CORR Insights®: Development and Characterization of a Novel Bipedal Standing Mouse Model of Intervertebral Disc and Facet Joint Degeneration

Where Are We Now?

Lower back pain has been the leading cause of disability since 1990 [4], affecting up to 85% of individuals at least once in their life [1].

While the descriptor “low-back pain” may be caused by a host of diagnoses, degenerative disc disease (DDD) is a key player. Despite being an active area of research, much is unknown about DDD. Assessing the early stages of DDD is particularly challenging, as the clinical symptoms of the disease do not often present until much later.

The current study by Ao and colleagues [2] provides a unique opportunity to assess degeneration not only based on clinical symptoms, but also highly informative endpoints that cannot be investigated in clinical or in vitro studies, such as histology and immunohistochemistry of the entire disc. The unique aspect of this work is that degeneration has been induced in a noninvasive manner; by inducing a bipedal posture on an animal that, although capable of bipedal posture, is a quadruped.

Naturally occurring models of disc degeneration are rare but include macaque monkeys, chondrodystrophoid dogs, and the sand rat. Due to their scarcity, several methods have been applied to induce degeneration in otherwise healthy discs. The most well-established models apply an acute injury via annular puncture [10], annular incision [3, 8], or chemical digestion [9]. These acute injuries do induce degenerative changes and generally demonstrate progression over time. Annular damage removes the barrier that contains and transfers loads generated by intradiscal pressure and shields the immune-privileged nucleus pulposus. Exposure to the body’s immune response can be beneficial in the case of absorption of herniated disc material but leads to further degeneration with time. This type of degeneration mimics that seen in herniation but may not simulate the common, slowly progressing condition with an intact annulus that is often seen in humans. Therein lies the opportunity to develop a model that more closely represents the human sequence. But how can we achieve this?

Where Do We Need To Go?

There are three key items from this study that guide future research. First, can this type of study be applied to large animals? This method is unlikely to translate directly to more commonly used large-animal models such as pigs and sheep. Certainly, bipedal posture can be attained by some animals such as dogs and cats when necessary. However, the connection between induced bipedalism and DDD with these species still needs to be established.

Second, we need to investigate the influence of factors that accompany bipedal posture, including increased physical activity and stress. The supplemental video data in the current study [2] includes a comparison between the posture of the treatment and control groups. It is evident in this short video that the mouse standing in water is engaged in grooming activities and is more active than the control animal. Might it be the additional activity and not the bipedal posture itself that caused the observed changes? Or, perhaps the increased activity is a function of the stress the bipedal animals experienced, and it is the stress, and not the bipedal posture that accounts for the study’s findings? Future researchers should measure cortisol levels, as this is relevant and applicable to humans as well. Additionally, motion tracking would provide a means to further quantify the activity of the subject.

Third, with these models at our disposal, researchers could evaluate whether certain interventions could arrest, and potentially reverse, degenerative changes. Does the intervertebral disc have regenerative capacities? If so, to what extent? An intact annulus may provide the most-promising candidate for recovery due to its continued shielding from immune responses that are beneficial to other healing tissues. But an intact annulus may be damaging to the intervertebral disc as a whole. By utilizing this model with a recovery period, we can also determine over what period can this altered loading be applied? Is a total removal of altered loading best or rather, a staged return? If regeneration does occur, what factors are most active during this stage?

How Do We Get There?

When attempting to create a degenerative disc that parallels the process that occurs in DDD, it is likely that the least invasive approach is the best. One approach to creating a degenerative disc is to modulate the loading conditions to which it is exposed. The intrinsically avascular nature of the disc dictates that it is reliant on loading, both cyclic and diurnal (daily unloading cycle, typically overnight), to transport waste out and nutrients in. Motion also is necessary for articular joints, including the facet joints. Removing or altering this load changes the environment of the residing cells, which may initiate a degenerative cascade by causing cell death, resulting in an inability to maintain the matrix and generate intradiscal pressure, leading to irregular motion and overloading of other spinal structures (facets and annulus). Moving towards methods like these, that do not otherwise disrupt the intravertebral disc, allows us to observe the degenerative cascade with minimal artefact caused by the inducing agent.

Modulation of loading has continued to evolve and points the way towards an animal model that more closely represents the human spine. Early investigations included a system of pins has been applied to the tail of mice [6] and rats [7] to immobilize the disc and initiate degenerative changes. The next step moved to a larger animal and incorporated facet joints. This has been performed in the rabbit lumbar spine, which was loaded for 28 days and exhibited degeneration [5]. More recently, researchers have developed the first large animal model of DDD induced by loading by immobilizing a single intervertebral level [11]. The benefits of using this large animal model include, similarity in size to human, which plays a role in diffusion throughout the disc, overall makeup, and biomechanical properties.

Ao and colleagues [2] sought to alter the loading using a very different approach; by inducing a bipedal posture in a mouse. The resulting change in posture loads the disc in a different manner, allowing increased loading without external constraint of ROM. The animal is also allowed to apply compensatory mechanisms, such as reactions to muscle fatigue, that are not permitted in more constrained models. This type of loading and activity may be more akin to that which is induced by workplace activities in physically demanding occupations. The natural progression of this model would also be towards tighter control or measurement of loading/motion as well as progression towards an animal model that more closely resembles the human.