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Infantile Malignant, Autosomal Recessive Osteopetrosis: The Rich and The Poor

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Abstract

Human recessive osteopetrosis (ARO) represents a group of diseases in which, due to a defect in osteoclasts, bone resorption is prevented. The deficit could arise either from failure in osteoclast differentiation or from inability to perform resorption by mature, multinucleated, but nonfunctional cells. Historically, osteopetrosis due to both these mechanisms was found in spontaneous and artificially created mouse mutants, but the first five genes identified in human ARO (CA-II, TCIRG1, ClCN7, OSTM1, and PLEKHM1) were all involved in the effector function of mature osteoclasts, being linked to acidification of the cell/bone interface or to intracellular processing of the resorbed material. Differentiation defects in human ARO have only recently been described, following the identification of mutations in both RANKL and RANK, which define a new form of osteoclast-poor ARO, as expected from biochemical, cellular, and animal studies. The molecular dissection of ARO has prognostic and therapeutic implications. RANKL-dependent patients, in particular, represent an interesting subset which could benefit from mesenchymal cell transplant and/or administration of soluble RANKL cytokine.

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Acknowledgments

This work was supported by grants from the Fondazione Telethon to C.S. (Grant GGP08176), from ISS Malattie Rare (New Cell Therapy Approaches for Infantile Malignant Osteopetrosis) and E-Rare Project JTC 2007 OSTEOPETR to A.V., and from Progetto Strategico, Ricerca Finalizzata 2007, Ministry of Health, to I.C.H. The work reported in this paper has also been funded by the NOBEL (Network Operativo per la Biomedicina di Eccellenza in Lombardia) Program from Fondazione Cariplo to A.V. The technical assistance of Maria Elena Caldana and Lucia Susani is acknowledged.

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Villa, A., Guerrini, M.M., Cassani, B. et al. Infantile Malignant, Autosomal Recessive Osteopetrosis: The Rich and The Poor. Calcif Tissue Int 84, 1–12 (2009). https://doi.org/10.1007/s00223-008-9196-4

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  • DOI: https://doi.org/10.1007/s00223-008-9196-4

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