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Clinical, genetic, and cellular analysis of 49 osteopetrotic patients: implications for diagnosis and treatment
  1. A Del Fattore1,
  2. B Peruzzi1,
  3. N Rucci1,
  4. I Recchia1,
  5. A Cappariello2,
  6. M Longo1,
  7. D Fortunati1,
  8. P Ballanti3,
  9. M Iacobini4,
  10. M Luciani5,
  11. R Devito5,
  12. R Pinto5,
  13. M Caniglia5,
  14. E Lanino6,
  15. C Messina7,
  16. S Cesaro7,
  17. C Letizia8,
  18. G Bianchini8,
  19. H Fryssira9,
  20. P Grabowski10,
  21. N Shaw10,
  22. N Bishop10,
  23. D Hughes10,
  24. R P Kapur11,
  25. H K Datta12,
  26. A Taranta1,
  27. R Fornari13,
  28. S Migliaccio13,
  29. A Teti1
  1. 1Department of Experimental Medicine, University of L’Aquila, L’Aquila, Italy
  2. 2Department of Pediatric Medicine, Ospedale Bambino Gesù, Rome, Italy
  3. 3Department of Experimental Medicine and Pathology, University “La Sapienza”, Rome, Italy
  4. 4Department of Pediatrics, University “La Sapienza”, Rome, Italy
  5. 5Division of Haematology, Ospedale Pedriatico Bambino Gesù, Rome, Italy
  6. 6Department of Pediatric Haematology and Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Giannina Gaslini, Genoa, Italy
  7. 7Clinic of Pediatric Haematology and Oncology, Department of Pediatrics, University of Padua, Padua, Italy
  8. 8Department of Clinical Science, Division of Internal Medicine, University “La Sapienza”, Rome, Italy
  9. 9Department of Medical Genetics, University of Athens, Athens, Greece
  10. 10Academic Unit of Child Health, University of Sheffield, Sheffield, UK
  11. 11Department of Pathology, Children’s Hospital and Regional Medical Center, Seattle, WA, USA
  12. 12School of Clinical and Laboratory Sciences, The Medical School, Framlington Place, University of Newcastle, Newcastle upon Tyne, UK
  13. 13Department of Medical Physiopathology, University “La Sapienza”, Rome, Italy
  1. Correspondence to:
 Professor Anna Teti
 Department of Experimental Medicine, Via Vetoio – Coppito 2, 67100 L’Aquila, Italy; teti{at}


Background: Osteopetrosis, a genetic disease characterised by osteoclast failure, is classified into three forms: infantile malignant autosomal recessive osteopetrosis (ARO), intermediate autosomal recessive osteopetrosis (IRO), and autosomal dominant osteopetrosis (ADO).

Methods: We studied 49 patients, 21 with ARO, one with IRO, and 27 with type II ADO (ADO II).

Results: Most ARO patients bore known or novel (one case) ATP6i (TCIRG1) gene mutations. Six ADO II patients had no mutations in ClCN7, the only so far recognised gene implicated, suggesting involvement of yet unknown genes. Identical ClCN7 mutations produced differing phenotypes with variable degrees of severity. In ADO II, serum tartrate resistant acid phosphatase was always elevated. Bone alkaline phosphatase (BALP) was generally low, but osteocalcin was high, suggesting perturbed osteoblast differentiation or function. In contrast, BALP was high in ARO patients. Elevated osteoclast surface/bone surface was noted in biopsies from most ARO patients. Cases with high osteoclasts also showed increased osteoblast surface/bone surface. ARO osteoclasts were morphologically normal, with unaltered formation rates, intracellular pH handling, and response to acidification. Their resorption activity was greatly reduced, but not abolished. In control osteoclasts, all resorption activity was abolished by combined inhibition of proton pumping and sodium/proton antiport.

Conclusions: These findings provide a rationale for novel therapies targeting pH handling mechanisms in osteoclasts and their microenvironment.

  • ADO, autosomal dominant osteopetrosis
  • ARO, autosomal recessive osteopetrosis
  • BALP, bone alkaline phosphatase
  • CA II, carbonic anhydrase II
  • EIPA, 5-(N-ethyl-N-iso-propyl)-amiloride
  • IRO, intermediate autosomal recessive osteopetrosis
  • M-CSF, macrophage colony stimulating factor
  • Ob.S/BS, osteoblast surface/bone surface
  • Oc.S/BS, osteoclast surface/bone surface
  • OSCA, osteocalcin
  • PTH, parathyroid hormone
  • RANKL, receptor activator of NF-κB ligand
  • TRAcP, tartrate resistant acid phosphatase
  • V-H+ATPase, vacuolar H+ATPase
  • ATP6i/TCIRG1 gene
  • ClCN7 gene
  • osteoblast
  • osteoclast
  • osteopetrosis

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  • Published Online First 23 August 2005

  • This work was supported by Telethon grant #E.0831 and by FIRB (Fondo per gli Investimenti per la Ricerca di Base) grant #RBAUO1X3NH to AT. This work was also partially supported by grant “Ricerca Corrente” #2003/02/P001132 to the Division of Haematology, Ospedale Pedriatico Bambino Gesù, Rome, Italy

  • Competing interests: none declared