title: 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.affiliation: Department of Woman, Child and of General and Specialist Surgery, Second University of Naples;
authors.forename: Francesca
authors.initials: F
authors.lastname: Rossi
authors.affiliation: Department of Woman, Child and of General and Specialist Surgery, Second University of Naples; silverio.perrotta@unina2.it.
authors.forename: Silverio
authors.initials: S
authors.lastname: Perrotta
authors.affiliation: Department of Experimental Medicine, Second University of Naples;
authors.forename: Giulia
authors.initials: G
authors.lastname: Bellini
authors.affiliation: Department of Experimental Medicine, Second University of Naples;
authors.forename: Livio
authors.initials: L
authors.lastname: Luongo
authors.affiliation: Department of Woman, Child and of General and Specialist Surgery, Second University of Naples; Department of Experimental Medicine, Second University of Naples;
authors.forename: Chiara
authors.initials: C
authors.lastname: Tortora
authors.affiliation: Department of Experimental Medicine, Second University of Naples;
authors.forename: Dario
authors.initials: D
authors.lastname: Siniscalco
authors.affiliation: Department of Woman, Child and of General and Specialist Surgery, Second University of Naples;
authors.forename: Matteo
authors.initials: M
authors.lastname: Francese
authors.affiliation: Department of Woman, Child and of General and Specialist Surgery, Second University of Naples;
authors.forename: Marco
authors.initials: M
authors.lastname: Torella
authors.affiliation: Department of Woman, Child and of General and Specialist Surgery, Second University of Naples;
authors.forename: Bruno
authors.initials: B
authors.lastname: Nobili
authors.affiliation: Institute of Biomolecular Chemistry and Institute of Cybernetics, National Research Council, Pozzuoli; and The Endocannabinoid Research Group, Pozzuoli, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.affiliation: Department of Experimental Medicine, Second University of Naples; The Endocannabinoid Research Group, Pozzuoli, Italy.
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
mesh_terms: D000135:Acid Phosphatase / Q000235:genetics / Q000378:metabolism; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology; D019190:Iron Overload / Q000503:physiopathology*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010024:Osteoporosis / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D000071681:Tartrate-Resistant Acid Phosphatase; D017086:beta-Thalassemia / Q000150:complications* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D007502:Iron Chelating Agents; D007527:Isoenzymes; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D056657:Cathepsin K