|Year : 2020 | Volume
| Issue : 1 | Page : 13-19
Rheumatoid pain models in rodents and the application of dynamic weight-bearing test
Dawei Geng1, Liming Wang2, Nancy Q Liu3, Jian Qin4
1 Department of Orthopaedic Surgery, Sir Run Run Hospital; Department of Orthopaedic Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China; Department of Orthopaedic Surgery, University of Southern California, Los Angeles, California, USA
2 Department of Orthopaedic Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
3 Department of Orthopaedic Surgery, University of Southern California, Los Angeles, California, USA
4 Department of Orthopaedic Surgery, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
|Date of Submission||13-Apr-2020|
|Date of Decision||24-Apr-2020|
|Date of Acceptance||27-Apr-2020|
|Date of Web Publication||26-Aug-2020|
Department of Orthopaedic Surgery, Sir Run Run Hospital, Nanjing Medical University, Nanjing
Nancy Q Liu
Department of Orthopaedic Surgery, University of Southern California, Los Angeles, California
Source of Support: None, Conflict of Interest: None
Rheumatoid arthritis (RA) is an autoimmune systemic disease of unknown etiology, characterized by chronic inflammation and synovial infiltration of immune cells. Pain is one of the most dominant symptoms for patients with RA, which affects the health and quality of life. Animal models are helpful to study the pathogenesis of RA and related factors and mechanisms of RA-induced pain, which may aid in the development of new and better treatment strategies. Several animal models of RA have been validated to predict for efficacy in humans that include collagen type II-induced arthritis in rats and mice, adjuvant-induced arthritis in rats, and antigen induced arthritis in several species. However, the quantitative evaluation of pain in animal models is technically challenging. Until recent years, behavior methods are used to characterize acute and chronic pain stages by observing behavioral changes in preclinical arthritis models. Significant progress has been made in pain assessment with the development of nonreflexive tools, dynamic weight-bearing (DWB) apparatus was developed for the measurement of pain in rodents by capturing weight-bearing and surface distribution of the paws. In this article, we summarize several classical animal models of rheumatoid pain as well as discussion of the advantages and disadvantages of DWB test for spontaneous pain used in these models.
Keywords: Dynamic weight-bearing test, rheumatoid pain models, rodents
|How to cite this article:|
Geng D, Wang L, Liu NQ, Qin J. Rheumatoid pain models in rodents and the application of dynamic weight-bearing test. Digit Med 2020;6:13-9
| Introduction|| |
Pain, according to the International Association for the Study of Pain, is defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Pain is considered to be one of the most dominant symptoms of rheumatoid arthritis (RA) patients and the primary reason for seeking medical care. It can be associated with psychological distress, can impair physical and social functioning, and can increase health-care utilization. Up to 70% of the RA patients consider pain improvement as their priority compared with other symptoms of RA., Therefore, it is urgent to deepen our understanding of the underlying mechanisms of pain and develop new therapies.
In both human and animals, we detect pain according to behavior. Pain studies are challenging to perform in humans attributed to the subjective and ethical limitation; therefore, the availability of animal pain models is widely used for pain research. Due to the low cost, ease of handling, and genetic homogeneity, the rodent models, commonly rats and mice, are widely used. However, since animals are unable to express pain, any response to the stimulus could not directly prove the experience of pain. Accordingly, it is necessary to establish indirect methods to quantify and evaluate pain behaviors in nonanesthetized animals which are reliable, reproducible, sensitive, and specific.
Most available methods for assessment of articular nociception in experimental animals present some limitations. For instance, these tests need one direct investigator responsible for application of the nociceptive stimuli (mechanical and thermal) and/or visualization/quantification of the behavior/nociceptive endpoint, which could be considered subjective analyses. Therefore, an objective method, dynamic weight-bearing (DWB), of rodents can be analyzed as a surrogate measure of nociception and is typically considered measures of nonevoked or stimulus-independent pain. It measures the weight-bearing for each of the front and rear paws, weight ratio, and paw surface area in freely moving animals without experimenter interference. It is proven in multiple pain models, including complete Freund's adjuvant (CFA)-induced inflammation, chronic constriction injury, bone cancer pain, and antigen-induced arthritis.,,
This review describes the existing animal models of RA that are commonly utilized for preclinical pain studies, discussing their specific advantages and drawbacks. We also will provide an overview of the DWB test which is used to assess pain behaviors in these models.
| Animal Models for Rheumatoid Arthritis|| |
The models of RA have been developed in a variety of animal species, but rats and mice are most commonly utilized for studying the progression and pathogenesis of RA, which is attributed to the low cost, homogeneity of the genetic background, and ease of handling. These models could be studied in a variety of animal species and can be classified into two broad categories: (A) induced animal models for RA and (B) genetic models of RA [Table 1].
| Induced Arthritis Models|| |
Multiple triggering agents such as live bacteria or bacterial components,,, oils, ubiquitous antigens, or cartilage-specific proteins,,, which can induce arthritis in genetically predisposed inbred mice.
Adjuvant arthritis (AA) is the first model of RA and can be reproducibly induced in susceptible strains of rats by intradermal injection of Freund's adjuvant containing mycobacterium tuberculosis. It causes a systemic acute inflammation through the immune response mediated by T-cells. About 10–14 days, the symptoms of polyarthritis can be observed, which as similar as human RA, like joint swelling, lymphocyte infiltration, and cartilage degradation. AA is very severe but self-relief. AA in rats usually recovers on their own within a few months. This is a common disadvantage of most animal models compared with the chronic process of human RA. Another characteristic of AA is that once spontaneously relieved, rats can no longer be reintroduced into the body to develop disease.
Collagen-induced arthritis (CIA) has been the most commonly used models of RA, the disease is induced by intradermal injections of an emulsion of type II collagen (CII) in CFA. CII is a major component of joint cartilage, CIA is an autoimmune disease mediated by both T- and B-cells immunity to autologous CII, which lead to a polyarthritis in articular and periarticular structures. Arthritis typically develops in 21–25 days after the initial immunization, which is most prominent in the hind and front paws and characterized by synovial inflammatory infiltration and hyperplasia, cartilage degradation, and bone erosions. CIA in mice shares many similar immunological and pathological features with human RA, such as breakage of self-tolerance, targeted cartilage immunity, and T-cell and B-cell activity,,, which is considered as an ideal model to study the pathogenesis and test therapeutics of RA [Figure 1]. However, a drawback of this model is considerably variable in the pathogenesis and disease course, which depending on the genetic background of the strain, the origin of CII, and environmental factors.
|Figure 1: Pathology of rheumatoid arthritis. Rheumatoid arthritis is an autoimmune systemic disease mediated by T-cells and B-cells. T-cell creates interleukin-17 which can stimulate macrophages to produce inflammatory cytokines, including interleukin-1, interleukin-6, and tumor necrosis factor-α. T-cell also expresses receptor activator of nuclear factor-kappa B ligand, which together with inflammatory cytokines activates the osteoclast leading to bone erosion. Inflammatory cytokines activate synovial cells to produce protease, which can cause cartilage degradation. Rheumatoid factor and anti-citrullinated protein antibodies are the two most important autoantibodies usually produced by plasma cells. All of these play an important role in the pathogenesis of rheumatoid arthritis|
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Antigen-induced arthritis (AIA) models have been used for around 40 years and now still be used widely. It is induced by immunizing with exogenous antigens such as ovalbumin or methylated bovine serum albumin (mBSA). The rodents are inoculated at the base of the tail with the antigen mixed in CFA, 3 weeks later, the same antigen is injected into the knee joint that induces a local inflammation. AIA shares similar histopathological features with human RA, including synovial hyperplasia, perivascular infiltration with lymphocytes and plasma cells, lymphoid follicles, and pannus and cartilage erosions. However, unlike RA, AIA model is a monoarticular disease that affects only the injected joints, it generates an immune response and subsequent arthritis limited to the antigen-induced joint, and demonstrates that the induction of arthritis does not require a joint-specific or endogenous antigen, but any immune response in the joint generates similar symptoms. AIA has a major advantage of applicability to multiple strains of mice, rats, guinea pigs, and rabbits.,, It is most suitable for studying the mechanism of cartilage destruction induced by the mix of immune complex and T-cells reactivity. This model is helpful to study the hyper-reactivity of local T-cells to retained exogenous antigens and to compare it with a similar reaction to autoantigens in CIA.
| Spontaneous Arthritis Models|| |
In addition to the induced-arthritis models, arthritis occurs spontaneously in some genetically modified mice, these mice are either deficient in or transgenic for a specific gene of interest. These models provide valuable information about the role of genes in the inflammatory process and provide a tool to study the therapeutic effect of spontaneous development of joint inflammation in mice. Two famous models are K/BxN mouse model and human tumor necrosis factor-transgenic (TNF-Tg) mouse model.
The K/BxN model
The K/BxN spontaneous mouse model of arthritis was first described by the group of Kouskoff, it was found accidentally that when KRN mice are crossed with nonobese diabetic mice (I-A g7), their offspring (K/BxN) developed arthritis spontaneously at the age of 4–5 weeks. The development of arthritis in K/BxN mice is caused by an immune response to the enzyme glucose-6-phosphate isomerase (G6PI). Autoreactive T-cells recognize a peptide from G6PI provided by APCs on I-A g7 class II MHC molecules and activate B cells to produce G6PI-specific autoantibodies., The arthritis could be blocked by the injection of an anti-CD4 antibody in the initiation phase of disease onset, attributes to the crucial role of T-cells, and it will not affect the development of arthritis when inject at a later time. The symptom of arthritis in K/BxN mice is severe and symmetrical and affects principally distal joints, which is similar to human RA in many important respects. Histologically, K/BxN disease is similar to human RA joints, including pannus formation, inflammatory infiltration, and articular erosions. Therefore, K/BxN mice duplicate human RA both in the autoimmune pathophysiology and key disease features.
The tumor necrosis factor-transgenic mouse model
TNF-Tg mouse over-expressing human TNF-α transgene was derived in the early 1990s. Two commonly used TNF-Tg mouse strains are the 3647 and 197 strains. In the 3647 strains, it contains one copy of the transgene and displays a milder arthritis; however, in the 197 strains, it contains multiple copies of transgene and displays more severe arthritis. Compared with CIA and AA, which are acute and self-limiting, the chronic progressive nature of the arthritis in this model closely mimics those of human RA. The histopathological features of symmetrical polyarthritis were also obvious in TNF-Tg mice. The proliferation of synovium as well as the infiltration of polymorphonuclear cells and lymphocytes in synovium space can be observed in every stage from the onset. In the late stage of the disease, pannus formation, articular cartilage destruction, and extensive destruction of fibrous tissue are obvious. At this time, there are a lot of cartilage and subchondral bone erosions in the joints of TNF-Tg mice, and the bone surface is covered by multinuclear TRAP + osteoclast-like cells, mediating between the “erosion front” of synovium and bone surface. Erosive arthritis can also occur when TNF-Tg mice hybridize with RAG-1 knockout mice without T-cells and B-cells. Therefore, TNF-Tg mice can be used to study the etiology of RA without autoimmune disease due to its independence on T-cells and B-cells, which significantly different from other arthritis models. It has been proved that the success of anti-TNF therapy for RA in humans was due to reducing inflammation, alleviating cartilage and bone erosions, and improving patient function and vitality., Therefore, the TNF-Tg mice can be used to evaluate the efficacy of novel therapies in RA, particularly in which novel targets are considered to operate downstream of TNF. In addition, the model is particularly useful in determining the different contributions of effector cytokines that regulate inflammation and cartilage and bone destruction. Therefore, TNF-Tg mouse is an excellent model to investigate TNF-induced inflammatory pathways in human disease.
| Dynamic Weight-Bearing Test for Rheumatoid Pain Used in Rodents|| |
The experimental model of pathological pain depends on the effective parameter evaluation method. Assessing joint function is a challenge when the animal response is difficult to interpret and requires extensive training for the experimenter. In addition, the correlation between preclinical behavioral responses in trials and clinical responses is unsatisfactory. Proof of this is that approximately 80% of prototype analgesic drugs tested in humans failed in Phase III. Therefore, establishing new animal pain testing standards is essential for developing novel pharmacological therapies to control pain.
Most of the pain assessment methods are based on reflex endpoints and widely used in pain assessment of animal models. Using different types of stimulation to induce pain endpoints is a powerful tool for measuring hyperalgesia. However, the stimulus-evoked endpoints may not truly reflect the spontaneous and persistent pain in humans. Therefore, several new nonreflexive methods have been developed to evaluate spontaneous pain in rats and mice, which could reflect pain experience more accurately in humans.,, For instance, wheel running or locomotor activity has been validated for effective evaluation of inflammatory pain in mice, which by examining reduced physical activity. Weight-bearing distribution has been a major observation target of pain research, the methods such as static weight-bearing, gait analysis, and DWB have been validated for assessment of pain in rodent models.,
The DWB is based on an instrumented floor-cage combined with a video recording to evaluate spontaneous pain in freely moving rodents. It is an efficient and advanced alternative to traditional incapacitance tests for assessing pain sensitivity in your research on analgesic/nociception involving rats and mice. The DWB instrument [Bioseb 2.0 (France);,, [Figure 2] comprised a transparent plexiglass enclosure (11 cm width × 11 cm length × 22 cm height) with a floor sensor containing around 2000 pressure transducers and a high definition camera placed above. Each mouse was individually placed into the DWB cage and allowed to move freely for a duration of approximately 5 min while a camera recorded each movement. The video recordings and pressure data relayed from the floor sensors were transmitted to a computer and stored for the analysis. The DWB test calculates multiple parameters in freely moving mice, including weight-bearing for each paw (gram and percent of total animal weight), weight for grouped front and rear paws (gram and percent total animal weight), left/right and front/rear weight ratio, surface for each paw (mm 2), surface for grouped front and rear paws (mm 2), and variability for each parameter. Parameters were given for each posture and as a mean for the whole experiment, the duration of different postures (four paws, rearing, and so on) over the whole experiment, and total time spent on each paw over the whole experiment. Following the recordings, the observer verified the accuracy in placement of rear and front right paw, rear and front left paw, and other areas such as the tail. The DWB software then determined surface and pressure parameters automatically.
|Figure 2: Instrument of dynamic weight-bearing test. A. High-resolution camera. B. Dynamic weight-bearing cage. C. Sensor pad. D. Handle input to Bioseb software. E and F. Bioseb software for data capture and analysis|
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DWB is a nonreflexive method for assessment of pain in rodents, it has been validated that it could assess alterations in weight-bearing in inflammatory pain models in both mice and rats.,,, There are several advantages for the use of DWB for the assessment of pain in rodents. (1) Operator independent: most standard pain methods are subject to the influence of experimenter subjectivity. However, the collection and analysis of DWB data are conducted in a nonsubjective way, which may produce more reliable data. (2) Unnecessary stress associated with restraint is eliminated. The animal is allowed to move freely in the enclosure without interference of human factors. This decreases anxiety and stress induced by handling, which result in either stress-induced analgesia or hyperalgesia.,, (3) Collecting and analyzing more information: compared with static weight-bearing, the DWB test captures more data such as weight-bearing and surface area for all four paws. Since mice are quadrupeds, it can be considered that the data are more reality only when four paws are taken into account. (4) Nonreflexive. DWB is a nonreflexive method for pain assessment. As mentioned above, these methods could reflect the human condition more realistic and may explore drug research more predictive and reliable.,,, (5) Longer observation time: compared with static weight-bearing, DWB offers longer observation time for animals, which is important for improved and more reliable evaluation.
DWB has been validated to be a sensitive and predictive approach for the assessment of joint pain in AIA model, it could detect the recovery based on changes in weight distribution caused by mBSA between affected and nonaffect hind limbs when mice were pretreated with different types of analgesic/anti-inflammatory drugs, it also could distinguish different doses of AIA pain and show the dose–response effects of these drugs for arthritic pain. Furthermore, DWB gives valuable information on joint pain during locomotion. In addition, DWB also provides a new method to evaluate mechanical hypersensitivity in the mouse pain model induced by CFA., A recent study identified that arthritis pain produced by intra-articular injection of collagenase into mice knee, which can be measured reliably and repeatedly by DWB test. Moreover, this method could be used to detect the effect of analgesic drugs.
As described above, the DWB test is a more suitable method for the evaluation of joint pain; however, some limitations should be considered. The arthritis model should be monoarticular since this method compares the differences between the weights exerted by each limb of the animal. Thereby, DWB would not be suitable to assess the joint pain in polyarthritis models such as CIA and collagen antibody-induced arthritis, which are the well-recognized models of RA. Another restriction of DWB is that only one mouse is put into the enclosure each time and assessed around a 5 min period, manual integration of video and sensor data is time consuming. In addition, even if the DWB test enclosure allows freedom of movement, there may be some confinement and displacement associated stress.
| Conclusion|| |
In this review, we have attempted to describe several important animal models of RA that are widely used or provide important insights. Although the etiology of RA still remains inconsiderable, there is no single treatment for RA. Among the many available animal models, it has been shown to help understand some of the mechanisms involved and provide key insights into the inflammatory pathophysiology of arthritis, leading to the revolution of biotherapy. In addition, this study recommends the DWB test as well as its advantages and disadvantages. DWB test, as a nonreflexive method, could directly quantify and evaluate pain-like behavior in free-moving animals which are reliable, reproducible, sensitive, and specific. It can be used to evaluate the efficacy of analgesics for joint pain, thereby increasing the predictability of preclinical new analgesics screening.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]