The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

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?

http://morelife.org/references/full_papers/12885586.pdf

Extracellular superoxide dismutase in biology and medicine.

http://cbm.msoe.edu/includes/pdf/smart2013/Review_Hyaluronidase_Eraser.pdf

The magic glue hyaluronan and its eraser hyaluronidase: a biological overview.

Study design An in vivo study to radiographically and histologically assess a new method of induction of disc degeneration. OBJECTIVE.: To establish a reproducible rabbit model of disc degeneration by puncturing the anulus with needles of defined gauges and to compare it to the classic stab model. Summary of background data New treatment approaches to disc degeneration are of great interest. Although animal models for disc degenerative disease exist, the quantitative measurement of disease progression remains difficult. A reproducible, progressive disc degeneration model, which can be induced in a reasonable time frame, is essential for development of new therapeutic interventions. Methods The classic anular stab model and the new needle puncture model were used in the rabbit. For the needle puncture model, 3 different gauges of needle (16G, 18G, and 21G) were used to induce an injury to the disc to a depth of 5 mm. Radiographic and histologic analyses were performed; magnetic resonance images were also assessed in the needle puncture model. Results Significant disc space narrowing was observed as early as 2 weeks after stabbing in the classic stab model; there was no further narrowing of the disc space. In the needle puncture model, all needle sizes tested induced a slower and more progressive decrease in disc height than in the classic stab model. The magnetic resonance imaging supported the results of disc height data. Conclusions The needle puncture approach, using 16G to 21G needles, resulted in a reproducible decrease of disc height and magnetic resonance imaging grade. The ease of the procedure and transfer of the methodology will benefit researchers studying disc degeneration.

A novel rabbit model of mild, reproducible disc degeneration by an anulus needle puncture: correlation between the degree of disc injury and radiological and histological appearances of disc degeneration.

Intra-articular injection of hyaluronate (HA) is widely used in the treatment of arthropathies. However, the mechanism of the effects of HA preparations on the arthritic synovium and the relationship between their effects and molecular weights (MW) remains unknown. The objectives of this study were to compare the effects of two hyaluronate preparations, HA84 (MW: 84 X 10(4)) and HA230 (MW: 230 X 10(4)), on the synovium of an arthritis model and to examine the mechanism of the effects of HA. The HA preparations were intra-articularly injected in a model of canine arthritis induced by anterior cruciate ligament transection for a total trial of 5 weeks. To define the accessibility of HA preparations to the synovial lining layers, fluorescein-labeled HA84 or HA230 was injected at the last administration. Pathological changes analyzed included increases in volumes and prostaglandin E2 concentrations in synovial fluids, thickening of the synovial lining layers, vacuolar alterations in the lining cells, and stainability of HA in the synovium. Expression levels of Heat shock protein 72 (Hsp72) were immunohistochemically detected in the tissues to investigate the ability of the cells to survive the degeneration. The pathological changes described above were more significantly suppressed in the HA84-treated than in the HA230-treated groups. In most cases of the HA84-treated group (five cases out of six), fluorescein particles were intensely distributed in the synovial lining layers, but only two cases in the HA230-treated group showed a weak distribution of fluorescein particles in the layers, indicating a certain difference in the accessibility of HA preparations to the lining cells between the two HA molecules. Moreover, the immunoreactivity for Hsp72 in the lining cells as more intense in the HA84-treated than in the HA230-treated groups. The difference in the accessibility of HA molecules corresponded well with that in the inducibility of Hsp72 in the lining cells. These results suggest that the up-regulation of Hsp72 may offer a new concept concerning mechanism of the effects of HA preparations on the arthritic synovium.

Molecular weight-dependent effects of hyaluronate on the arthritic synovium.

To demonstrate the intra- and extracellular localization of hyaluronic acid (HA) in articular cartilage of the rabbit tibia, biotinylated HA binding region, which specifically binds to the HA molecule, was applied to the tissue. In comparison with the localization of HA, that of chondroitin sulfate (CS), keratan sulfate (KS), and the protein core (PC) of the proteoglycan was examined by immunohistochemistry. Strong positive staining for HA was detected in chondrocytes located in the transition between the superficial and middle zones of the tissue. Pre-treatment with chondroitinase ABC, keratanase II, or trypsin enhanced the stainability for HA in peri- and intercellular matrices. Immunohistochemistry with or without enzymatic pre-treatment demonstrated that immunoreactivity for CS, KS, and PC was distinctly discerned in chondrocytes and in the extracellular matrix located in the middle and deep zones. In particular, the immunoreactivity for KS and PC was augmented by pre-treatment with chondroitinase ABC not only in chondrocytes but in the extracellular matrix located in the middle and deep zones. Microbiochemical analysis corresponded well with histochemical and immunohistochemical results. These results suggest that HA is abundantly synthesized and secreted in chondrocytes located in the transition between the superficial and middle zones.

Intra- and extracellular localization of hyaluronic acid and proteoglycan constituents (chondroitin sulfate, keratan sulfate, and protein core) in articular cartilage of rabbit tibia.

The effect of topically administered sodium hyaluronate (Na-HA) on the healing of corneal epithelial defect was investigated using rabbit eyes. The corneal epithelium was removed surgically or with iodine vapor or n-heptanol, and saline was administered to one eye as the control, and 0.1% or 0.25% Na-HA with a molecular weight of 87.3 × 104 to the other eye once daily. The area of epithelial defect was measured once daily before a topical administration, and the healing rate of epithelial defect was calculated. When the corneal epithelium was removed with iodine vapor, a topical administration of 0.1% or 0.25% Na-HA did not significantly accelerate the epithelial healing. But when removed surgically or with n-heptanol, the healing rates of the corneas treated with 0.25% Na-HA significantly exceeded those of the control eyes. When the epithelium was removed surgically, treatment with 0.1% Na-HA also significantly accelerated the healing. To determine why the effect of Na-HA differed in these three...

The effect of sodium hyaluronate on the migration of rabbit corneal epithelium. II. The effect of topical administration.

Hyaluronan, CD44 and fibronectin in rabbit corneal epithelial wound healing.

Study design This study demonstrated the chemonucleolytic effects of chondroitinase ABC and its histologic and biochemical background. Objectives To determine the course of chondroitinase ABC action on normal rabbit discs, and to find its minimum effective dosage. Summary of background data No previous study has assessed the chemonucleolytic action of chondroitinase ABC in a time- and dose-dependent manner. This study also investigated the biochemical causes of radiologic and histologic changes in the discs. Methods Rabbits were injected with 4 U of pharmaceutical-grade chondroitinase ABC intradiscally. They were radiologically and histologically observed, and biochemical analyses of the discs were conducted on days 1, 3, 5, 7, and 10 postinjection in the time course study. Different doses of chondroitinase ABC were injected, and radiologic observations and water content of the discs were measured in the dose-finding study. Results The time course study revealed that the chondroitin sulfate content of discs significantly decreased from day 1 postinjection until the end of the experimental period. The weight and water content of the nucleus pulposus decreased on day 3, and disc space narrowing was observed from the day after injection. The dose-finding study showed that a dose of 0.0002 U/disc still induced disc space narrowing and a decrease in water content. Conclusions Chondroitinase ABC is estimated to have a chemonucleolytic effect at least by day 3 postinjection at a dose level of 0.0002 U/disc or higher in rabbits.

Chemonucleolytic effects of chondroitinase ABC on normal rabbit intervertebral discs. Course of action up to 10 days postinjection and minimum effective dose.

Satoshi Miyauchi

Papers

Molecular weight-dependent effects of hyaluronate on the arthritic synovium.

Intra- and extracellular localization of hyaluronic acid and proteoglycan constituents (chondroitin sulfate, keratan sulfate, and protein core) in articular cartilage of rabbit tibia.

The effect of sodium hyaluronate on the migration of rabbit corneal epithelium. II. The effect of topical administration.

Hyaluronan, CD44 and fibronectin in rabbit corneal epithelial wound healing.

Chemonucleolytic effects of chondroitinase ABC on normal rabbit intervertebral discs. Course of action up to 10 days postinjection and minimum effective dose.