Abstract
Inflammation is a complex cellular and humoral response against trauma and infection, and its presence leads to destruction of tissue in humans. The mechanisms that initiate inflammatory diseases remain largely unknown because of complex interactions between multiple genetic and environmental factors during pathogenesis. Animal models for human diseases offer dissection of complex pathogenesis by inbred genetic backgrounds and controlled circumstances. In this article we report a chemically induced new mutation, Ali18 (Abnormal limb), as a mouse model for inflammatory arthritis and dermatitis. Ali18/+ mice exhibit rubor and swelling of footpads in hindlimbs in adults. In Ali18/Ali18 mice, the digits in forelimbs and hindlimbs and tails were necrotic and/or deformed by severe swelling. Histologic analysis revealed infiltration of mixed populations of inflammatory cells into bone marrow, peripheral joints, and skin in the affected areas of Ali18/Ali18 mice. In addition, generalized osteoporosis-like phenotypes were confirmed by dual energy X-ray absorptiometry (DXA), microcomputed tomography (μCT), and peripheral quantitative computed tomography (pQCT) in homozygous animals. Whereas the Ali18 mutation was mapped to a single locus, the phenotype presentation was altered by complex modifier effects from other inbred genetic backgrounds. Detailed analysis of the Ali18 phenotype and identification of the mutation and its modifier genes may provide molecular insights into the complex nature of inflammatory diseases and the relationship between inflammation and bone metabolism.
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Acknowledgments
The authors thank S. Manz and M. Schultz for the genotyping work; R. Seeliger and S. Wittich for DXA and CT analyses; Drs. K. Imai, G. Michel, and V. Blanquet for reagents and helpful discussions; and Dr. J. Favor for critical comments on the manuscript. We are also grateful to D. Soewarto, Dr. S. Wagner, A. Mayer, S. Hoffmann, and members of ENU mutagenesis core facility for production and maintenance of the Ali18 strain. This work was supported by grants from the Deutsches Humangenom Projekt (DHGP), the Nationales Genomforschungsnetz (NGFN), and ANABONOS (EU contract no: LSHM-CT-2003-503020) to M. HdA.
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Abe, K., Fuchs, H., Lisse, T. et al. New ENU-induced semidominant mutation, Ali18, causes inflammatory arthritis, dermatitis, and osteoporosis in the mouse. Mamm Genome 17, 915–926 (2006). https://doi.org/10.1007/s00335-006-0014-x
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DOI: https://doi.org/10.1007/s00335-006-0014-x