Paget's disease is a chronic skeletal disease characterized by abnormally rapid bone turnover. Little is known about the causative agents, etiology or pathogenesis of the disease except for a possible link with slow virus infection. Bone pathology identified in mice that are transgenic for the human T lymphotropic virus I (HTLV-1 trans acting gene tax includes a very high and coupled bone turnover, reminiscent of Paget's disease. HTLV-I is associated in humans with activation of lymphotoxin (LT, TNF-beta) and GM-CSF, two cytokines associated with bone cell activation. Preliminary evidence tax mice suggests that cytokine gene activation occurs. The hypothesis to be tested is that the presence of the tax gene activates bone cells or induces increased production of a specific set of cytokines which result in accelerated bone turnover with increased osteoblast and osteoclast activity. The pathophysiology of high bone turnover of tax mice will be characterized by biochemical and hormone analysis, histomorphometry, and ultrastructure. Calcitonin will be administered. The mechanisms by which high bone turnover is induced in HTLV-I tax mice will be analyzed by evaluating osteoblast and osteoclast functional characteristic and differentiation. Tax mice will be analyzed for increased cytokine production (LT, TNF-a IL-1, IL-2, IL-4, GM-CSF, IL-6, PTHrP) by standard biological assays and by their ability to activate osteoblasts and osteoclasts. The cellular origin of increased cytokine production will be determined and correlated with expression of the Tax protein by Western and Northern blot analysis. The molecular mechanism of activation of cytokines contributing to high bone turnover in tax mice will be evaluated using LT as a model, by transfection of constructs consisting of LT 5' sequences driving expression of a bacterial reporter gene, chloramphenicol acetyl transferase into Tax expressing cell lines. LT 5' sequence activation will be evaluated by crossing LTCAT transgenic mice with tax mice. Additional transgenics will be prepared to allow further analysis of the LT gene, and other cytokine genes induced in tax mice. The accomplishments of these goals could help in understanding the pathogenesis of Paget's disease and the mechanism by which viral genes can induce high bone turnover, and will also contribute to basic understanding concerning the mechanism of trans activation of cytokine genes.
| Paul, N L; Millet, I; Ruddle, N H (1993) The lymphotoxin promoter is stimulated by HTLV-I tax activation of NF-kappa B in human T-cell lines. Cytokine 5:372-8 |
| Ruddle, N H; Li, C B; Horne, W C et al. (1993) Mice transgenic for HTLV-I LTR-tax exhibit tax expression in bone, skeletal alterations, and high bone turnover. Virology 197:196-204 |
