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Equine Osteoarthritis Treatment with Stem Cells

 
September 2012
 
Stem cells are receiving a great deal of scientific attention as well as coverage in the lay press. One of the many reasons for the attention stems from these cells having the potential to regenerate tissues without the production of scar tissue that is generally associated with healing processes. Doctors Frisbie and Kisiday have been heading up a multi-center clinical trial to assess how adult bone marrow derived stems cells can help horses with orthopaedic disease. This research began with a comparison of stem cells derived from either fat or bone marrow. The preliminary research suggests that bone marrow derived cells are more suited for use in damaged joints, which is why the Equine Orthopaedic Research Center is pursuing bone marrow derived cells in their clinical cases.
 
The current multi-center trial is still underway, but results of the first 15 horses are promising. In collaboration with Oakridge Equine Hospital (Dr. Hague), Washington State University (Dr. Schneider), and Texas A&M (Dr. Watkins), the team at Colorado State has been treating horses that they felt would have little hope of recovery with conventional therapy. These first 15 horses were all treated at least 6 months prior to follow-up, with the first case now out 18 months from treatment. Conditions treated included subchondral bone cysts, cartilage damage and/or loss, and torn menisci. In horses that became sound, the average days post treatment with stem cells before they became sound was 78 days, with a range from 30-240 days. There were 10 of 15 (67%) horses that became sound and returned to their previous level of work in the discipline for which they were used prior to treatment. Given the fact that all horses in the treatment group had a poor prognosis prior to treatment, the group feels MSC therapy has yielded favorable results. To date the group has treated 40 joint related cases and hopefully will have continued success. The next step is to acquire funding to compare fat derived cells (the only source commercially available to date) to the bone derived cells used in the current study, in a controlled clinical case study. From this work it would become clearer if researchers indeed need to continue to use the more labor intensive bone derived cells.
 

Investigation of Gene Regulation Cell by Cell in Equine Osteoarthritis Stem Cells as a Treatment for Osteoarthritis

 
Osteoarthritis remains a common and debilitating disease in humans, horses and other mammalian species, despite advances in diagnosis and treatment. Hyaline cartilage is considered to play a central role in the pathophysiology of osteoarthritis. The investigation of differences in gene expression in cells from osteoarthritic and normal cartilage is expected to yield genes that may play a role in the pathophysiology of osteoarthritis, representing possible new targets for the treatment of the disease. Tissue heterogenetically (differences between areas of a tissue) have thwarted exact definition of processes analyzed whole piece of tissue.
 
The goals of this investigation, which was the basis of Dr Katja Düsterdieck's PhD, were to develop the techniques to isolate RNA from individual cells of various cartilage layers, a feat not accomplished before in articular cartilage. The second step was to determine what genes are differentially expressed in osteoarthritic versus normal articular cartilage from different depths within the cartilage.
 
Laser capture microdissection was used to isolate the cartilage cells, called chondrocytes. Next the samples underwent an extraction procedure followed by linear amplification of the mRNA, which increases the concentration of the mRNA in such a fashion it is readily detectable. These procedures allowed the researchers to obtain enough material to be analyzed on an equine gene chip. In collaboration with Ohio State University, the researchers were able to screen over 3,000 gene sequences using this unique equine gene chip.
 
Once the method of producing samples for the gene chip analysis was validated, tissue from adult horses with carpal osteoarthritis was assessed. 154 genes were found to be differentially expressed based on depth of the chondrocytes in the articular cartilage. The gene expression pattern of chondrocytes from the superficial layer reflected support of cell proliferation, suppression of apoptosis (cell death) and up-regulation of several genes involved in cell-matrix interactions or inflammatory processes. In contrast, the gene expression pattern of chondrocytes from the deeper layers were dominated by genes supporting the synthesis of proteins and proteoglycans, suggesting a higher matrix synthetic activity in these chondrocytes compared to those from the tangential layer.
 
Seventeen genes were found to be differentially expressed between osteoarthritic and normal cartilage (fold change>1.5). Similar to the comparisons between cartilage layers, different expression patterns were found for osteoarthritic and control cartilage. The expression pattern for osteoarthritic cartilage was similar for the 2 cartilage layers, but changes in expression were more pronounced in the deeper compared to the superficial layer. The gene expression pattern in osteoarthritic chondrocytes indicated the activation of the pro-inflammatory, catabolic NF-κB pathway. It further suggested an increased response to stress, but decreased ability to resist cell death, as well as down-regulation of genes involved in proteoglycan synthesis and energy production compared to control cartilage.
 
This study was the first to determine gene expression patterns between 2 different layers of osteoarthritic and control articular cartilage. The present results improve our knowledge of spatial dependence of chondrocyte metabolism and its alterations under the influence of osteoarthritis. They provide the basis for future research into the pathophysiology of osteoarthritis and to identify new therapeutic targets for the treatment of this debilitating disease. These research efforts are on-going with support from Dr Düsterdieck and under the guidance of Dr David Frisbie.
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