{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/107935"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/107935","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"The independent and combined effects of rapamycin and metformin on naturally occurring osteoarthritis","abstract":"Osteoarthritis (OA) is among the top 10 diseases limiting human healthspan, and no disease modifying therapies currently exist. OA is a degenerative disease of the whole joint, characterized by articular cartilage loss, subchondral bone sclerosis, meniscal calcification, synovitis, and skeletal muscle dysfunction. Inhibiting the mechanistic target of rapamycin (mTOR) and stimulating AMP-activated protein kinase (AMPK) has extended lifespan and protected against post-traumatic (secondary) OA in mice. However, it remains unknown if manipulation of these pathways can protect against naturally occurring, age-related (primary) OA, the form most commonly observed in humans. The outbred Dunkin-Hartley (DH) guinea pig develops primary OA beginning at 5 months of age and displays high histological similarity to human OA. Therefore, at 5 months we sacrificed a group of DH guinea pigs to serve as young control and the remaining animals were randomized to receive a standard diet (age-matched controls) or diets enriched with rapamycin (Rap; 14ppm), metformin (Met; 1000ppm), or a combination of rapamycin plus metformin (Rap+Met) for 3 months. Hind limbs were collected for histopathological and radiographic evaluation of the knee joint. Histological OA scores in DH guinea pigs receiving Rap and Rap+Met were significantly lower than their age-matched controls. Rap treatment also reduced subchondral cortical bone thickness in the medial and lateral tibia, while Rap+Met reduced cortical thickness only in the lateral tibia. Both OA scores and cortical thickness were highly correlated with bodyweight, suggesting reduced joint loading could be contributing to the protective effects of Rap and Rap+Met. The minimal effect of Met may be attributed to low dose and indicates that Rap likely drove the protective effects of Rap+Met. Together, these data are the first to suggest that mTOR inhibition delays the onset of primary, age- related OA in the DH guinea pig.","abstract_html":"Osteoarthritis (OA) is among the top 10 diseases limiting human healthspan, and no disease modifying therapies currently exist. OA is a degenerative disease of the whole joint, characterized by articular cartilage loss, subchondral bone sclerosis, meniscal calcification, synovitis, and skeletal muscle dysfunction. Inhibiting the mechanistic target of rapamycin (mTOR) and stimulating AMP-activated protein kinase (AMPK) has extended lifespan and protected against post-traumatic (secondary) OA in mice. However, it remains unknown if manipulation of these pathways can protect against naturally occurring, age-related (primary) OA, the form most commonly observed in humans. The outbred Dunkin-Hartley (DH) guinea pig develops primary OA beginning at 5 months of age and displays high histological similarity to human OA. Therefore, at 5 months we sacrificed a group of DH guinea pigs to serve as young control and the remaining animals were randomized to receive a standard diet (age-matched controls) or diets enriched with rapamycin (Rap; 14ppm), metformin (Met; 1000ppm), or a combination of rapamycin plus metformin (Rap+Met) for 3 months. Hind limbs were collected for histopathological and radiographic evaluation of the knee joint. Histological OA scores in DH guinea pigs receiving Rap and Rap+Met were significantly lower than their age-matched controls. Rap treatment also reduced subchondral cortical bone thickness in the medial and lateral tibia, while Rap+Met reduced cortical thickness only in the lateral tibia. Both OA scores and cortical thickness were highly correlated with bodyweight, suggesting reduced joint loading could be contributing to the protective effects of Rap and Rap+Met. The minimal effect of Met may be attributed to low dose and indicates that Rap likely drove the protective effects of Rap+Met. Together, these data are the first to suggest that mTOR inhibition delays the onset of primary, age- related OA in the DH guinea pig.","abstract_has_math":false,"creators":["Minton, Dennis Michael"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"M.S.","degree_level":"Thesis","degree_discipline":"Kinesiology","degree_department":null,"school":null,"contributors":["Konopka, Adam R"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2020,"date_issued":"2020-08-26T21:54:33Z","date_published":"2020-08-26T21:54:33Z","updated_at":"2026-07-22T22:24:47Z","subjects":["Osteoarthritis, Rapamycin, Metformin, mTOR"],"languages":["en"],"rights":["Copyright 2020 Dennis Minton"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/2142/107935","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Konopka, Adam R"]},{"key":"dc:creator","label":"Author","values":["Minton, Dennis Michael"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2020-08-26T21:54:33Z","2020-04-28","2020-05"]},{"key":"dc:type","label":"Dc Type","values":["text","Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Kinesiology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Thesis"]},{"key":"thesis:degree_name","label":"Degree Name","values":["M.S."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Osteoarthritis, Rapamycin, Metformin, mTOR"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2020 Dennis Minton"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/107935"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Osteoarthritis (OA) is among the top 10 diseases limiting human healthspan, and no disease modifying therapies currently exist. OA is a degenerative disease of the whole joint, characterized by articular cartilage loss, subchondral bone sclerosis, meniscal calcification, synovitis, and skeletal muscle dysfunction. Inhibiting the mechanistic target of rapamycin (mTOR) and stimulating AMP-activated protein kinase (AMPK) has extended lifespan and protected against post-traumatic (secondary) OA in mice. However, it remains unknown if manipulation of these pathways can protect against naturally occurring, age-related (primary) OA, the form most commonly observed in humans. The outbred Dunkin-Hartley (DH) guinea pig develops primary OA beginning at 5 months of age and displays high histological similarity to human OA. Therefore, at 5 months we sacrificed a group of DH guinea pigs to serve as young control and the remaining animals were randomized to receive a standard diet (age-matched controls) or diets enriched with rapamycin (Rap; 14ppm), metformin (Met; 1000ppm), or a combination of rapamycin plus metformin (Rap+Met) for 3 months. Hind limbs were collected for histopathological and radiographic evaluation of the knee joint. Histological OA scores in DH guinea pigs receiving Rap and Rap+Met were significantly lower than their age-matched controls. Rap treatment also reduced subchondral cortical bone thickness in the medial and lateral tibia, while Rap+Met reduced cortical thickness only in the lateral tibia. Both OA scores and cortical thickness were highly correlated with bodyweight, suggesting reduced joint loading could be contributing to the protective effects of Rap and Rap+Met. The minimal effect of Met may be attributed to low dose and indicates that Rap likely drove the protective effects of Rap+Met. Together, these data are the first to suggest that mTOR inhibition delays the onset of primary, age- related OA in the DH guinea pig.","Submission original under an indefinite embargo labeled 'Open Access'. The submission was exported from vireo on 2020-08-25 without embargo terms","The student, Dennis Minton, accepted the attached license on 2020-04-28 at 11:18.","The student, Dennis Minton, submitted this Thesis for approval on 2020-04-28 at 12:34.","This Thesis was approved for publication on 2020-04-28 at 15:38.","DSpace SAF Submission Ingestion Package generated from Vireo submission #15101 on 2020-08-25 at 17:09:14","Made available in DSpace on 2020-08-26T21:54:33Z (GMT). No. of bitstreams: 2 MINTON-THESIS-2020.pdf: 1958092 bytes, checksum: 0b8aff645922829e99a6a32b3c7e7d25 (MD5) LICENSE.txt: 4210 bytes, checksum: 8fecf31a8903eb3e794a1e74cda5b15a (MD5) Previous issue date: 2020-04-28"]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["The independent and combined effects of rapamycin and metformin on naturally occurring osteoarthritis"]}]}],"canonical_facts":{"dc:contributor":["Konopka, Adam R"],"dc:creator":["Minton, Dennis Michael"],"dc:date":["2020-08-26T21:54:33Z","2020-04-28","2020-05"],"dc:description":["Osteoarthritis (OA) is among the top 10 diseases limiting human healthspan, and no disease modifying therapies currently exist. OA is a degenerative disease of the whole joint, characterized by articular cartilage loss, subchondral bone sclerosis, meniscal calcification, synovitis, and skeletal muscle dysfunction. Inhibiting the mechanistic target of rapamycin (mTOR) and stimulating AMP-activated protein kinase (AMPK) has extended lifespan and protected against post-traumatic (secondary) OA in mice. However, it remains unknown if manipulation of these pathways can protect against naturally occurring, age-related (primary) OA, the form most commonly observed in humans. The outbred Dunkin-Hartley (DH) guinea pig develops primary OA beginning at 5 months of age and displays high histological similarity to human OA. Therefore, at 5 months we sacrificed a group of DH guinea pigs to serve as young control and the remaining animals were randomized to receive a standard diet (age-matched controls) or diets enriched with rapamycin (Rap; 14ppm), metformin (Met; 1000ppm), or a combination of rapamycin plus metformin (Rap+Met) for 3 months. Hind limbs were collected for histopathological and radiographic evaluation of the knee joint. Histological OA scores in DH guinea pigs receiving Rap and Rap+Met were significantly lower than their age-matched controls. Rap treatment also reduced subchondral cortical bone thickness in the medial and lateral tibia, while Rap+Met reduced cortical thickness only in the lateral tibia. Both OA scores and cortical thickness were highly correlated with bodyweight, suggesting reduced joint loading could be contributing to the protective effects of Rap and Rap+Met. The minimal effect of Met may be attributed to low dose and indicates that Rap likely drove the protective effects of Rap+Met. Together, these data are the first to suggest that mTOR inhibition delays the onset of primary, age- related OA in the DH guinea pig.","Submission original under an indefinite embargo labeled 'Open Access'. The submission was exported from vireo on 2020-08-25 without embargo terms","The student, Dennis Minton, accepted the attached license on 2020-04-28 at 11:18.","The student, Dennis Minton, submitted this Thesis for approval on 2020-04-28 at 12:34.","This Thesis was approved for publication on 2020-04-28 at 15:38.","DSpace SAF Submission Ingestion Package generated from Vireo submission #15101 on 2020-08-25 at 17:09:14","Made available in DSpace on 2020-08-26T21:54:33Z (GMT). No. of bitstreams: 2 MINTON-THESIS-2020.pdf: 1958092 bytes, checksum: 0b8aff645922829e99a6a32b3c7e7d25 (MD5) LICENSE.txt: 4210 bytes, checksum: 8fecf31a8903eb3e794a1e74cda5b15a (MD5) Previous issue date: 2020-04-28"],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/2142/107935"],"dc:language":["en"],"dc:rights":["Copyright 2020 Dennis Minton"],"dc:subject":["Osteoarthritis, Rapamycin, Metformin, mTOR"],"dc:title":["The independent and combined effects of rapamycin and metformin on naturally occurring osteoarthritis"],"dc:type":["text","Thesis"],"thesis:degree_discipline":["Kinesiology"],"thesis:degree_level":["Thesis"],"thesis:degree_name":["M.S."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:24:47Z"}