Iron overload causes osteoporosis in thalassemia major patients through interaction with transient receptor potential vanilloid type 1 (TRPV1) channels.

Abstract

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, it may be instructive to examine a potential role for this system in the development of osteoporosis in patients with β-thalassemia major and its relationship with iron overload and iron chelation therapy. 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 influences tartrate-resistant acid phosphatase expression and activity, and this effect is dependent on iron, suggesting a pivotal role for iron overload in the dysregulation of bone metabolism in patients with thalassemia major. 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 -preventing iron-overload and alleviating associated osteoporotic changes - is exciting.

• Authors: Francesca Rossi, Silverio Perrotta, Giulia Bellini, Livio Luongo, Chiara Tortora, Dario Siniscalco, Matteo Francese, Marco Torella, Bruno Nobili, Vincenzo Di Marzo, Sabatino Maione
• Journal: Haematologica (Haematologica) Vol. 99 Issue 12 Pg. 1876-84 (Dec 2014) ISSN: 1592-8721 [Electronic] Italy
• PMID: 25216685 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© Ferrata Storti Foundation.

Chemical References

• Biomarkers
• Iron Chelating Agents
• Isoenzymes
• RNA, Messenger
• Receptor, Cannabinoid, CB1
• Receptor, Cannabinoid, CB2
• TRPV Cation Channels
• TRPV1 protein, human
• Acid Phosphatase
• Tartrate-Resistant Acid Phosphatase
• Cathepsin K

Topics

• Acid Phosphatase (genetics, metabolism)
• Adult
• Biomarkers (metabolism)
• Blotting, Western
• Case-Control Studies
• Cathepsin K (genetics, metabolism)
• Cells, Cultured
• Female
• Fluorescent Antibody Technique
• Follow-Up Studies
• Humans
• Iron Chelating Agents (pharmacology)
• Iron Overload (physiopathology)
• Isoenzymes (genetics, metabolism)
• Male
• Osteoclasts (cytology, drug effects, metabolism)
• Osteoporosis (drug therapy, etiology, metabolism)
• Prognosis
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Receptor, Cannabinoid, CB1 (genetics, metabolism)
• Receptor, Cannabinoid, CB2 (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• TRPV Cation Channels (genetics, metabolism)
• Tartrate-Resistant Acid Phosphatase
• beta-Thalassemia (complications, metabolism)