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- Open Access
Spontaneous arthritis and ankylosis in male DBA/1 mice: further evidence for a role of behavioral factors in “stress-induced arthritis”
© Braem et al.; licensee BioMed Central Ltd. 2012
- Received: 13 February 2012
- Accepted: 15 December 2012
- Published: 19 December 2012
Ageing male DBA/1 mice spontaneously develop arthritis in the hind paws. We and others have demonstrated that this model shares striking features with human spondyloarthritis, in particular entheseal involvement, progressive ankylosis but also dactylitis. Here, we report on our recent experience with this model highlighting how changes in the animal facility affect the development of the disease.
Ageing male DBA/1 mice from different litters were caged together (6 mice per cage) at the age of 10 weeks. The mice were checked twice a week for clinical signs of arthritis. Disease severity was assessed in further detail post-mortem by scoring for histomorphological characteristics. DBA/1 mice spontaneously develop macroscopically detectable arthritis, presenting as joint swelling or toe stiffness. Standard settings with open cages lead to an almost 100% incidence by the age of 26 weeks. The introduction of larger cages and filter tops reducing exposure to other cages dramatically affected incidence. Other negative factors include excess bedding material reducing the impact of walking and running. Switching back to the original conditions resulted again in a high incidence, further optimized by sensory exposure to female mice. We also showed that the related DBA/2 strain is sensitive to the disease.
Changing environmental factors in the housing conditions of DBA/1 mice severely affects the spontaneous development of arthritis. This points out that the model is very sensitive to external stress and sensory factors that are likely affecting the behavior of the male mice and that the model needs to be optimized in different situations.
- Spontaneous arthritis
- Behavioral factors
Changed environmental factors in animal housing
Spontaneous arthritis in male DBA/1 mice (SpAD): description of the model
The arthritis in the toes is mostly nonsymmetrical and mainly affects the fourth and fifth digits. Dactylitis and onychoperiostitis are also manifestations of the disease process in SpAD, indicating that this model mimics some specific features of psoriatic arthritis.
The model is particularly helpful to study molecular aspects of ankylosis but also to study links between inflammation and new bone formation. Depending on the specific experimental question, mice are usually observed up till the age of 26 weeks with the incidence of arthritis approaching 100%. The mice are evaluated using a dedicated scoring system. Disease severity is assessed in further detail post-mortem with histomorphological scoring of the different characteristics of pathological endochondral bone formation: inflammation, entheseal cell proliferation, cartilage and bone formation and ankylosis.
Changing housing conditions affects spontaneous arthritis in DBA/1 mice
First, new cages were introduced which were 35 cm2 larger (10% surface increase) and had a different shape. The shape changed from long and narrow to more square-shaped. Since mice are very territorial, one of the factors that increase aggressive behavior in the male mice is keeping them in small cages. At the same time, filter tops were brought in creating a more sterile environment. Mice are thus maintained under non-specific pathogen-free conditions. Putting filter tops on the cages also lowers noise from the environment and reduces the smell of other mice in the facility including pheromones. Pheromones are secreted or excreted chemical factors that can trigger a response in the behavior of conspecifics. Consequently, this could have a great impact on a mouse model that is stress-induced. Lastly, excess bedding material was put into the cages. This could also have an effect, as we hypothesized that biomechanical factors may play a role in the development of the disease. Extensive use of the spontaneous model in our lab suggests that the fourth and fifth toes are preferentially affected.
In the period following changes in animal housing, the incidence of spontaneous arthritis dropped dramatically. Solely 20 – 30% of the mice developed spontaneous arthritis exhibiting a strongly reduced clinical severity score (Figure4A-B). The typical arthritis became rare and the clinical inflammatory signs often became transient and did not persist until the end of the experiment. Also, no clear enthesitis or inflammation in the paws could be detected by histomorphology.
Restoration of arthritis in DBA/1 mice
All the above-described environmental factors could have an influence on the spontaneous mouse model individually or in combination with each other. To try to restore the spontaneous model, we changed the environmental factors again. First, the old smaller cages were re-introduced without the filter top, exposing the mice again to different smells and more noise. Second, excess bedding material was removed. To further increase stress to the DBA/1 mice, female mice were put next to them, also in cages without filter top. Only together, these changes increased the incidence to almost 70%.
In summary, these observations suggest that this model is very sensitive to external stress and sensory factors. These environmental factors are likely affecting the behavior of the male mice and influence the development of arthritis.
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