Genetically segregating crosses and positional cloning in animal models

Cure Arthritis Naturally

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One way of overcoming many of the problems that are mentioned in correlation with linkage studies in human populations could be solved by the use of animal models for identification of arthritis regulating genes.

For studies of arthritis, there exist several animal models. The most common model of arthritis is induced both in mice [41] and in rats [42] with collagen type II emulsified in incomplete Freund's adjuvant (i.e., mineral oil) or complete Freund's adjuvant (i.e., mycobacteria cell walls in mineral oil). Besides the arthritis induced with cartilage specific proteins like the type II collagen induced arthritis (CIIIA) [41, 42], type XI collagen induced arthritis (CIXIA) [43] or the cartilage oligomeric matrix protein induced arthritis (COMPIA) [44], it is also possible to induce arthritis with mycobacterium emulsified in adjuvant (MIA), or for that matter even with mineral oil only (oil induced arthritis, OIA) or with synthetic adjuvants like pristane (pristane induced arthritis, PIA) [45-50]. All models of arthritis in mice and rats have different characteristics and upon comparison with criteria used for diagnosing RA [51] it is clear that the consensus knowledge of all these models can be used to study most aspects of RA.

There are several advantages in using animal models to study the genetic contribution in complex diseases. Firstly, many animals can be used in a single study where the environment is controlled. Secondly, inbred strains can be crossed using defined crossing procedures to provide controlled genetic segregation in the offspring in order to identify chromosomal regions, or even genes which regulate the disease. Thirdly, the function of identified chromosomal regions or isolated genes can be extensively studied by several techniques, for example transfer of bone marrow or inflammatory cells, as well as various treatments both preventive and therapeutic. Finally also, once a new drug target has been identified in one inbred animal strain, a direct proof of concept experiment can be designed in these animals to target the pathway by new treatment regimes. Such experiments performed in these well characterised and recognised arthritis models will strengthen further drug development into clinical trials.

Inbred rat and mouse strains have normally been inbred for at least 20 generations, which means that all loci are homozygous within each species, and there are several inbred strains that are either susceptible or resistant to a specific form of arthritis.

After the identification of significant QTL that regulates a specific arthritic condition in the animals it is easy, but time-consuming, to isolate the genomic region of interest in a congenic strain [52]. Established congenic strains in comparison with the parental strains could be used for 1) fine mapping of a genetic region by the creation of further recombinations; 2) comparative sequencing to identify polymorphisms; 3) expression analysis of selected proteins or mRNA; 4) functional studies of identified candidate genes.

Then again, when analysing genetic regulation of arthritis in animal models one must keep in mind the evolutionary difference between man and rodents, as well as the fact that an animal model of RA is not the same as the human disease. Hence, the most important finding, obtained from positional cloning of arthritis regulating genes in animal models, for future studies of RA is not the identified genes per se, but rather the identification of previously unknown pathological mechanisms and pathways of disease regulation. Since the first publication, in 1996, of genetic linkage analysis of CIA in rats [53] and mice [54, 55], studies of linkage analysis of arthritis in rats has been ongoing using various models of arthritis and different inbred mouse and rat strains (reviewed in [56-58]).

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