Gravity Stations. AIAA, 4111.","DOI":"10.2514\/6.2020-4111"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.3389\/fphys.2020.01032","article-title":"Short-Term Response of Serum Cartilage Oligomeric Matrix Protein to Different Types of Impact Loading under Normal and Artificial Gravity","volume":"11","author":"Dreiner","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"112463","DOI":"10.1016\/j.yexcr.2020.112463","article-title":"Sixty days of head-down tilt bed rest with or without artificial gravity do not affect the neuromuscular secretome","volume":"399","author":"Ganse","year":"2021","journal-title":"Exp. Cell Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1007\/s00421-021-04673-w","article-title":"Daily 30-min exposure to artificial gravity during 60 days of bed rest does not maintain aerobic exercise capacity but mitigates some deteriorations of muscle function: Results from the AGBRESA RCT","volume":"121","author":"Kramer","year":"2021","journal-title":"Eur. J. Appl. Physiol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/s41526-021-00145-9","article-title":"Findings from recent studies by the Japan Aerospace Exploration Agency examining musculoskeletal atrophy in space and on Earth","volume":"7","author":"Furukawa","year":"2021","journal-title":"NPJ Microgravity"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1001\/jama.2019.14735","article-title":"Effect of Intra-Articular Sprifermin vs. Placebo on Femorotibial Joint Cartilage Thickness in Patients with Osteoarthritis: The FORWARD Randomized Clinical Trial","volume":"322","author":"Hochberg","year":"2019","journal-title":"JAMA"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"86","DOI":"10.7326\/M19-0675","article-title":"Disease-Modifying Effects of a Novel Cathepsin K Inhibitor in Osteoarthritis: A Randomized Controlled Trial","volume":"172","author":"Conaghan","year":"2020","journal-title":"Ann. Intern. Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.joca.2021.02.004","article-title":"A Phase 2b randomized trial of lorecivivint, a novel intra-articular CLK2\/DYRK1A inhibitor and Wnt pathway modulator for knee osteoarthritis","volume":"29","author":"Yazici","year":"2021","journal-title":"Osteoarthr. Cartil."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"105276","DOI":"10.1016\/j.jbspin.2021.105276","article-title":"The application of whole-body vibration training in knee osteoarthritis","volume":"89","author":"Wang","year":"2022","journal-title":"Jt. Bone Spine"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1016\/j.ultrasmedbio.2019.12.007","article-title":"Therapeutic Potential Low-Intensity Pulsed Ultrasound for Osteoarthritis: Pre-clinical and Clinical Perspectives","volume":"46","author":"Uddin","year":"2020","journal-title":"Ultrasound Med. Biol."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Moretti, L., Bizzoca, D., Giancaspro, G.A., Cassano, G.D., Moretti, F., Setti, S., and Moretti, B. (2021). Biophysical Stimulation in Athletes\u2019 Joint Degeneration: A Narrative Review. Medicina, 57.","DOI":"10.3390\/medicina57111206"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1089\/ars.2013.5649","article-title":"Health risks of space exploration: Targeted and nontargeted oxidative injury by high-charge and high-energy particles","volume":"20","author":"Li","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1016\/j.asr.2003.10.051","article-title":"Implementation of ALARA radiation protection on the ISS through polyethylene shielding augmentation of the Service Module Crew Quarters","volume":"34","author":"Shavers","year":"2004","journal-title":"Adv. Space Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.lssr.2014.12.004","article-title":"Active magnetic radiation shielding system analysis and key technologies","volume":"4","author":"Washburn","year":"2015","journal-title":"Life Sci. Space Res."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Herrmann, M., Engelke, K., Ebert, R., M\u00fcller-Deubert, S., Rudert, M., Ziouti, F., Jundt, F., Felsenberg, D., and Jakob, F. (2020). Interactions between Muscle and Bone\u2014Where Physics Meets Biology. Biomolecules, 10.","DOI":"10.3390\/biom10030432"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"494","DOI":"10.3389\/fphys.2018.00494","article-title":"Hypoxia Aggravates Inactivity-Related Muscle Wasting","volume":"9","author":"Debevec","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1111\/j.1748-1716.2007.01728.x","article-title":"Influence of concurrent exercise or nutrition countermeasures on thigh and calf muscle size and function during 60 days of bed rest in women","volume":"191","author":"Trappe","year":"2007","journal-title":"Acta Physiol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1007\/s00421-004-1172-8","article-title":"Knee extensor and plantar flexor muscle size and function following 90 days of bed rest with or without resistance exercise","volume":"93","author":"Alkner","year":"2004","journal-title":"Eur. J. Appl. Physiol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1152\/jappl.2000.89.6.2158","article-title":"Muscle volume, MRI relaxation times (T2), and body composition after spaceflight","volume":"89","author":"LeBlanc","year":"2000","journal-title":"J. Appl. Physiol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"161","DOI":"10.3233\/VES-1997-72-307","article-title":"Locomotor head-trunk coordination strategies following space flight","volume":"7","author":"Bloomberg","year":"1997","journal-title":"J. Vestib. Res."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"919","DOI":"10.3357\/ASEM.2680.2010","article-title":"Changes in toe clearance during treadmill walking after long-duration spaceflight","volume":"81","author":"Miller","year":"2010","journal-title":"Aviat. Space Environ. Med."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/S0021-9290(98)00065-7","article-title":"Multivariate changes in coordination of postural control following spaceflight","volume":"31","author":"Speers","year":"1998","journal-title":"J. Biomech."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1016\/j.jbiomech.2012.01.029","article-title":"Predictive simulation of gait at low gravity reveals skipping as the preferred locomotion strategy","volume":"45","author":"Ackermann","year":"2012","journal-title":"J. Biomech."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1152\/japplphysiol.01021.2014","article-title":"Skipping vs. running as the bipedal gait of choice in hypogravity","volume":"119","author":"Pavei","year":"2015","journal-title":"J. Appl. Physiol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"22555","DOI":"10.1038\/s41598-021-00527-9","article-title":"Gastrocnemius medialis contractile behavior during running differs between simulated Lunar and Martian gravities","volume":"11","author":"Richter","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"583","DOI":"10.3389\/fphys.2017.00583","article-title":"Human Biomechanical and Cardiopulmonary Responses to Partial Gravity\u2014A Systematic Review","volume":"8","author":"Richter","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1244797","DOI":"10.1126\/science.1244797","article-title":"Mars\u2019 surface radiation environment measured with the Mars Science Laboratory\u2019s Curiosity rover","volume":"343","author":"Hassler","year":"2014","journal-title":"Science"}],"container-title":["Biomedicines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9059\/10\/6\/1356\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:26:20Z","timestamp":1760138780000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9059\/10\/6\/1356"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,8]]},"references-count":118,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["biomedicines10061356"],"URL":"https:\/\/doi.org\/10.3390\/biomedicines10061356","relation":{},"ISSN":["2227-9059"],"issn-type":[{"value":"2227-9059","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,8]]}}}