Elsevier

Gait & Posture

Volume 63, June 2018, Pages 73-79
Gait & Posture

Full length article
Quadrupedal rodent gait compensations in a low dose monoiodoacetate model of osteoarthritis

https://doi.org/10.1016/j.gaitpost.2018.04.023Get rights and content

Highlights

  • Examined rat quadrupedal gait after intra-articular injection of saline or 1 mg MIA.

  • 1 mg MIA resulted in minor joint degeneration and a shuffle-step compensation.

  • Shuffle-step compensations in rats were previously reported in a surgical OA model.

  • Antalgic compensations in rats were previously reported in a 3 mg MIA model

Abstract

Background

Rodent gait analysis provides robust, quantitative results for preclinical musculoskeletal and neurological models. In prior work, surgical models of osteoarthritis have been found to result in a hind limb shuffle-stepping gait compensation, while a high dose monoiodoacetate (MIA, 3 mg) model resulted in a hind limb antalgic gait. However, it is unknown whether the antalgic gait caused by MIA is associated with severity of degeneration from the high dosage or the whole-joint degeneration associated with glycolysis inhibition.

Research question

This study evaluates rodent gait changes resulting from a low dose, 1 mg unilateral intra-articular injection of MIA compared to saline injected and naïve rats.

Methods

Spatiotemporal and dynamic gait parameters were collected from a total of 42 male Lewis rats spread across 3 time points: 1, 2, and 4 weeks post-injection. To provide a detailed analysis of this low dose MIA model, gait analysis was used to uniquely quantify both fore and hind limb gait parameters.

Results

Our data indicate that 1 mg of MIA caused relatively minor degeneration and a shuffle-step gait compensation, similar to the compensation observed in prior surgical models.

Significance

These data from a 1 mg MIA model show a different gait compensation compared to a previously studied 3 mg model. This 1 mg MIA model resulted in gait compensations more similar to a previously studied surgical model of osteoarthritis. Additionally, this study provides detailed 4 limb analysis of rodent gait that includes spatiotemporal and dynamic data from the same gait trial. These data highlight the importance of measuring dynamic data in combination with spatiotemporal data, since compensatory gait patterns may not be captured by spatial, temporal, or dynamic characterizations alone.

Introduction

Gait analysis is a common method to quantify changes in orthopaedic diseases. While gait analysis is traditionally performed in humans, rodent gait analysis is becoming more popular as a behavioral assay. Rodent gait analysis provides a method for recording natural animal behavior, while providing robust, quantitative results for characterization of musculoskeletal models.

In our prior work, custom gait recording methods have been used to collect spatiotemporal gait parameters via high speed cameras, while simultaneously recording ground reaction forces [1], [2], [3]. This work introduced a custom rodent gait system, termed EDGAR (Experimental Dynamic Gait Arena for Rodents) [2], where EDGAR was used to evaluate gait in rats with either medial meniscus transection (surgical model) or intra-articular injection of monoiodoacetate (3 mg, chemical model). Here, meniscus transection resulted in a shuffle-step while injection of monoiodoacetate resulted in an antalgic gait [2]. These results confirm other prior work which found rats develop a shuffle-step compensation between 4 and 6 weeks after medial meniscus transection [3]. However, MIA is a glycolysis inhibitor which causes widespread joint damage, and 3 mg of MIA is the upper range traditionally used in joint degeneration models [4], [5], [6], [7], [8], [9], [10], [11]. Thus, the varying gait compensations observed in the 3 mg MIA model may be associated with the severity of joint destruction or the widespread inhibition of glycolysis in the joint.

In the MIA model, the severity of joint damage and limb hypersensitivity can be titered with dose [12]. Thus, while previous work investigated a relatively high 3 mg dose of MIA, this study aims to evaluate gait changes resulting from 1 mg intra-articular injection of MIA. Again, EDGAR is used to evaluate rodent gait compensations, but since gait changes may be mild in a lower dose of MIA, gait analysis will be used to uniquely quantify both fore and hind limb gait parameters. Our data shows that gait compensations subsequent to 1 mg of MIA are relatively minor and tend to follow the shuffle-step compensations; this type of compensation is similar to those observed in prior surgical models, rather than a 3 mg dose of MIA [2].

Section snippets

Experimental design and methods

Animal use was approved by the University of Florida’s Institutional Animal Care and Use Committee. Male Lewis rats (n = 42, 250–400 g, Charles Rivers Laboratories, Wilmington, MA) were divided into three groups: monoiodoacetate (MIA) injection (n = 6 per time point), saline injection (n = 6 per time point), or naïve (n = 6 total). Six animals from each group underwent gait testing at 1, 2, and 4 weeks post-injection. After gait testing at each time point, 6 MIA and 6 saline animals were

Histology

MIA knees showed more regions of cell death in the tibial cartilage, where cells were no longer present. This continued into week 4, where delamination at the bone-cartilage interface began to occur. Saline animal histology was mostly normal; however, some evidence of cell cloning was observed (see supplemental Fig. S3).

Spatiotemporal gait results

Average velocities were 39.7 ± 7.2 cm/s for saline animals and 38.2 ± 6.2 cm/s for MIA animals (p=0.1968). Temporally, while all animals tended to have lower fore limb duty

Discussion

At week 1, MIA animals tended to exhibit an antalgic gait pattern, as indicated by imbalanced duty factors where animals spent less time on their right (injected) limb and lower peak vertical forces on the right (injected) limb. While the spatial pattern was symmetric in MIA animals at weeks 1 and 2, the hind peak vertical force was imbalanced, offloading the right (injected) limb. Imbalanced limb loading with a symmetric gait pattern was previously observed in early stages of the MMT model but

Conclusions

This work examined quadrupedal spatiotemporal and dynamic gait parameters of rats given intra-articular injections of saline or 1 mg MIA. Our data demonstrates that animals injected with 1 mg MIA developed shuffle-step compensations, similar to the previously reported compensation in a surgical model of knee osteoarthritis. Additionally, this work provided detailed spatiotemporal and dynamic gait parameters for all 4 limbs of a walking rodent, which suggested minor fore limb compensations for

Conflicts of interest

None.

Contributors

EHL and KDA designed this experiment, while EHL implemented the methods and collected all data. EHL and KDA analyzed data, while EHL drafted the manuscript with editing from KDA. All authors have reviewed the manuscript and approve of the final version.

Acknowledgements

The authors wish to acknowledge Ania Lipat from the University of Florida for her support in this study. Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health under K99/R00AR057426 and R01AR068424. Besides providing funds, the funding sources did not participate in collection, analysis, or interpretation of these data, and have not participated in the decision to submit this

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