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

ABSTRACT: 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.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.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.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.

SUBMITTER: Nam J

PROVIDER: S-EPMC3106131 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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

Nam Jin J Perera Priyangi P Liu Jie J Wu Lai Chu LC Rath Björn B Butterfield Timothy A TA Agarwal Sudha S

Arthritis and rheumatism 20110601 6

<h4>Objective</h4>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.<h4>Methods</h4>Knees were obtained from untreated control rats, rats with MIA that did not undergo GTW, rats with M ...[more]

PMID: 21400474

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Project description:Chronic inflammation is one of the major causes of cartilage destruction in osteoarthritis. Here, we systematically analyzed the changes in gene expression associated with the progression of cartilage destruction in monoiodoacetate-induced arthritis (MIA) of the rat knee. Sprague Dawley female rats were given intra-articular injection of monoiodoacetate in the knee. The progression of MIA was monitored macroscopically, microscopically and by micro-computed tomography. Grade 1 damage was observed by day 5 post-monoiodoacetate injection, progressively increasing to Grade 2 by day 9, and to Grade 3-3.5 by day 21. Affymetrix GeneChip was utilized to analyze the transcriptome-wide changes in gene expression, and the expression of salient genes was confirmed by real-time-PCR. Functional networks generated by Ingenuity Pathways Analysis (IPA) from the microarray data correlated the macroscopic/histologic findings with molecular interactions of genes/gene products. Temporal changes in gene expression during the progression of MIA were categorized into five major gene clusters. IPA revealed that Grade 1 damage was associated with upregulation of acute/innate inflammatory responsive genes (Cluster I) and suppression of genes associated with musculoskeletal development and function (Cluster IV). Grade 2 damage was associated with upregulation of chronic inflammatory and immune trafficking genes (Cluster II) and downregulation of genes associated with musculoskeletal disorders (Cluster IV). The Grade 3 to 3.5 cartilage damage was associated with chronic inflammatory and immune adaptation genes (Cluster III). These findings suggest that temporal regulation of discrete gene clusters involving inflammatory mediators, receptors, and proteases may control the progression of cartilage destruction. In this process, IL-1?, TNF-?, IL-15, IL-12, chemokines, and NF-?B act as central nodes of the inflammatory networks, regulating catabolic processes. Simultaneously, upregulation of asporin, and downregulation of TGF-? complex, SOX-9, IGF and CTGF may be central to suppress matrix synthesis and chondrocytic anabolic activities, collectively contributing to the progression of cartilage destruction in MIA.

Project description:The temporal dynamics of stride-to-stride fluctuations in steady-state walking reveal important information about locomotor control and can be quantified using so-called fractal analyses, notably the detrended fluctuation analysis (DFA). Gait dynamics are often collected during treadmill walking using 3-D motion capture to identify gait events from kinematic data. The sampling frequency of motion capture systems may impact the precision of event detection and consequently impact the quantification of stride-to-stride variability. This study aimed i) to determine if collecting multiple walking trials with different sampling frequency affects DFA values of spatiotemporal parameters during treadmill walking, and ii) to determine the reliability of DFA values across downsampled conditions. Seventeen healthy young adults walked on a treadmill while their gait dynamics was captured using different sampling frequency (60, 120 and 240 Hz) in each condition. We also compared data from the highest sampling frequency to downsampled versions of itself. We applied DFA to the following time series: step length, time and speed, and stride length, time and speed. Reliability between experimental conditions and between downsampled conditions were measured with 1) intraclass correlation estimates and their 95% confident intervals, calculated based on a single-measurement, absolute-agreement, two-way mixed-effects model (ICC 3,1), and 2) Bland-Altman bias and limits of agreement. Both analyses revealed a poor reliability of DFA results between conditions using different sampling frequencies, but a relatively good reliability between original and downsampled spatiotemporal variables. Collectively, our results suggest that using sampling frequencies of 120 Hz or 240 Hz provide similar results, but that using 60 Hz may alter DFA values. We recommend that gait kinematics should be collected at around 120 Hz, which provides a compromise between event detection accuracy and processing time.

Project description:Variability is ubiquitous in human movement, arising from internal and external noise, inherent biological redundancy, and from the neurophysiological control actions that help regulate movement fluctuations. Increased walking variability can lead to increased energetic cost and/or increased fall risk. Conversely, biological noise may be beneficial, even necessary, to enhance motor performance. Indeed, encouraging more variability actually facilitates greater improvements in some forms of locomotor rehabilitation. Thus, it is critical to identify the fundamental principles humans use to regulate stride-to-stride fluctuations in walking. This study sought to determine how humans regulate stride-to-stride fluctuations in stepping movements during treadmill walking. We developed computational models based on pre-defined goal functions to compare if subjects, from each stride to the next, tried to maintain the same speed as the treadmill, or instead stay in the same position on the treadmill. Both strategies predicted average behaviors empirically indistinguishable from each other and from that of humans. These strategies, however, predicted very different stride-to-stride fluctuation dynamics. Comparisons to experimental data showed that human stepping movements were generally well-predicted by the speed-control model, but not by the position-control model. Human subjects also exhibited no indications they corrected deviations in absolute position only intermittently: i.e., closer to the boundaries of the treadmill. Thus, humans clearly do not adopt a control strategy whose primary goal is to maintain some constant absolute position on the treadmill. Instead, humans appear to regulate their stepping movements in a way most consistent with a strategy whose primary goal is to try to maintain the same speed as the treadmill at each consecutive stride. These findings have important implications both for understanding how biological systems regulate walking in general and for being able to harness these mechanisms to develop more effective rehabilitation interventions to improve locomotor performance.

Dataset Information

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

Publications

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

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