Inherited rickets in Corriedale sheep : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Massey University, Palmerston North, New Zealand

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Massey University
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Inherited rickets of Corriedale sheep is a newly discovered skeletal disease of sheep with simple autosomal recessive inheritance. The clinical signs resemble rickets in other species and include decreased growth rate, thoracic lordosis and angular limb deformities. Radiographic features include physeal thickening, blurred metaphyseal trabeculae and thickened porous cortices. Computed tomography scanning of long bones reveals increased bone mineral content and cortical area, but decreased bone mineral density. Gross lesions include segmental thickening of physes, growth arrest lines, collapse of subchondral bone of the humeral head, thickened cortices and enthesophytes around distal limb joints. Microscopically there is persistence of hypertrophic chondrocytes at sites of endochondral ossification, inappropriate and excessive osteoclastic resorption, microfractures and wide, unmineralised osteoid seams lining trabeculae and filling secondary osteons. Affected sheep are persistently hypophosphataemic and hypocalcaemic. Normal serum 25-hydroxyvitamin D3 concentration accompanied by a two-fold elevation in 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) suggested a defect in endorgan responsiveness to vitamin D as a likely mechanism, but this was not supported by in vitro studies using cultured skin fibroblasts. These studies revealed normal vitamin D receptor function and the presence of 24- hydroxylase mRNA in cells from affected sheep, even without induction by 1,25(OH)2D3. Inappropriate overexpression of 25-hydroxyvitamin D3-24- hydroxylase, the enzyme that breaks down active vitamin D, is therefore considered the probable cause of inherited rickets in Corriedale sheep. Such a mechanism has not previously been described as a cause of inherited rickets in humans or other animal species. Treatment of affected sheep with high oral doses of vitamin D3 weekly for 3 months showed a trend towards increased bone mineral density, thus supporting an intact vitamin D receptor. Preliminary studies on immune function revealed reduced numbers of CD4+ and CD8+ lymphocytes and reduced interferon-? production by lymphocytes stimulated with parasite antigen. This new form of inherited rickets may be widespread in
Skeletal disease, Vitamin D