The present study explored the use of the non-invasive video-capture gait-analysis instrumentation in the evaluation of a mouse model of CIA. We demonstrated that postural and kinematic gait disturbances corresponded to clinical scores with increasing severity of the CIA. CIA mice exhibited increased paw areas, increased stride frequency, shorter stride length, relative paw placement inversion, and reduced stride, stance, braking, swing, and propulsion durations. To the best of our knowledge, this is the first work seeking to apply comprehensive gait analysis in rodent CIA models.
RA is an autoimmune disease of unknown etiology which leads to chronic inflammation in the joints and subsequent destruction of the cartilage and erosion of the bone [1]. The rodent model of CIA has been proven as a successful animal model for RA research because it is also an autoimmune model and in many ways resembles RA, including the chronic inflammation [4, 14]. The primary manifestation of this model is the inflammation-induced joint swelling [15–17]. Although the clinical scoring system may give a numerical score corresponding to the degree of inflammation based on the severity of joint swelling and redness, it provides a semi-quantitative and subjective assessment. Although the degree of inflammation and joint swelling can also be determined by measuring the volume of the paws using a water displacement method in a rat model of CIA [18, 19], this method is less practical in mice given the small size and volume of the paws. Using DigiGait, we are able to quantify the maximal paw area in contact with the treadmill during the stance phase of the step cycle and demonstrate that the paw area increased with increasing clinical scores. Thus, the paw area measured digitally by DigiGait is an objective index of tissue swelling and inflammation, which is superior to other parameters of joint inflammation and swelling, such as paw joint thickness [7] and ankle diameter [6], by avoiding experimenter biases.
Ankylosis and joint angle malformation are major pathological changes in CIA, especially at the late stage of the disease [20]. X-ray radiographic analysis has been used to assess this change [6, 8]; however, this method is an endpoint outcome, requiring sacrificing the animals, and is also based on a semi-quantitative scoring system [6, 8]. In the present study, we used the DigiGait system to measure the paw angle. The measured paw angle corresponds to the severity of the clinical scores. This may reflect either ankylosis or joint angle malformation which forces the placement of paws at these angles or may reflect a conscious compensation for balance or gait disturbances caused by joint pain or inflammation. Thus, to the best of our knowledge, this is the first work indicating that gait analysis by this non-invasive video-capture device could provide a simple alternative way to detect the joint malformation in CIA mice.
To date, the major examination in studies of CIA mouse models includes clinical symptoms as well as radiographic and histological assessments of arthritis. Most of them are endpoint examinations, and there is no method available for assessment of the functional and behavioral defects during the progression of the disease [5–10]. Although an animal's locomotion velocity over ground itself can provide valuable information relating to pain and gait deficits, a change in velocity would make it difficult to analyze the gait parameters. By allowing the investigators to set the treadmill belt speed (15 cm/s), the DigiGait system enables the evaluation and comparison of changes in numerous gait parameters between subjects without the interference of changes in velocity and the requisite changes in gait. In the present study, we measured the stride frequency, stride length, as well as stride, stance, braking, propulsion, and swing times. It has been reported that arthritic changes in the articular surfaces within the joint manifest themselves as an increase in the frequency and a reduction in the length of strides in both human and animal subjects [21]. In the present study, we have observed that the stride frequency indeed increased and the stride length decreased linearly with increasing clinical scores, thus confirming this important observation in the current CIA model. Consistent with these changes, we also observed a linear decrease in stride time. Changes in stride frequency can also be reflected in changes in stance, swing, propulsion, and braking times. Each of these individual parameters comprises one portion of a full stride. Consistent with a decrease in stride time, the time spent in these four phases also decreased linearly with increasing clinical scores. Thus, the present data demonstrate that gait parameters could be used as objective indices for the progression of CIA.