On Disc Degeneration Models. Commentary on: “Intervertebral Disc Degeneration Models for Pathophysiology and Regenerative Therapy – Benefits and Limitations”

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Intervertebral Disc Degeneration Models for Pathophysiology and Regenerative Therapy -Benefits and Limitations

Disc degeneration has become a “trending topic” in spine research in recent years, although it was almost a century ago that the first description of something going wrong in the intervertebral discs [1] and the “disc era,” with a pathogenic role attributed to intervertebral discs, was born [2]. But even these classic hallmarks have some previous publications focusing toward the intervertebral disc.

At this point, I would like to make a remark: disc herniations, disc degeneration and low back pain are related, but they are by no means synonyms.

Besides these papers, few people focused on it until late twentieth century. It was Kirkaldy-Willis [3] who first published a description of the degenerative cascade of the spine; and the initial events began in the disc.

There have been a myriad paper on disc degeneration since then, on cell cultures, animal models, therapy trials, … and all finished always with some reference to the need of further research because, for instance, the “chondrocyte-like cells.” So, first point: what kind of cells are we dealing with? Which of them and to what degree, are responsible for the cascade?. And then, The Question (with capitals): What ignites all this cascade?. But even, another question: why some patients become symptomatic while others do not with similar images?

Of course, low back pain (and neck pain) are quite common in the human beings, as far as 80% lifetime incidence is accepted; being the second reason for medical consultancy only after acute respiratory infections. Then, another issue stands up immediately: is disc degeneration a pathology or just physiological ageing?. The answer to this seems to be that we can define pathological degeneration. Some recent paper in a dog model differentiates painful discs from non-painful degenerated discs [4].

As the authors state: “IDD is a complex process, the pathogenesis of which has not been elucidated to date” [5]. With such an immense horizon to search, with such a huge (80%!) potential incidence, it seems advisable to trim this process of disc degeneration to a model we can control.

But the unknown is so much that a tremendous diversity in these models happens. That is the value of this paper, to put some order and classification on the various perspectives that basic research has adopted to try to get into the disc degeneration process. There are changes described (or proposed) in: nucleus pulposus cells senescence, apoptosis, matrix degradation, structural disarrangement of annulus fibrosus, calcification and microfractures of the cartilage endplate. So two main hypotheses have risen: abnormal mechanical stress, and primary dysfunction of nutrient transport; but also a genetic predisposition, so the authors propose that there is first such a genetic predisposition that brings about structural abnormalities, and then a second strike by the imbalance anabolism/catabolism [5].

With such a mess and so many possibilities, a model is clearly needed to try to put order into all these issues linked to disc degeneration. And, in the same line of thought, some order is needed to clarify and define what does exactly each model account for.

Having said that, we can differentiate [5]:

1. in vitro culture models, based on mechanical overload, inflammation, enzyme digestion or structural injury. There are cell models and organ (whole disc, endplates included), especially these late ones on the rise, but they can only recreate short-term changes, not lifetime ones.

2. in vivo live animal models, in which we must consider the differences among species in disc anatomy (volume, geometry), biomechanics and notochordal cell variations. These models may also try to reproduce the events of degeneration through several mechanisms: mechanical stress change, injury models (puncture, nucleotomy,…), endplate injury and nutritional disorders, chemical induction, genetic correlation (genes have an important role, either some animals tend to have spontaneously a similar process – e.g. sand rats– or else, transgenic animals regarding several manipulations – e.g. beta cathenin, dystrophin-utrophin, hypoxia inducible factor 1-alpha, GDF-5-).

To this I would add also finite element models and, contrary to the classical mechanical overloading, a model based on microgravity [6], in which a decrease in GAG is measured.

No doubt genes have something to do in the different natural history of different people, as in everything, making definite subgroups (the patients) more prone to develop some problems, but probably it is all about the healing potential that defines life as such in itself: repair damage. In this direction, I would highlight a published model [7] based on nutrient deprivation in which not only a degeneration process similar to the stepwise human one was caused, but also when somehow nutrients came back there was a partial reversion and also, when only one side of the disc was isolated, no clear degenerative process developed. Then, perhaps there is tissue damage due to cell starvation that renders the disc unable to cope with the homeostatic repair of microdamage.

I do fully agree with the authors that we must pick (or devise) a model which is repeatable, measurable and controllable (the basis of the scientific method), but also one that reproduces the human intervertebral disc degeneration process step by step.

The authors point at stress change models [5]…, and I agree, but depending on the event considered as the initial, we can stress either mechanical structures or else metabolic pathways (oxidative stress).

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