共查询到20条相似文献,搜索用时 78 毫秒
1.
Sabine Drevet Bertrand Favier Emmanuel Brun Gaëtan Gavazzi Bernard Lardy 《Comparative medicine》2022,72(1):3
Osteoarthritis (OA) is a multidimensional health problem and a common chronic disease. It has a substantial impact on patient quality of life and is a common cause of pain and mobility issues in older adults. The functional limitations, lack of curative treatments, and cost to society all demonstrate the need for translational and clinical research. The use of OA models in mice is important for achieving a better understanding of the disease. Models with clinical relevance are needed to achieve 2 main goals: to assess the impact of the OA disease (pain and function) and to study the efficacy of potential treatments. However, few OA models include practical strategies for functional assessment of the mice. OA signs in mice incorporate complex interrelations between pain and dysfunction. The current review provides a comprehensive compilation of mouse models of OA and animal evaluations that include static and dynamic clinical assessment of the mice, merging evaluation of pain and function by using automatic and noninvasive techniques. These new techniques allow simultaneous recording of spontaneous activity from thousands of home cages and also monitor environment conditions. Technologies such as videography and computational approaches can also be used to improve pain assessment in rodents but these new tools must first be validated experimentally. An example of a new tool is the digital ventilated cage, which is an automated home-cage monitor that records spontaneous activity in the cages.Osteoarthritis (OA) is a multidimensional health problem and a common chronic disease.36 Functional limitations, the absence of curative treatments, and the considerable cost to society result in a substantial impact on quality of life.76 Historically, OA has been described as whole joint and whole peri-articular diseases and as a systemic comorbidity.9,111 OA consists of a disruption of articular joint cartilage homeostasis leading to a catabolic pathway characterized by chondrocyte degeneration and destruction of the extracellular matrix (ECM). Low-grade chronic systemic inflammation is also actively involved in the process.42,92 In clinical practice, mechanical pain, often accompanied by a functional decline, is the main reason for consultations. Recommendations to patients provide guidance for OA management.22, 33,49,86 Evidence-based consensus has led to a variety of pharmacologic and nonpharmacologic modalities that are intended to guide health care providers in managing symptomatic patients. Animal-based research is of tremendous importance for the study of early diagnosis and treatment, which are crucial to prevent the disease progression and provide better care to patients.The purpose of animal-based OA research is 2-fold: to assess the impact of the OA disease (pain and function) and to study the efficacy of a potential treatment.18,67 OA model species include large animals such as the horse, goat, sheep, and dog, whose size and anatomy are expected to better reflect human joint conditions. However, small animals such as guinea pig, rabbit, mouse, and rat represent 77% of the species used.1,87 In recent years, mice have become the most commonly used model for studying OA. Mice have several advantageous characteristics: a short development and life span, easy and low-cost breeding and maintenance, easy handling, small joints that allow histologic analysis of the whole joint,32 and the availability of genetically modified lines.108 Standardized housing, genetically defined strains and SPF animals reduce the genetic and interindividual acquired variability. Mice are considered the best vertebrate model in terms of monitoring and controlling environmental conditions.7,14,15,87 Mouse skeletal maturation is reached at 10 wk, which theoretically constitutes the minimal age at which mice should be entered into an OA study.64,87,102 However, many studies violate this limit by testing mice at 8 wk of age.Available models for OA include the following (32,111 physical activity and exercise induced OA; noninvasive mechanical loading (repetitive mild loading and single-impact injury); and surgically induced (meniscectomy models or anterior cruciate ligament transection). The specific model used would be based on the goal of the study.7 For example, OA pathophysiology, OA progression, and OA therapies studies could use spontaneous, genetic, surgical, or noninvasive models. In addition, pain studies could use chemical models. Lastly, post-traumatic studies would use surgical or noninvasive models; the most frequently used method is currently destabilization of the medial meniscus,32 which involves transection of the medial meniscotibial ligament, thereby destabilizing the joint and causing instability-driven OA. An important caveat for mouse models is that the mouse and human knee differ in terms of joint size, joint biomechanics, and histologic characteristics (layers, cellularity),32,64 and joint differences could confound clinical translation.10 Table 1. Mouse models of osteoarthritis.
Open in a separate windowSince all animal models have strengths and weaknesses, it is often best to plan using a number of models and techniques together to combine the results.In humans, the lack of correlation between OA imaging assessment and clinical signs highlights the need to consider the functional data and the quality of life to personalize OA management. Clinical outcomes are needed to achieve 2 main goals: to assess the impact of the OA in terms of pain and function and to study the efficacy of treatments.65 Recent reviews offer few practical approaches to mouse functional assessment and novel approaches to OA models in mice.7,32,67,75,79,83,87, 100,120 This review will focus on static and dynamic clinical assessment of OA using automatic and noninvasive emerging techniques (Test name Techniques Kind of assessment Output Specific equipment required Static measurement Von Frey filament testing Calibrated nylon filaments of various thickness (and applied force) are pressed against the skin of the plantar surface of the paw in ascending order of force Stimulus- evoked pain-like behavior
Mechanical stimuli - Tactile allodynia
The most commonly used test Latency to paw withdrawal
and
Force exerted are recorded Yes Knee extension test Apply a knee extension on both the intact and affected knee
or
Passive extension range of the operated knee joint under anesthesia Stimulus-evoked pain-like behavior Number of vocalizations evoked in 5 extensions None Hotplate Mouse placed on hotplate. A cutoff latency has been determined to avoid lesions Stimulus-evoked pain-like behavior
Heat stimuli- thermal sensitivity Latency of paw withdrawal Yes Righting ability Mouse placed on its back Neuromuscular screening Latency to regain its footing None Cotton swab test Bringing a cotton swab into contact with eyelashes, pinna, and whiskers Stimulus-evoked pain-like behavior
Neuromuscular screening Withdrawal or twitching response None Spontaneous activity Spontaneous cage activity One by one the cages must be laid out in a specific platform Spontaneous pain behavior
Nonstimulus evoked pain
Activity Vibrations evoked by animal movements Yes Open field analysis Experiment is performed in a clear chamber and mice can freely explore Spontaneous pain behavior
Nonstimulus evoked pain
Locomotor analysis Paw print assessment
Distance traveled, average walking speed, rest time, rearing Yes Gait analysis Mouse is placed in a specific cage equipped with a fluorescent tube and a glass plate allowing an automated quantitative gait analysis Nonstimulus evoked pain
Gait analysis
Indirect nociception Intensity of the paw contact area, velocity, stride frequency, length, symmetry, step width Yes Dynamic weight bearing system Mouse placed is a specific cage. This method is a computerized capacitance meter (similar to gait analysis) Nonstimulus evoked pain
Weight-bearing deficits
Indirect nociception Body weight redistribution to a portion of the paw surface Yes Voluntary wheel running Mouse placed is a specific cage with free access to stainless steel activity wheels. The wheel is connected to a computer that automatically record data Nonstimulus evoked pain
Activity Distance traveled in the wheel Yes Burrowing analysis Mouse placed is a specific cage equipped with steel tubes (32 cm in length and 10 cm in diameter) and quartz sand in Plexiglas cages (600 · 340x200 mm) Nonstimulus evoked pain
Activity Amount of sand burrowed Yes Digital video recordings Mouse placed is a specific cage according to the tool Nonstimulus evoked pain
Or
Evoked pain Scale of pain or specific outcome Yes Digital ventilated cage system Nondisrupting capacitive-based technique: records spontaneous activity 24/7, during both light and dark phases directly from the home cage rack Spontaneous pain behavior
Nonstimulus evoked pain
Activity-behavior Distance walked, average speed, occupation front, occupation rear, activation density.
Animal locomotion index, animal tracking distance, animal tracking speed, animal running wheel distance and speed or rotation Yes Challenged activity Rotarod test Gradual and continued acceleration of a rotating rod onto which mice are placed Motor coordination
Indirect nociception Rotarod latency: riding time and speed with a maximum cut off. Yes Hind limb and fore grip strength Mouse placed over a base plate in front of a connected grasping tool Muscle strength of limbs Peak force, time resistance Yes Wire hang analysis Suspension of the mouse on the wire and start the time Muscle strength of limbs: muscle function and coordination Latency to fall gripping None
(self -constructed)
Models | Pros | Cons | |
---|---|---|---|
Spontaneous | Wild type mice7,9,59,67,68,70,72,74,80,85,87,115,118,119,120 | - Model of aging phenotype - The less invasive model - Physiological relevance: mimics human pathogenesis - No need for technical expertise - No need for specific equipment | - Variability in incidence - Large number of animals at baseline - Long-term study: Time consuming (time of onset: 4 -15 mo) - Expensive (husbandry) |
Genetically modified mice2,7,25,40,50,52,67,72,79,80, 89,120 | - High incidence - Earlier time of onset: 18 wk - No need for specific equipment - Combination with other models | - Time consuming for the strain development - Expensive | |
Chemical- induced | Mono-iodoacetate injection7,11,46,47,60,66,90,91,101,128 | - Model of pain-like phenotype - To study mechanism of pain and antalgic drugs - Short-term study: Rapid progression (2-7 wk) - Reproducible - Low cost | - Need for technical expertise - Need for specific equipment - Systemic injection is lethal - Destructive effect: does not allow to study the early phase of pathogenesis |
Papain injection66,67,120 | - Short-term study: rapid progression - Low cost | - Need for technical expertise - Need for specific equipment - Does not mimic natural pathogenesis | |
Collagenase injection7,65,67,98 | - Short-term study: rapid progression (3 wk) - Low cost | - Need for technical expertise - Need for specific equipment - Does not mimic natural pathogenesis | |
Non-invasive | High-fat diet (Alimentary induced obesity model)5,8,43,45,57,96,124 | Model of metabolic phenotype No need for technical expertise No need for specific equipment Reproducible | Long-term study: Time consuming (8 wk–9 mo delay) Expensive |
Physical activity and exercise model45,73 | Model of post traumatic phenotype No need for technical expertise | Long-term study: time consuming (18 mo delay) Expensive Disparity of results | |
Mechanical loading models Repetitive mild loading models Single-impact injury model7,16,23,24, 32,35,104,105,106 | Model of post traumatic phenotype Allow to study OA development Time of onset: 8-10 wk post injury Noninvasive | Need for technical expertise Need for specific equipment Heterogeneity in protocol practices Repetitive anesthesia required or ethical issues | |
Surgical | Ovariectomy114 | Contested. | |
Meniscectomy model7,32,63,67,87 | Model of post traumatic phenotype High incidence Short-term study: early time of onset (4 wk from surgery) To study therapies | Need for technical expertise Need for specific equipment Surgical risks Rapid progression compared to human | |
Anterior cruciate ligament transection (ACLT)7,39,40,61,48,67,70,87,126 | Model of posttraumatic phenotype High incidence Short-term study: early time of onset (3-10 wk from surgery) Reproducible To study therapies | Need for technical expertise Need for specific equipment Surgical risks Rapid progression compared to human | |
Destabilization of medial meniscus (DMM)7,32,39,40 | Model of post traumatic phenotype High incidence Short-term study: early time of onset (4 wk from surgery) To study therapies The most frequently used method | Need for technical expertise Need for specific equipment Surgical risks Rapid progression compared to human |
Mechanical stimuli - Tactile allodynia
The most commonly used test
and
Force exerted are recorded
or
Passive extension range of the operated knee joint under anesthesia
Heat stimuli- thermal sensitivity
Neuromuscular screening
Nonstimulus evoked pain
Activity
Nonstimulus evoked pain
Locomotor analysis
Distance traveled, average walking speed, rest time, rearing
Gait analysis
Indirect nociception
Weight-bearing deficits
Indirect nociception
Activity
Activity
Or
Evoked pain
Nonstimulus evoked pain
Activity-behavior
Animal locomotion index, animal tracking distance, animal tracking speed, animal running wheel distance and speed or rotation
Indirect nociception
(self -constructed)