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

IntroductionArticular 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.MethodssGAGs 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.ResultsAll 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.ConclusionsModerate 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.

[1]  Harrie Weinans,et al.  An Improved Segmentation Method for In Vivo μCT Imaging , 2004 .

[2]  H. Sun.  Mechanical loading, cartilage degradation, and arthritis , 2010, Annals of the New York Academy of Sciences.

[3]  B. Beynnon,et al.  Chronic in vivo load alteration induces degenerative changes in the rat tibiofemoral joint. , 2013, Osteoarthritis and cartilage.

[4]  S. Goldring,et al.  The role of synovitis in osteoarthritis pathogenesis. , 2012, Bone.

[5]  L. Hocking,et al.  Bone remodelling at a glance , 2011, Journal of Cell Science.

[6]  A. Roessner,et al.  Development of osteoarthritis in the knee joints of Wistar rats after strenuous running exercise in a running wheel by intracranial self-stimulation. , 1998, Pathology, research and practice.

[7]  R. Schneiderman,et al.  Some biochemical and biophysical parameters for the study of the pathogenesis of osteoarthritis: a comparison between the processes of ageing and degeneration in human hip cartilage. , 1989, Connective tissue research.

[8]  J. Pomonis,et al.  Development and pharmacological characterization of a rat model of osteoarthritis pain , 2005, Pain.

[9]  R. Katzberg,et al.  Epinephrine enhanced knee arthrography. , 1978, Investigative radiology.

[10]  P. Low,et al.  Folate-targeted imaging of activated macrophages in rats with adjuvant-induced arthritis. , 2002, Arthritis and rheumatism.

[11]  Benedicte Vanwanseele,et al.  A review on the mechanical quality of articular cartilage - implications for the diagnosis of osteoarthritis. , 2006, Clinical biomechanics.

[12]  H. Weinans,et al.  Quantifying osteoarthritic cartilage changes accurately using in vivo microCT arthrography in three etiologically distinct rat models , 2011, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[13]  H J Helminen,et al.  Biomechanical properties of the canine knee articular cartilage as related to matrix proteoglycans and collagen. , 1988, Engineering in medicine.

[14]  W. B. van den Berg,et al.  Synovial lining macrophages mediate osteophyte formation during experimental osteoarthritis. , 2004, Osteoarthritis and cartilage.

[15]  R. Arida,et al.  Effect of exhaustive ultra-endurance exercise in muscular glycogen and both Alpha1 and Alpha2 Ampk protein expression in trained rats , 2012, Journal of Physiology and Biochemistry.

[16]  R. Guldberg,et al.  Localized 3D analysis of cartilage composition and morphology in small animal models of joint degeneration. , 2013, Osteoarthritis and cartilage.

[17]  Harrie Weinans,et al.  An improved segmentation method for in vivo microCT imaging. , 2004, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[18]  H. Weinans,et al.  Hsp90 inhibition protects against biomechanically induced osteoarthritis in rats. , 2013, Arthritis and rheumatism.

[19]  W. Breeman,et al.  Improving radiopeptide pharmacokinetics by adjusting experimental conditions for bombesin receptor-targeted imaging of prostate cancer. , 2012, The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of....

[20]  J. Bijlsma,et al.  The canine 'groove' model, compared with the ACLT model of osteoarthritis. , 2002, Osteoarthritis and cartilage.

[21]  C. McDevitt,et al.  The ultrastructure and biochemistry of meniscal cartilage. , 1990, Clinical orthopaedics and related research.

[22]  M. Freeman,et al.  Correlations between stiffness and the chemical constituents of cartilage on the human femoral head. , 1970, Biochimica et Biophysica Acta.

[23]  H Weinans,et al.  Cartilage damage pattern in relation to subchondral plate thickness in a collagenase-induced model of osteoarthritis. , 2008, Osteoarthritis and cartilage.

[24]  W. B. van den Berg,et al.  Crucial role of synovial lining macrophages in the promotion of transforming growth factor beta-mediated osteophyte formation. , 2004, Arthritis and rheumatism.

[25]  J. Jurvelin,et al.  pQCT study on diffusion and equilibrium distribution of iodinated anionic contrast agent in human articular cartilage--associations to matrix composition and integrity. , 2009, Osteoarthritis and cartilage.

[26]  M. Sevick,et al.  Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: the Arthritis, Diet, and Activity Promotion Trial. , 2004, Arthritis and rheumatism.

[27]  H J Helminen,et al.  Articular cartilage thickness and glycosaminoglycan distribution in the canine knee joint after strenuous running exercise. , 1992, Clinical orthopaedics and related research.

[28]  J. Bondeson,et al.  The role of synovial macrophages and macrophage-produced cytokines in driving aggrecanases, matrix metalloproteinases, and other destructive and inflammatory responses in osteoarthritis , 2006, Arthritis research & therapy.

[29]  Timothy E. McAlindon,et al.  Osteoarthritis: New Insights , 2002 .

[30]  D. Walsh,et al.  Osteochondral alterations in osteoarthritis. , 2012, Bone.

[31]  H. Weinans,et al.  Imaging of activated macrophages in experimental osteoarthritis using folate-targeted animal single-photon-emission computed tomography/computed tomography. , 2011, Arthritis and rheumatism.

[32]  K. A. Clarke,et al.  Gait Analysis in a Rat Model of Osteoarthrosis , 1997, Physiology & Behavior.

[33]  R. E. Guzman,et al.  Mono-Iodoacetate-Induced Histologic Changes in Subchondral Bone and Articular Cartilage of Rat Femorotibial Joints: An Animal Model of Osteoarthritis , 2003, Toxicologic pathology.

[34]  I. Kiviranta,et al.  Moderate running exercise augments glycosaminoglycans and thickness of articular cartilage in the knee joint of young beagle dogs , 1988, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[35]  C. Finch,et al.  Sports Participation, Sports Injuries and Osteoarthritis , 1999, Sports medicine.

[36]  M. Adams.  The mechanical environment of chondrocytes in articular cartilage. , 2006, Biorheology.

[37]  V. Karatosun,et al.  [Quantification of papain-induced rat osteoarthritis in relation to time with the Mankin score]. , 2007, Acta orthopaedica et traumatologica turcica.

[38]  Ricardo Aurino Pinho,et al.  Decrease in oxidative stress and histological changes induced by physical exercise calibrated in rats with osteoarthritis induced by monosodium iodoacetate. , 2010, Osteoarthritis and cartilage.

[39]  B. Moed,et al.  Excessive running induces cartilage degeneration in knee joints and alters gait of rats , 2012, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[40]  C. Little,et al.  The effect of strenuous versus moderate exercise on the metabolism of proteoglycans in articular cartilage from different weight-bearing regions of the equine third carpal bone. , 1997, Osteoarthritis and cartilage.

[41]  C H Turner,et al.  Three rules for bone adaptation to mechanical stimuli. , 1998, Bone.

[42]  H. Weinans,et al.  In vivo imaging of cartilage degeneration using microCT-arthrography. , 2007, Osteoarthritis and cartilage.

[43]  D. Felson,et al.  An update on the epidemiology of knee and hip osteoarthritis with a view to prevention. , 1998, Arthritis and rheumatism.

[44]  K. Brandt,et al.  Gait alterations in dogs after transection of the anterior cruciate ligament. , 1989, Arthritis and rheumatism.

[45]  P. Gillet,et al.  Mono-iodoacetate-induced experimental osteoarthritis: a dose-response study of loss of mobility, morphology, and biochemistry. , 1997, Arthritis and rheumatism.

[46]  A. Hollander,et al.  Type II collagen degradation in articular cartilage fibrillation after anterior cruciate ligament transection in rats. , 2001, Osteoarthritis and cartilage.

[47]  T. Nagai,et al.  Functional folate receptor beta-expressing macrophages in osteoarthritis synovium and their M1/M2 expression profiles , 2012, Scandinavian journal of rheumatology.

[48]  Didier Mainard,et al.  Dose-response relationship for exercise on severity of experimental osteoarthritis in rats: a pilot study. , 2004, Osteoarthritis and cartilage.

[49]  C. Chai,et al.  Effects of sonication on articular cartilage in experimental osteoarthritis. , 1997, The Journal of rheumatology.

[50]  W. Horton,et al.  Chondrocyte apoptosis increases with age in the articular cartilage of adult animals , 1998, The Anatomical record.

[51]  J. Edwards,et al.  Exploring the full spectrum of macrophage activation , 2008, Nature Reviews Immunology.

[52]  L. Wancket,et al.  Anatomical Localization of Cartilage Degradation Markers in a Surgically Induced Rat Osteoarthritis Model , 2005, Toxicologic pathology.

[53]  J. Beyene,et al.  The effect of exercise on pQCT parameters of bone structure and strength in postmenopausal women—a systematic review and meta-analysis of randomized controlled trials , 2011, Osteoporosis International.

[54]  Roland Haubner,et al.  A fully automated synthesis for the preparation of 68Ga-labelled peptides , 2007, Nuclear medicine communications.

[55]  A. Tsukise,et al.  Ultracytochemistry of glycosaminoglycans in the canine knee synovium. , 2001, Annals of Anatomy.

[56]  Philip S Low,et al.  Discovery and development of folic-acid-based receptor targeting for imaging and therapy of cancer and inflammatory diseases. , 2008, Accounts of chemical research.

[57]  Kozo Nakamura,et al.  Osteoarthritis development in novel experimental mouse models induced by knee joint instability. , 2005, Osteoarthritis and cartilage.

[58]  Harrie Weinans,et al.  Osteoarthritis induction leads to early and temporal subchondral plate porosity in the tibial plateau of mice: an in vivo microfocal computed tomography study. , 2011, Arthritis and rheumatism.

[59]  M. Bihari-varga,et al.  Thermoanalytical and histological study of intra-articular papain-induced degradation and repair of rabbit cartilage. II. Mature animals. , 1974, Annals of the rheumatic diseases.

[60]  S. Carroll,et al.  Meta-analysis of walking for preservation of bone mineral density in postmenopausal women. , 2008, Bone.

[61]  Robert E. Guldberg,et al.  Analysis of cartilage matrix fixed charge density and three-dimensional morphology via contrast-enhanced microcomputed tomography , 2006, Proceedings of the National Academy of Sciences.

[62]  A. Pinzano,et al.  Moderate-impact exercise is associated with decreased severity of experimental osteoarthritis in rats. , 2003, Rheumatology.

[63]  T. Spector,et al.  Osteoarthritis: New Insights. Part 1: The Disease and Its Risk Factors , 2000, Annals of Internal Medicine.

[64]  Marion de Jong,et al.  Radiolabelling DOTA-peptides with 68Ga , 2005, European Journal of Nuclear Medicine and Molecular Imaging.

[65]  W. Horton,et al.  Chondrocyte apoptosis in development, aging and disease. , 1998, Matrix biology : journal of the International Society for Matrix Biology.

[66]  H Weinans,et al.  Quantification of subchondral bone changes in a murine osteoarthritis model using micro-CT. , 2006, Biorheology.

[67]  I. Otterness,et al.  Exercise protects against articular cartilage degeneration in the hamster. , 1998, Arthritis and rheumatism.

[68]  P. Low,et al.  A functional folate receptor is induced during macrophage activation and can be used to target drugs to activated macrophages. , 2009, Blood.

[69]  D. Murray.  EXPERIMENTALLY INDUCED ARTHRITIS USING INTRA-ARTICULAR PAPAIN. , 1964, Arthritis and rheumatism.