Transcriptome-wide gene regulation by gentle treadmill walking during the progression of monoiodoacetate-induced arthritis.

OBJECTIVE Physiotherapies are the most widely recommended conservative treatment for arthritic diseases. The present study was undertaken to examine the molecular mechanisms underlying the effects of gentle treadmill walking (GTW) on various stages of monoiodoacetate-induced arthritis (MIA) to elucidate the basis for the success or failure of such therapies in joint damage. METHODS Knees were obtained from untreated control rats, rats with MIA that did not undergo GTW, rats with MIA in which GTW regimens were started 1 day post-MIA induction, and rats with MIA in which GTW regimens were started after cartilage damage had progressed to grade 1 or grade 2. The cartilage was examined macroscopically, microscopically, and by microfocal computed tomography imaging. Transcriptome-wide gene expression analysis was performed, and microarray data were assessed by Ingenuity Pathways Analysis to identify molecular functional networks regulated by GTW. RESULTS GTW intervention started on day 1 post-MIA induction significantly prevented the progression of MIA, but its efficacy was reduced when implemented on knees exhibiting close to grade 1 cartilage damage. GTW accelerated cartilage damage in knees with close to grade 2 damage. Transcriptome-wide gene expression analysis revealed that GTW intervention started 1 day post-MIA inception significantly suppressed inflammation-associated genes and up-regulated matrix-associated gene networks. However, delayed GTW intervention after grade 1 damage had occurred was less effective in suppressing proinflammatory genes or up-regulating matrix synthesis. CONCLUSION The present findings suggest that GTW suppresses proinflammatory gene networks and up-regulates matrix synthesis to prevent progression of cartilage damage in MIA-affected knees. However, the extent of cartilage damage at the initiation of GTW may be an important determinant of the success or failure of such therapies.

[1]  K. Chakravarty,et al.  Evidence-based recommendations for the role of exercise in the management of osteoarthritis of the hip or knee--the MOVE consensus. , 2005, Rheumatology.

[2]  W. Herzog,et al.  Differential serial sarcomere number adaptations in knee extensor muscles of rats is contraction type dependent. , 2005, Journal of applied physiology.

[3]  J. Deschner,et al.  Role of NF-kappaB transcription factors in antiinflammatory and proinflammatory actions of mechanical signals. , 2004, Arthritis and rheumatism.

[4]  S. Kiechl,et al.  Vascular cell adhesion molecule 1 as a predictor of severe osteoarthritis of the hip and knee joints. , 2009, Arthritis and rheumatism.

[5]  B. Pedersen.  The anti-inflammatory effect of exercise: its role in diabetes and cardiovascular disease control. , 2006, Essays in biochemistry.

[6]  M. Nevitt,et al.  Summary of the OA biomarkers workshop 2009--biochemical biomarkers: biology, validation, and clinical studies. , 2010, Osteoarthritis and cartilage.

[7]  J. Schrooten,et al.  Articular cartilage and biomechanical properties of the long bones in Frzb-knockout mice. , 2007, Arthritis and rheumatism.

[8]  Sankar Ghosh,et al.  Signaling to NF-kappaB. , 2004, Genes & development.

[9]  J. Hootman.  Osteoarthritis in elderly persons: risks of exercise and exercise as therapy. , 2010, Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine.

[10]  M. Goldring,et al.  NF-kappaB signaling: multiple angles to target OA. , 2010, Current drug targets.

[11]  Felix Eckstein,et al.  Exercise and osteoarthritis , 2009, Journal of anatomy.

[12]  J. Williamson,et al.  Physical exercise and the prevention of disability in activities of daily living in older persons with osteoarthritis. , 2001, Archives of internal medicine.

[13]  Kyriacos A. Athanasiou,et al.  Biomechanical Strategies for Articular Cartilage Regeneration , 2003, Annals of Biomedical Engineering.

[14]  R. Curi,et al.  Moderate exercise improves leucocyte function and decreases inflammation in diabetes , 2010, Clinical and experimental immunology.

[15]  S. Agarwal,et al.  Regulation of biomechanical signals by NF-kappaB transcription factors in chondrocytes. , 2008, Biorheology.

[16]  P Tugwell,et al.  OARSI recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence following systematic cumulative update of research published through January 2009. , 2010, Osteoarthritis and cartilage.

[17]  F Eckstein,et al.  Longitudinal analysis of cartilage atrophy in the knees of patients with spinal cord injury. , 2003, Arthritis and rheumatism.

[18]  B. Pedersen,et al.  Exercise as a Mean to Control Low-Grade Systemic Inflammation , 2009, Mediators of inflammation.

[19]  L. Sharma,et al.  Moving to maintain function in knee osteoarthritis: evidence from the osteoarthritis initiative. , 2010, Archives of physical medicine and rehabilitation.

[20]  P. Clegg,et al.  Biomarkers of cartilage turnover. Part 1: Markers of collagen degradation and synthesis. , 2010, Veterinary journal.

[21]  D. Hunter,et al.  The management of osteoarthritis: an overview and call to appropriate conservative treatment. , 2008, Rheumatic diseases clinics of North America.

[22]  H. Langberg,et al.  Exercise increases interleukin-10 levels both intraarticularly and peri-synovially in patients with knee osteoarthritis: a randomized controlled trial , 2010, Arthritis research & therapy.

[23]  F. Guilak,et al.  Dynamic loading enhances integrative meniscal repair in the presence of interleukin-1. , 2010, Osteoarthritis and cartilage.

[24]  D. Guttridge,et al.  Biomechanical Signals Suppress TAK1 Activation to Inhibit NF-κB Transcriptional Activation in Fibrochondrocytes1 , 2007, The Journal of Immunology.

[25]  Carol Muehleman,et al.  Vulnerability of the superficial zone of immature articular cartilage to compressive injury. , 2010, Arthritis and rheumatism.

[26]  D. Broomhead,et al.  Sensitivity analysis of parameters controlling oscillatory signalling in the NFk B pathway : the roles of IKK and I k B a , 2004 .

[27]  David T Felson,et al.  Risk factors for osteoarthritis: understanding joint vulnerability. , 2004, Clinical orthopaedics and related research.

[28]  Steven A Olson,et al.  The role of biomechanics and inflammation in cartilage injury and repair. , 2004, Clinical orthopaedics and related research.

[29]  D. Schurman,et al.  Mechanoregulation of human articular chondrocyte aggrecan and type II collagen expression by intermittent hydrostatic pressure in vitro , 2003, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[30]  U. Müller-Ladner,et al.  Differential transcriptome analysis of intraarticular lesional vs intact cartilage reveals new candidate genes in osteoarthritis pathophysiology. , 2009, Osteoarthritis and cartilage.

[31]  R. Gassner,et al.  Biomechanical Signals Suppress Proinflammatory Responses in Cartilage: Early Events in Experimental Antigen-Induced Arthritis1 , 2006, The Journal of Immunology.

[32]  Baltazar D. Aguda,et al.  Biomechanical Thresholds Regulate Inflammation through the NF-κB Pathway: Experiments and Modeling , 2009, PloS one.

[33]  P. Chomczyński,et al.  The single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction: twenty-something years on , 2006, Nature Protocols.

[34]  E. Roos,et al.  Joint injury causes knee osteoarthritis in young adults , 2005, Current opinion in rheumatology.

[35]  T. Chowdhury,et al.  Dynamic compression alters NFκB activation and IκB-α expression in IL-1β-stimulated chondrocyte/agarose constructs , 2009, Inflammation Research.

[36]  H. Northoff,et al.  Exercise in fibromyalgia and related inflammatory disorders: known effects and unknown chances. , 2009, Exercise immunology review.

[37]  Raveendhara R. Bannuru,et al.  OARSI recommendations for the management of hip and knee osteoarthritis: the semantics of differences and changes. , 2010, Osteoarthritis and cartilage.

[38]  E. Roos,et al.  Clinical update: treating osteoarthritis , 2007, The Lancet.

[39]  M. Nevitt,et al.  The effects of impaired joint position sense on the development and progression of pain and structural damage in knee osteoarthritis. , 2009, Arthritis and rheumatism.

[40]  D. Carter,et al.  Pressure and Shear Differentially Alter Human Articular Chondrocyte Metabolism: A Review , 2004, Clinical orthopaedics and related research.

[41]  L. Sharma,et al.  Physical activity levels and functional performance in the osteoarthritis initiative: a graded relationship. , 2011, Arthritis and rheumatism.

[42]  T. Iwanaga,et al.  High levels of serum IL-18 promote cartilage loss through suppression of aggrecan synthesis. , 2008, Bone.

[43]  H. Potter,et al.  Local cytokine profiles in knee osteoarthritis: elevated synovial fluid interleukin-15 differentiates early from end-stage disease. , 2009, Osteoarthritis and cartilage.

[44]  T. Spector,et al.  OARSI-OMERACT definition of relevant radiological progression in hip/knee osteoarthritis. , 2009, Osteoarthritis and cartilage.

[45]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[46]  S. Jimenez,et al.  Osteoarthritis cartilage histopathology: grading and staging. , 2006, Osteoarthritis and cartilage.

[47]  D. Baribeau,et al.  Is Regular Exercise a Friend or Foe of the Aging Immune System? A Systematic Review , 2008, Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine.

[48]  S. Agarwal,et al.  Biomechanical signals inhibit IKK activity to attenuate NF-kappaB transcription activity in inflamed chondrocytes. , 2007, Arthritis and rheumatism.

[49]  David S. Broomhead,et al.  Sensitivity analysis of parameters controlling oscillatory signalling in the NF-/sub K/Bpathway: the roles of IKK and I/sub K/B/sub alpha/ , 2004 .

[50]  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.

[51]  K. Miyazono,et al.  Mechanisms for Asporin Function and Regulation in Articular Cartilage* , 2007, Journal of Biological Chemistry.