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Recommendations for the analysis of rodent gait data to evaluate osteoarthritis treatments

  • Kiara M. Chan
    Affiliations
    J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
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  • Markia T. Bowe
    Affiliations
    J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
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  • Kyle D. Allen
    Correspondence
    Address correspondence and reprint requests to: K.D. Allen, J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, 1275 Center Drive, Biomedical Sciences Building, Gainesville, FL 32611, USA. Tel: (352) 273-9337; Fax: (352) 273-9221.
    Affiliations
    J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA

    Department of Orthopedics and Sports Medicine, University of Florida, Gainesville, FL, USA
    Search for articles by this author
Published:November 23, 2022DOI:https://doi.org/10.1016/j.joca.2022.11.006

      Summary

      Behavioral assays of animal pain and disability can increase the clinical relevance of a preclinical study. However, pain and symptoms are difficult to measure in preclinical models. Because animals often alter their movement patterns to reduce or avoid joint pain, gait analysis can be an important tool for quantifying OA-related symptoms in rodents. Technologies to measure rodent gait continue to advance and have been the focus of prior reviews. Regardless of the techniques used, the analysis of rodent gait data can be complex due to multiple confounding variables. The goal of this review is to discuss recent advances in the understanding of OA-related gait changes and provide recommendations on the analysis of gait data. Recent studies suggest OA-affected animals reduce vertical loading through their injured limb while walking, indicating dynamic ground reaction forces are important data to collect when possible. Moreover, gait data analysis depends on accurately measuring and accounting for the confounding effects of velocity and other covariates (such as animal size) when interpreting shifts in various gait parameters. Herein, we discuss different statistical techniques to account for covariates and interpret gait shifts. In particular, this review will discuss residualization and linear mixed effects models, including how both techniques can account for inter- and intra-animal variability and the effects of velocity. Furthermore, this review discusses future considerations for using rodent gait analysis, while highlighting the intricacies of gait analysis as a tool to measure joint function and behavioral outcomes.

      Keywords

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      References

        • Bendele A.M.
        Animal models of osteoarthritis.
        J Musculoskelet Neuronal Interact. 2001; 1 (PMID: 15758487): 363-376
        • Teeple E.
        • Jay G.D.
        • Elsaid K.A.
        • Fleming B.C.
        Animal models of osteoarthritis: challenges of model selection and analysis.
        AAPS J. 2013; 15: 438-446https://doi.org/10.1208/s12248-013-9454-x
        • Serra C.I.
        • Soler C.
        Animal models of osteoarthritis in small mammals.
        Vet Clin North Am Exot Anim Pract. 2019; 22: 211-221https://doi.org/10.1016/J.CVEX.2019.01.004
        • Pritzker K.P.H.
        • Gay S.
        • Jimenez S.A.
        • Ostergaard K.
        • Pelletier J.P.
        • Revell P.A.
        • et al.
        Osteoarthritis cartilage histopathology: grading and staging.
        Osteoarthritis Cartilage. 2006; 14: 13-29https://doi.org/10.1016/j.joca.2005.07.014
        • Gerwin N.
        • Bendele A.M.
        • Glasson S.
        • Carlson C.S.
        The OARSI histopathology initiative – recommendations for histological assessments of osteoarthritis in the rat.
        Osteoarthritis Cartilage. 2010; 18: S24-S34https://doi.org/10.1016/J.JOCA.2010.05.030
        • Glasson S.S.
        • Chambers M.G.
        • van den Berg W.B.
        • Little C.B.
        The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the mouse.
        Osteoarthritis Cartilage. 2010; 18: S17-S23https://doi.org/10.1016/j.joca.2010.05.025
        • Little C.B.
        • Zaki S.
        What constitutes an “animal model of osteoarthritis” - the need for consensus?.
        Osteoarthritis Cartilage. 2012; 20: 261-267https://doi.org/10.1016/j.joca.2012.01.017
        • Malfait A.-M.
        • Little C.B.
        On the predictive utility of animal models of osteoarthritis.
        Arthritis Res Ther. 2015; 17: 225https://doi.org/10.1186/s13075-015-0747-6
        • O'Brien M.
        • Philpott H.T.
        • McDougall J.J.
        Understanding osteoarthritis pain through animal models.
        Clin Exp Rheumatol. 2017; 35 (PMID: 28967367): S47-S52
        • Zhang W.
        • Moskowitz R.W.
        • Nuki G.
        • Abramson S.
        • Altman R.D.
        • Arden N.
        • et al.
        OARSI recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence.
        Osteoarthritis Cartilage. 2007; 15: 981-1000https://doi.org/10.1016/J.JOCA.2007.06.014
        • Zhang W.
        • Moskowitz R.W.
        • Nuki G.
        • Abramson S.
        • Altman R.D.
        • Arden N.
        • et al.
        OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines.
        Osteoarthritis Cartilage. 2008; 16: 137-162https://doi.org/10.1016/J.JOCA.2007.12.013
        • Zhang W.
        • Nuki G.
        • Moskowitz R.W.
        • Abramson S.
        • Altman R.D.
        • Arden N.
        • 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.
        Osteoarthritis Cartilage. 2010; 18: 476-499https://doi.org/10.1016/J.JOCA.2010.01.013
        • Mogil J.S.
        Animal models of pain: progress and challenges.
        Nat Rev Neurosci. 2009; 10: 283-294https://doi.org/10.1038/nrn2606
        • Mogil J.S.
        • Davis K.D.
        • Derbyshire S.W.
        The necessity of animal models in pain research.
        Pain. 2010; 151: 12-17https://doi.org/10.1016/j.pain.2010.07.015
        • Deuis J.R.
        • Dvorakova L.S.
        • Vetter I.
        Methods used to evaluate pain behaviors in rodents.
        Front Mol Neurosci. 2017; 10: 284https://doi.org/10.3389/fnmol.2017.00284
        • Jacobs B.Y.
        • Kloefkorn H.E.
        • Allen K.D.
        Gait analysis methods for rodent models of osteoarthritis.
        Curr Pain Headache Rep. 2014; 18: 456https://doi.org/10.1007/s11916-014-0456-x
        • Lakes E.H.
        • Allen K.D.
        Gait analysis methods for rodent models of arthritic disorders: reviews and recommendations.
        Osteoarthritis Cartilage. 2016; 24: 1837-1849https://doi.org/10.1016/J.JOCA.2016.03.008
        • Hildebrand M.
        The quadrupedal gaits of vertebrates: the timing of leg movements relates to balance, body shape, agility, speed, and energy expenditure.
        Bioscience. 1989; 39: 766-775https://doi.org/10.2307/1311182
        • Roach H.I.
        • Mehta G.
        • Oreffo R.O.C.
        • Clarke N.M.P.
        • Cooper C.
        Temporal analysis of rat growth plates: cessation of growth with age despite presence of a physis.
        J Histochem Cytochem. 2003; 51: 373-383https://doi.org/10.1177/002215540305100312
        • Allen K.D.
        • Mata B.A.
        • Gabr M.A.
        • Huebner J.L.
        • Adams S.B.
        • Kraus V.B.
        • et al.
        Kinematic and dynamic gait compensations resulting from knee instability in a rat model of osteoarthritis.
        Arthritis Res Ther. 2012; 14: R78https://doi.org/10.1186/ar3801
        • Jacobs B.Y.
        • Dunnigan K.
        • Pires-Fernandes M.
        • Allen K.D.
        Unique spatiotemporal and dynamic gait compensations in the rat monoiodoacetate injection and medial meniscus transection models of knee osteoarthritis.
        Osteoarthritis Cartilage. 2017; 25: 750-758https://doi.org/10.1016/J.JOCA.2016.12.012
        • Lakes E.H.
        • Allen K.D.
        Quadrupedal rodent gait compensations in a low dose monoiodoacetate model of osteoarthritis.
        Gait Posture. 2018; 63: 73-79https://doi.org/10.1016/J.GAITPOST.2018.04.023
        • Chan K.M.
        • Yeater T.D.
        • Allen K.D.
        Age alters gait compensations following meniscal injury in male rats.
        J Orthop Res. 2022; (Published online)https://doi.org/10.1002/JOR.25306
        • Kloefkorn H.E.
        • Jacobs B.Y.
        • Loye A.M.
        • Allen K.D.
        Spatiotemporal gait compensations following medial collateral ligament and medial meniscus injury in the rat: correlating gait patterns to joint damage.
        Arthritis Res Ther. 2015; 17: 1-15https://doi.org/10.1186/s13075-015-0791-2
        • Kloefkorn H.E.
        • Pettengill T.R.
        • Turner S.M.F.
        • Streeter K.A.
        • Gonzalex-Rothi E.J.
        • Fuller D.D.
        • et al.
        Automated gait analysis through hues and areas (AGATHA): a method to characterize the spatiotemporal pattern of rat gait.
        Ann Biomed Eng. 2017; 45: 711-725https://doi.org/10.1007/s10439-016-1717-0
        • Fang H.
        • Huang L.
        • Welch I.
        • Norley C.
        • Holdsworth D.W.
        • Beier F.
        • et al.
        Early changes of articular cartilage and subchondral bone in the DMM mouse model of osteoarthritis.
        Sci Rep. 2018; 8: 1-9https://doi.org/10.1038/s41598-018-21184-5
        • Wu J.
        • Kuang L.
        • Chen C.
        • Yang J.
        • Zeng W.N.
        • Li T.
        • et al.
        miR-100-5p-abundant exosomes derived from infrapatellar fat pad MSCs protect articular cartilage and ameliorate gait abnormalities via inhibition of mTOR in osteoarthritis.
        Biomaterials. 2019; 206: 87-100https://doi.org/10.1016/J.BIOMATERIALS.2019.03.022
        • Çağlar C.
        • Kara H.
        • Ateş O.
        • Uğurlu M.
        Evaluation of different intraarticular injection therapies with gait analysis in a rat osteoarthritis model.
        Cartilage. 2021; 13: 1134S-1143Shttps://doi.org/10.1177/19476035211046042
        • Jacobs B.Y.
        • Allen K.D.
        Factors affecting the reliability of behavioral assessments for rodent osteoarthritis models.
        Lab Anim. 2020; 54: 317https://doi.org/10.1177/0023677219867715
        • Jacobs B.Y.
        • Lakes E.H.
        • Reiter A.J.
        • Lake S.P.
        • Ham T.R.
        • Leipzig N.D.
        • et al.
        The open source GAITOR suite for rodent gait analysis.
        Sci Rep. 2018; 8: 9797https://doi.org/10.1038/s41598-018-28134-1
        • Pollet T.V.
        • Stulp G.
        • Henzi S.P.
        • Barrett L.
        Taking the aggravation out of data aggregation: a conceptual guide to dealing with statistical issues related to the pooling of individual-level observational data.
        Am J Primatol. 2015; 77: 727-740https://doi.org/10.1002/AJP.22405
        • van der Kraan P.M.
        Factors that influence outcome in experimental osteoarthritis.
        Osteoarthritis Cartilage. 2017; 25: 369-375https://doi.org/10.1016/j.joca.2016.09.005
        • Salvarrey-Strati A.
        • Watson L.
        • Blanchet T.
        • Lu N.
        • Glasson S.S.
        The influence of enrichment devices on development of osteoarthritis in a surgically induced murine model.
        ILAR J. 2008; 49: 23-30https://doi.org/10.1093/ILAR.49.3.E23
        • Meakin L.B.
        • Sugiyama T.
        • Galea G.L.
        • Browne W.J.
        • Lanyon L.E.
        • Price J.S.
        Male mice housed in groups engage in frequent fighting and show a lower response to additional bone loading than females or individually housed males that do not fight.
        Bone. 2013; 54: 113-117https://doi.org/10.1016/J.BONE.2013.01.029
        • Kc R.
        • Li X.
        • Voigt R.M.
        • Ellman M.B.
        • Summa K.C.
        • Vitaterna M.H.
        • et al.
        Environmental disruption of circadian rhythm predisposes mice to osteoarthritis-like changes in knee joint.
        J Cell Physiol. 2015; 230: 2174-2183https://doi.org/10.1002/JCP.24946
        • Temp J.
        • Labuz D.
        • Negrete R.
        • Sunkara V.
        • Machelska H.
        Pain and knee damage in male and female mice in the medial meniscal transection-induced osteoarthritis.
        Osteoarthritis Cartilage. 2020; 28: 475-485https://doi.org/10.1016/J.JOCA.2019.11.003
        • Ro J.Y.
        • Zhang Y.
        • Tricou C.
        • Yang D.
        • da Silva J.T.
        • Zhang R.
        Age and sex differences in acute and osteoarthritis-like pain responses in rats.
        J Gerontol A Biol Sci Med Sci. 2020; 75: 1465-1472https://doi.org/10.1093/gerona/glz186
        • Blaker C.L.
        • Ashton D.M.
        • Doran N.
        • Little C.B.
        • Clarke E.C.
        Sex- and injury-based differences in knee biomechanics in mouse models of post-traumatic osteoarthritis.
        J Biomech. 2021; 114110152https://doi.org/10.1016/J.JBIOMECH.2020.110152
        • Lakes E.H.
        • Haus S.H.
        • Pacheco Y.C.
        • Allen K.D.
        Male and female gait compensations in a mouse model of medial meniscus destabilization.
        Osteoarthritis Cartilage. 2018; 26: S366-S367https://doi.org/10.1016/j.joca.2018.02.725
        • Barbosa G.M.
        • Cunha J.E.
        • Cunha T.M.
        • Martinho L.B.
        • Castro P.A.T.S.
        • Oliveira F.F.B.
        • et al.
        Clinical-like cryotherapy improves footprint patterns and reduces synovial inflammation in a rat model of post-traumatic knee osteoarthritis.
        Sci Rep. 2019; 9https://doi.org/10.1038/S41598-019-50958-8
        • Trevisan E.S.
        • Martignago C.C.S.
        • Assis L.
        • Tarocco J.C.
        • Salman S.
        • Dos Santos L.
        • et al.
        Effectiveness of led photobiomodulation therapy on treatment with knee osteoarthritis: a rat study.
        Am J Phys Med Rehabil. 2020; 99: 725-732https://doi.org/10.1097/PHM.0000000000001408
        • Kimmerling K.A.
        • Gomoll A.H.
        • Farr J.
        • Mowry K.C.
        Amniotic suspension allograft improves pain and function in a rat meniscal tear-induced osteoarthritis model.
        Arthritis Res Ther. 2022; 24: 63https://doi.org/10.1186/S13075-022-02750-9
        • Spittler A.P.
        • Afzali M.F.
        • Martinez R.B.
        • Culver L.A.
        • Leavell S.E.
        • Timkovich A.E.
        • et al.
        Evaluation of electroacupuncture for symptom modification in a rodent model of spontaneous osteoarthritis.
        Acupunct Med. 2021; 39: 700-707https://doi.org/10.1177/09645284211020755
        • Tschon M.
        • Salamanna F.
        • Martini L.
        • Giavaresi G.
        • Lorenzini L.
        • Calzà L.
        • et al.
        Boosting the intra-articular efficacy of low dose corticosteroid through a biopolymeric matrix: an in vivo model of osteoarthritis.
        Cells. 2020; 9: 1571https://doi.org/10.3390/CELLS9071571
        • Mok S.W.
        • Fu S.C.
        • Cheuk Y.C.
        • Chu I.M.
        • Chan K.M.
        • Qin L.
        • et al.
        Intra-articular delivery of quercetin using thermosensitive hydrogel attenuate cartilage degradation in an osteoarthritis rat model.
        Cartilage. 2020; 11: 490-499https://doi.org/10.1177/1947603518796550
        • Liu Y.
        • Peng L.
        • Li L.
        • Huang C.
        • Shi K.
        • Meng X.
        • et al.
        3D-bioprinted BMSC-laden biomimetic multiphasic scaffolds for efficient repair of osteochondral defects in an osteoarthritic rat model.
        Biomaterials. 2021; 279121216https://doi.org/10.1016/J.BIOMATERIALS.2021.121216