The pathogenesis of bone resorption in β-Thalassemia Major is multifactorial and our understanding of the underlying molecular and cellular mechanisms remains incomplete. Considering the emerging importance of the endocannabinoid/endovanilloid system in bone metabolism, examining a potential role for this system in the development of osteoporosis in β-Thalassemia Major and its relationship with iron overload and iron chelation therapy is warranted. This study demonstrates that, in thalassemic-derived osteoclasts, Tartrate-resistant Acid Phosphatase expression inversely correlates with femoral and lumbar bone mineral density, and directly correlates with ferritin levels and liver iron concentration. The vanilloid agonist resiniferatoxin dramatically reduces cathepsin K levels and osteoclast numbers in vitro, without affecting Tartrate-resistant Acid Phosphatase expression. The iron chelators deferoxamine, deferiprone and deferasirox decrease both Tartrate-resistant Acid Phosphatase and cathepsin K expression, as well as osteoclast activity. Taken together, these data show that Transient Receptor Potential Vanilloid type 1 activation/desensitization influence Tartrate-resistant Acid Phosphatase expression and activity, and this is dependent on iron, suggesting a pivotal role for iron overload in the dysregulation of bone metabolism in Thalassemia Major patients. Our applied pharmacology provides evidence for the potential of iron chelators to abrogate these effects by reducing osteoclast activity. Whether iron chelation therapy is capable of restoring bone health in humans requires further study, but the potential to provide dual benefits for patients with β-Thalassemia Major, in respect to preventing iron-overload and alleviating associated osteoporotic changes is exciting indeed.
Copyright © 2014, Ferrata Storti Foundation.