title: Physiological exercise loading suppresses post-traumatic osteoarthritis progression via an increase in bone morphogenetic proteins expression in an experimental rat knee model.
abstract: To evaluate the dose-response relationship of exercise loading in the cartilage-subchondral bone (SB) unit in surgically-induced post-traumatic osteoarthritis (PTOA) of the knee.
  
  
  
  Destabilized medial meniscus (DMM) surgery was performed on the right knee of 12-week-old male Wistar rats, and sham surgery was performed on the contralateral knee. Four weeks after the surgery, the animals were subjected to moderate (12 m/min) or intense (21 m/min) treadmill exercises for 30 min/day, 5 days/week for 4 weeks. PTOA development in articular cartilage and SB was examined using histological and immunohistochemical analyses, micro-computed tomography (micro-CT) analysis, and biomechanical testing at 8 weeks after surgery. Gremlin-1 was injected to determine the role of bone morphogenetic protein (BMP) signaling on PTOA development following moderate exercise.
  
  
  
  Moderate exercise increased BMP-2, BMP-4, BMP-6, BMP receptor 2, pSmad-5, and inhibitor of DNA binding protein-1 expression in the superficial zone chondrocytes and suppressed cartilage degeneration, osteophyte growth, SB damage, and osteoclast-mediated SB resorption. However, intense exercise had little effect on BMP expression and even caused progression of these osteoarthritis (OA) changes. Gremlin-1 injection following moderate exercise caused progression of the PTOA development down to the level of the non-exercise DMM-operated knee.
  
  
  
  Exercise regulated cartilage-SB PTOA development in DMM-operated knees in a dose-dependent manner. Our findings shed light on the important role of BMP expression in superficial zone chondrocytes in attenuation of PTOA development following physiological exercise loading. Further studies to support a mechanism by which BMPs would be beneficial in preventing PTOA progression are warranted.
authors.affiliation: Department of Motor Function Analysis, Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Japan Society for the Promotion of Science, Tokyo, Japan. Electronic address: iijima.hirotaka.75s@st.kyoto-u.ac.jp.
authors.forename: H
authors.initials: H
authors.lastname: Iijima
authors.affiliation: Department of Motor Function Analysis, Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: ito.akira.4m@kyoto-u.ac.jp.
authors.forename: A
authors.initials: A
authors.lastname: Ito
authors.affiliation: Congenital Anomaly Research Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: nagai@cac.med.kyoto-u.ac.jp.
authors.forename: M
authors.initials: M
authors.lastname: Nagai
authors.affiliation: Department of Development and Rehabilitation of Motor Function, Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: tajino.junichi.6c@kyoto-u.ac.jp.
authors.forename: J
authors.initials: J
authors.lastname: Tajino
authors.affiliation: Department of Motor Function Analysis, Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: sho_ki62@yahoo.co.jp.
authors.forename: S
authors.initials: S
authors.lastname: Yamaguchi
authors.affiliation: Department of Motor Function Analysis, Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: kiyan.wataru.32c@st.kyoto-u.ac.jp.
authors.forename: W
authors.initials: W
authors.lastname: Kiyan
authors.affiliation: Department of Motor Function Analysis, Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: nakahata.akihiro.45a@st.kyoto-u.ac.jp.
authors.forename: A
authors.initials: A
authors.lastname: Nakahata
authors.affiliation: Department of Motor Function Analysis, Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: zhang.jue.43s@st.kyoto-u.ac.jp.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Motor Function Analysis, Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: wang.tianshu.75e@st.kyoto-u.ac.jp.
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Development and Rehabilitation of Motor Function, Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: aoyama.tomoki.4e@kyoto-u.ac.jp.
authors.forename: T
authors.initials: T
authors.lastname: Aoyama
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: nkohei@kuhp.kyoto-u.ac.jp.
authors.forename: K
authors.initials: K
authors.lastname: Nishitani
authors.affiliation: Department of Motor Function Analysis, Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: kuroki.hiroshi.6s@kyoto-u.ac.jp.
authors.forename: H
authors.initials: H
authors.lastname: Kuroki
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000187:drug effects / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000187:drug effects / Q000378:metabolism; D055418:Bone Morphogenetic Protein 6 / Q000187:drug effects / Q000378:metabolism; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000187:drug effects / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000187:drug effects / Q000378:metabolism*; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism*; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D016207:Cytokines; D051798:Inhibitor of Differentiation Protein 1; D007719:Knee Joint / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D020370:Osteoarthritis, Knee / Q000209:etiology / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D011506:Proteins / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D051902:Smad5 Protein / Q000187:drug effects / Q000378:metabolism; D000070600:Tibial Meniscus Injuries / Q000150:complications / Q000378:metabolism; D016474:Weight-Bearing
chemical_list: C525720:Bmp2 protein, rat; C525811:Bmp4 protein, rat; C525818:Bmp6 protein, rat; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D016207:Cytokines; C107276:Grem1 protein, rat; D051798:Inhibitor of Differentiation Protein 1; D011506:Proteins; D051902:Smad5 Protein; C497799:Smad5 protein, rat; C498220:Bmpr2 protein, rat; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: Bone micro-CT; Bone morphogenetic protein; Cartilage; Exercise; Gremlin-1; Osteoarthritis