J K Meckes1, B Caramés2, M Olmer3, W B Kiosses4, S P Grogan5, M K Lotz6, D D D'Lima7. 1. Materials Science and Engineering Program, Department of Mechanical and Aerospace Engineering, University of California, San Diego, CA, USA. Electronic address: jeaniekwok@gmail.com. 2. Instituto de Investigación Biomédica de A Coruña, Complexo Hospitalario Universitario de A Coruña, SERGAS, and Universidade da Coruña, A Coruña, Spain. Electronic address: bcarper2@gmail.com. 3. Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA. Electronic address: molmer@scripps.edu. 4. Core Microscopy, The Scripps Research Institute, La Jolla, CA, USA. Electronic address: wkiosses@scripps.edu. 5. Shiley Center for Orthopaedic Research and Education at Scripps Clinic, La Jolla, CA, USA. Electronic address: Grogan.Shawn@scrippshealth.org. 6. Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA. Electronic address: mlotz@scripps.edu. 7. Shiley Center for Orthopaedic Research and Education at Scripps Clinic, La Jolla, CA, USA. Electronic address: ddlima@scripps.edu.
Abstract
OBJECTIVE: Autophagy is a cellular homeostasis mechanism that facilitates normal cell function and survival. Objectives of this study were to determine associations between autophagic responses with meniscus injury, joint aging, and osteoarthritis (OA), and to establish the temporal relationship with structural changes in menisci and cartilage. METHODS: Constitutive activation of autophagy during aging was measured in GFP-LC3 transgenic reporter mice between 6 and 30 months. Meniscus injury was created by surgically destabilizing the medial meniscus (DMM) to induce posttraumatic OA in C57BL/6J mice. Levels of autophagy proteins and activation were analyzed by confocal microscopy and immunohistochemistry. Associated histopathological changes, such as cellularity, matrix staining, and structural damage, were graded in the meniscus and compared to changes in articular cartilage. RESULTS: In C57BL/6J mice, basal autophagy was lower in the meniscus than in articular cartilage. With increasing age, expression of the autophagy proteins ATG5 and LC3 was significantly reduced by 24 months. Age-related changes included abnormal Safranin-O staining and reduced cellularity, which preceded structural damage in the meniscus and articular cartilage. In mice with DMM, autophagy was induced in the meniscus while it was suppressed in cartilage. Articular cartilage exhibited the most profound changes in autophagy and structure that preceded meniscus degeneration. Systemic administration of rapamycin to mice with DMM induced autophagy activation in cartilage and reduced degenerative changes in both meniscus and cartilage. CONCLUSION: Autophagy is significantly affected in the meniscus during aging and injury and precedes structural damage. Maintenance of autophagic activity appears critical for meniscus and cartilage integrity.
OBJECTIVE: Autophagy is a cellular homeostasis mechanism that facilitates normal cell function and survival. Objectives of this study were to determine associations between autophagic responses with meniscus injury, joint aging, and osteoarthritis (OA), and to establish the temporal relationship with structural changes in menisci and cartilage. METHODS: Constitutive activation of autophagy during aging was measured in GFP-LC3transgenic reporter mice between 6 and 30 months. Meniscus injury was created by surgically destabilizing the medial meniscus (DMM) to induce posttraumatic OA in C57BL/6J mice. Levels of autophagy proteins and activation were analyzed by confocal microscopy and immunohistochemistry. Associated histopathological changes, such as cellularity, matrix staining, and structural damage, were graded in the meniscus and compared to changes in articular cartilage. RESULTS: In C57BL/6J mice, basal autophagy was lower in the meniscus than in articular cartilage. With increasing age, expression of the autophagy proteins ATG5 and LC3 was significantly reduced by 24 months. Age-related changes included abnormal Safranin-O staining and reduced cellularity, which preceded structural damage in the meniscus and articular cartilage. In mice with DMM, autophagy was induced in the meniscus while it was suppressed in cartilage. Articular cartilage exhibited the most profound changes in autophagy and structure that preceded meniscus degeneration. Systemic administration of rapamycin to mice with DMM induced autophagy activation in cartilage and reduced degenerative changes in both meniscus and cartilage. CONCLUSION: Autophagy is significantly affected in the meniscus during aging and injury and precedes structural damage. Maintenance of autophagic activity appears critical for meniscus and cartilage integrity.
Authors: L H W Kung; S Zaki; V Ravi; L Rowley; M M Smith; K M Bell; J F Bateman; C B Little Journal: Osteoarthritis Cartilage Date: 2016-09-09 Impact factor: 6.576
Authors: S C M van Dalen; A B Blom; A W Slöetjes; M M A Helsen; J Roth; T Vogl; F A J van de Loo; M I Koenders; P M van der Kraan; W B van den Berg; M H J van den Bosch; P L E M van Lent Journal: Osteoarthritis Cartilage Date: 2016-09-18 Impact factor: 6.576
Authors: M-J Berthiaume; J-P Raynauld; J Martel-Pelletier; F Labonté; G Beaudoin; D A Bloch; D Choquette; B Haraoui; R D Altman; M Hochberg; J M Meyer; G A Cline; J-P Pelletier Journal: Ann Rheum Dis Date: 2004-09-16 Impact factor: 19.103
Authors: Kwang Il Lee; Sungwook Choi; Tokio Matsuzaki; Oscar Alvarez-Garcia; Merissa Olmer; Shawn P Grogan; Darryl D D'Lima; Martin K Lotz Journal: Proc Natl Acad Sci U S A Date: 2020-01-24 Impact factor: 11.205
Authors: Jeffrey B Driban; Matthew S Harkey; Mary F Barbe; Robert J Ward; James W MacKay; Julie E Davis; Bing Lu; Lori Lyn Price; Charles B Eaton; Grace H Lo; Timothy E McAlindon Journal: BMC Musculoskelet Disord Date: 2020-05-29 Impact factor: 2.362