Richard Read

These investigations into the effect of tetrathiomolybdate (TTM) on bone and cartilage development in the growing dog were initiated after similarities were noted between the radiographic appearance of bone lesions in TTM-treated rats and hypertrophic osteodystrophy (HOD) in dogs. HOD is a bone disease of unknown aetiology which affects young, large breed dogs. Copper deficiency frequently causes thickening of the growth plate cartilage and osteoporosis in the bones of many species. However, the type and severity of the bone lesions vary considerably between and within species. TTM is believed to exert its effects by antagonising copper and causing a functional deficiency of this trace element. The effects of TTM on the growth plate cartilage and bone morphology of dogs were examined in detail and the lesions compared with cases of HOD. The oral administration of TTM induced several signs of copper deficiency, including depletion of plasma and liver copper concentrations and depressed activity of copper-dependent enzymes. This technique of inducing copper deficiency allowed greater control over the severity of the bone lesions than would have been possible with copper-deficient diets. Lesions in bone were examined by radiography, gross pathology and histopathology. Bone metabolism and osteoporosis were investigated by histomorphometry, tetracycline bone labelling, bone ashing and bone densitometry. The growth plate cartilage matrix was examined by analysis of collagen and proteoglycan content and in vitro culture of chondrocytes. In thiomolybdate-treated dogs, the growth plate cartilage was thickened due to disordered provisional calcification associated with changes in the collagen and proteoglycans of the chondroid matrix. In addition, osteoporosis developed due to suppression of osteoblast activity. The histologic appearance of the lesions did not resemble that seen in the clinical disease HOD. It was concluded that TTM reduces the copper status of dogs and thereby causes changes in the matrix of the growth plate cartilage which affect the orderly progression of provisional calcification. Osteoporosis occurs due to decreased osteoblastic bone formation. The lesions were not typical of those seen in HOD.