Intervertebral disc (IVD) degeneration is an often investigated pathophysiological condition because of its implication in causing low back pain. As human material for such studies is difficult to obtain because of ethical and government regulatory restriction, animal tissue, organs and in vivo models have often been used for this purpose. However, there are many differences in cell population, tissue composition, disc and spine anatomy, development, physiology and mechanical properties, between animal species and human. Both naturally occurring and induced degenerative changes may differ significantly from those seen in humans. This paper reviews the many animal models developed for the study of IVD degeneration aetiopathogenesis and treatments thereof. In particular, the limitations and relevance of these models to the human condition are examined, and some general consensus guidelines are presented. Although animal models are invaluable to increase our understanding of disc biology, because of the differences between species, care must be taken when used to study human disc degeneration and much more effort is needed to facilitate research on human disc material.

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Are animal models useful for studying human disc disorders/degeneration?

Spondyloarthropathies are a cluster of interrelated and overlapping chronic inflammatory rheumatic diseases that primarily include ankylosing spondylitis, reactive arthritis, and the arthritis associated with psoriasis and inflammatory bowel diseases. The primary pathologic sites are the entheses (the sites of bony insertion of ligaments and tendons); the axial skeleton, including the sacroiliac joints; the limb joints; and some nonarticular structures, such as the gut, skin, eye, and aortic valve. Although spondyloarthropathies are not associated with rheumatoid factor, they show a strong association with HLA-B27; however, this association varies markedly among various spondyloarthropathies and among ethnic groups. The most widely used classification criterion, from the European Spondyloarthropathy Study Group, encompasses the currently recognized wider disease spectrum, with a sensitivity and specificity that generally exceed 85%. Spondyloarthropathies occur in genetically predisposed persons and are triggered by environmental factors, but the cellular and molecular mechanisms of inflammation are not yet fully understood. Chlamydial and many enterobacterial infections can trigger reactive arthritis, but an infectious trigger for ankylosing spondylitis has not yet been established. HLA-B27 itself is involved in enhancing genetic susceptibility, but the underlying molecular basis is still unknown; additional genes include the putative susceptibility genes for Crohn disease, ulcerative colitis, and psoriasis. A specific susceptibility gene for Crohn disease, NOD2, is located on chromosome 16q12, and one of the candidate genes for psoriasis, PSORS1, has been mapped to a 60-kb fragment on chromosome 6p, which is telomeric to the HLA-C locus. This paper reviews the efficacy of anti-tumor necrosis factor-alpha therapy and other therapeutic advances.

Update on Spondyloarthropathies

Objective

To determine whether HLA–B27 misfolding and the unfolded protein response (UPR) result in cytokine dysregulation and whether this is associated with Th1 and/or Th17 activation in HLA–B27/human β2-microglobulin (Huβ2m)–transgenic rats, an animal model of spondylarthritis.



Methods

Cytokine expression in lipopolysaccharide (LPS)–stimulated macrophages was analyzed in the presence and absence of a UPR induced by chemical agents or by HLA–B27 up-regulation. Cytokine expression in colon tissue and in cells purified from the lamina propria was determined by real-time reverse transcription–polymerase chain reaction analysis, and differences in Th1 and Th17 CD4+ T cell populations were quantified after intracellular cytokine staining.



Results

Interleukin-23 (IL-23) was found to be synergistically up-regulated by LPS in macrophages undergoing a UPR induced by pharmacologic agents or by HLA–B27 misfolding. IL-23 was also increased in the colon tissue from B27/Huβ2m-transgenic rats concurrently with the development of intestinal inflammation, and IL-17, a downstream target of IL-23, exhibited robust up-regulation in a similar temporal pattern. IL-23 and IL-17 transcripts were localized to CD11+ antigen-presenting cells and CD4+ T cells, respectively, from the colonic lamina propria. Colitis was associated with a 6-fold expansion of CD4+ IL-17–expressing T cells.



Conclusion

The IL-23/IL-17 axis is strongly activated in the colon of B27/Huβ2m-transgenic rats with spondylarthritis-like disease. HLA–B27 misfolding and UPR activation in macrophages can result in enhanced induction of the pro-Th17 cytokine IL-23. These results suggest a possible link between HLA–B27 misfolding and immune dysregulation in this animal model, with implications for human disease.

HLA-B27 misfolding and the unfolded protein response augment interleukin-23 production and are associated with Th17 activation in transgenic rats.

The discovery of a second estrogen receptor (ER), called ERβ, in 1996 sparked intense interest within the scientific community to discover its role in mediating estrogen action. However, despite more than 6 yr of research into the function of this receptor, its physiological role in mediating estrogen action remains unclear and controversial. We have developed a series of highly selective agonists for ERβ and have characterized their activity in several clinically relevant rodent models of human disease. The activity of one such compound, ERB-041, is reported here. We conclude from these studies that ERβ does not mediate the bone-sparing activity of estrogen on the rat skeleton and that it does not affect ovulation or ovariectomy-induced weight gain. In addition, these compounds are nonuterotrophic and nonmammotrophic. However, ERB-041 has a dramatic beneficial effect in the HLA-B27 transgenic rat model of inflammatory bowel disease and the Lewis rat adjuvant-induced arthritis model. Daily oral doses as l...

Evaluation of an Estrogen Receptor-β Agonist in Animal Models of Human Disease

The unexpected discovery of a second form of the estrogen receptor (ER), designated ERβ, surprised and energized the field of estrogen research. In the 9 yr since its identification, the remarkable efforts from academic and industrial scientists of many disciplines have made significant progress in elucidating its biology. A powerful battery of tools, including knockout mice as well as a panel of receptor-selective agonists, has allowed an investigation into the role of ERβ. To date, in vivo efficacy studies are limited to rodents. Current data indicate that ERβ plays a minor role in mediating estrogen action in the uterus, on the hypothalamus/pituitary, the skeleton, and other classic estrogen target tissues. However, a clear role for ERβ has been established in the ovary, cardiovascular system, and brain as well as in several animal models of inflammation including arthritis, endometriosis, inflammatory bowel disease, and sepsis. The next phase of research will focus on elucidating, at a molecular level...

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Estrogen Receptor-β: Recent Lessons from in Vivo Studies

HLA-B27 is a human major histocompatibility complex (MHC) class I allele that is found with strikingly increased prevalence in patients with the spondyloarthropathies, a group of disorders that includes ankylosing spondylitis, reactive arthritis (formerly commonly referred to as Reiter’s syndrome), arthritis and spondylitis associated with inflammatory bowel disease or psoriasis, as well as a more general diagnosis of spondyloarthropathy that shares features of the other entities (1–3). Some of these disorders are known to be directly triggered by infectious agents, and microbial agents have been implicated in most of the rest of these disorders as well. A thorough elucidation of the basis for the association between B27 and disease would enhance our understanding of the roles that both genes and environmental agents play in producing chronic inflammatory diseases.

Graham M. Fox

Papers

Inflammatory disease in HLA-B27 transgenic rats