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Increased physical activity severely induces osteoarthritic changes in knee joints with papain induced sulfate-glycosaminoglycan depleted cartilage

Michiel Siebelt1*, Harald C Groen2, Stuart J Koelewijn2, Erik de Blois2, Marjan Sandker1, Jan H Waarsing1, Cristina Müller3, Gerjo JVM van Osch14, Marion de Jong2 and Harrie Weinans567

Author Affiliations

1 Department of Orthopedics, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands

2 Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

3 Center for Radiopharmaceutical Sciences PSI-ETH-USZ, Paul Scherrer Institute, Villigen-PSI, Villigen, Switzerland

4 Department of Otorhinolaryngology, Erasmus Medical Center, Rotterdam, The Netherlands

5 Department of Biomechanical Engineering, Delft University of Technology, Delft, The Netherlands

6 Department of Orthopaedics, UMC Utrecht, Utrecht, The Netherlands

7 Department of Rheumatology, UMC Utrecht, Utrecht, The Netherlands

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Arthritis Research & Therapy 2014, 16:R32  doi:10.1186/ar4461

Published: 29 January 2014



Articular cartilage needs sulfated-glycosaminoglycans (sGAGs) to withstand high pressures while mechanically loaded. Chondrocyte sGAG synthesis is regulated by exposure to compressive forces. Moderate physical exercise is known to improve cartilage sGAG content and might protect against osteoarthritis (OA). This study investigated whether rat knee joints with sGAG depleted articular cartilage through papain injections might benefit from moderate exercise, or whether this increases the susceptibility for cartilage degeneration.


sGAGs were depleted from cartilage through intraarticular papain injections in the left knee joints of 40 Wistar rats; their contralateral joints served as healthy controls. Of the 40 rats included in the study, 20 rats remained sedentary, and the other 20 were subjected to a moderately intense running protocol. Animals were longitudinally monitored for 12 weeks with in vivo micro-computed tomography (μCT) to measure subchondral bone changes and single-photon emission computed tomography (SPECT)/CT to determine synovial macrophage activation. Articular cartilage was analyzed at 6 and 12 weeks with ex vivo contrast-enhanced μCT and histology to measure sGAG content and cartilage thickness.


All outcome measures were unaffected by moderate exercise in healthy control joints of running animals compared with healthy control joints of sedentary animals. Papain injections in sedentary animals resulted in severe sGAG-depleted cartilage, slight loss of subchondral cortical bone, increased macrophage activation, and osteophyte formation. In running animals, papain-induced sGAG-depleted cartilage showed increased cartilage matrix degradation, sclerotic bone formation, increased macrophage activation, and more osteophyte formation.


Moderate exercise enhanced OA progression in papain-injected joints and did not protect against development of the disease. This was not restricted to more-extensive cartilage damage, but also resulted in pronounced subchondral sclerosis, synovial macrophage activation, and osteophyte formation.