Effects of deferoximine on chondrocyte alkaline phosphatase activity: Proxidant role of deferoximine in thalassemia

Abstract

The homozygous form of beta-thalassemia, the most common single gene disorder, is treated by red cell transfusion therapy. Following transfusion, the chelator, deferoximine, is administered to patients to remove excess iron. However, when this drug is given to young children, metaphyseal dysplasia and abnormalities of linear growth are frequently observed. To explore the notion that deferoximine interferes with endochondral growth by chelating zinc, we examined the effect of the drug on chondrocytes maintained in long-term culture. We found that deferoximine caused a dose-dependent inhibition of a wide range of functions including cell proliferation, protein synthesis (and possibly under-hydroxylation of type X collagen), and mineral deposition. Directly relevant to the mineralization process was the observation that the drug dramatically lowered the activity of alkaline phosphatase, a zinc-requiring enzyme. To test the hypothesis that enzyme inhibition was due to chelation of zinc by deferoximine, the cell culture medium was supplemented with excess zinc. However, this treatment did not overcome the deferoximine-dependent change in enzyme activity. We next examined the possibility that deferoximine, in the presence of ascorbate, could form a free radical system that would serve to inactivate the enzyme. Using alkaline phosphatase extracted from chick cartilage, we noted that the activity of the phosphatase was markedly reduced in the presence of deferoximine and ascorbate. These effects were consistant with the notion that deferoximine and ascorbate can act as a prooxidant couple. This conclusion was confirmed when we measured the oxidative activities of the system using nitrobule tetrazolium and cytochrome c. Indeed, we noted that deferoximine markedly activates the autocatalytic oxidation of ascorbate.(ABSTRACT TRUNCATED AT 250 WORDS)

Short stature and failure of pubertal development in thalassaemia major: evidence for hypothalamic neurosecretory dysfunction of growth hormone secretion and defective pituitary gonadotropin secretion

“…De Sanctis et al [10] observed an inverse correlation between sitting height and ferritin values in thalassaemic patients with low haemoglobin levels and a late start of chelation therapy at adolescence. However, growth retardation and bone abnormalities have also been described in patients who were started on high-dose chelation therapy in the ®rst years of life [12,14,25].…”

Bone Metabolism in Thalassemiaa

“…Iron chelation has been correlated to growth failure and bone abnormalities, 14,15 and a high desferrioxamine dosage has been indicated as the main factor 16,17 of cartilage alterations. We actually found an inverse correlation between height velocity and DF dosages, but this was surprising, as the dose range we have been prescribing for 12 years is considered safe, and it has been chosen mainly to prevent desferrioxamine side effects.…”

Bone Disease in Haemoglobin Disorders

“…The typical delay in sexual maturation, the presence of diabetes and hypothyroidism, the parathyroid gland dysfunction, the accelerated haemopoiesis with progressive marrow expansion, the direct iron toxicity on osteoblasts and the deficiency of growth hormone (GH) or insulin growth factor I (IGF-I) have been indicated as possible causes for thalassemia-induced osteoporosis (2-4). Furthermore, iron chelation has correlated with growth failure and bone abnormalities, and high desferrioxamine dosage has been associated with cartilage alterations (5,6). More puzzling, however, is the observation that, despite the normalization of haemoglobin levels, adequate hormone replacement, and effective iron chelation, patients continue to show an unbalanced bone turnover with an increased resorptive phase resulting in seriously diminished bone mineral density (BMD) (7,8).…”