Journal ArticleDOI
Osteopetrosis: genetics, treatment and new insights into osteoclast function
TLDR
The genetics of ARO are described, the diagnostic role of next-generation sequencing methods are discussed and novel treatments, including preclinical data on in utero stem cell treatment, RANKL replacement therapy and denosumab therapy for hypercalcaemia are discussed.Abstract:
Osteopetrosis is a genetic condition of increased bone mass, which is caused by defects in osteoclast formation and function. Both autosomal recessive and autosomal dominant forms exist, but this Review focuses on autosomal recessive osteopetrosis (ARO), also known as malignant infantile osteopetrosis. The genetic basis of this disease is now largely uncovered: mutations in TCIRG1, CLCN7, OSTM1, SNX10 and PLEKHM1 lead to osteoclast-rich ARO (in which osteoclasts are abundant but have severely impaired resorptive function), whereas mutations in TNFSF11 and TNFRSF11A lead to osteoclast-poor ARO. In osteoclast-rich ARO, impaired endosomal and lysosomal vesicle trafficking results in defective osteoclast ruffled-border formation and, hence, the inability to resorb bone and mineralized cartilage. ARO presents soon after birth and can be fatal if left untreated. However, the disease is heterogeneous in clinical presentation and often misdiagnosed. This article describes the genetics of ARO and discusses the diagnostic role of next-generation sequencing methods. The management of affected patients, including guidelines for the indication of haematopoietic stem cell transplantation (which can provide a cure for many types of ARO), are outlined. Finally, novel treatments, including preclinical data on in utero stem cell treatment, RANKL replacement therapy and denosumab therapy for hypercalcaemia are also discussed.read more
Citations
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Journal ArticleDOI
Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells
Rinaldo Florencio-Silva,Gisela Rodrigues da Silva Sasso,Estela Sasso-Cerri,Manuel Simões,Paulo Sérgio Cerri +4 more
TL;DR: Current data about the structure and functions of bone cells and the factors that influence bone remodeling are discussed, indicating the dynamic nature of bone tissue.
Journal ArticleDOI
V‐ATPase Interacts with ARNO and Arf6 in Early Endosomes and Regulates the Protein Degradative Pathway
Andrés Hurtado-Lorenzo,Mhairi A. Skinner,Jaafar El Annan,Masamitsu Futai,Ge-Hong Sun-Wada,Sylvain G. Bourgoin,James E. Casanova,Alan G. Wildeman,Dennis A. Ausiello,Dennis Brown,Vladimir Marshansky +10 more
TL;DR: In this paper, the authors demonstrate that the recruitment of the small GTPase Arf6 and ARNO from cytosol to endosomal membranes is driven by V-ATPase-dependent intra-endosomal acidification.
Journal ArticleDOI
Osteoblast-Osteoclast Communication and Bone Homeostasis
TL;DR: The current knowledge regarding membrane bound- and soluble factors governing cross-talk between osteoblasts and osteoclasts is reviewed.
Journal ArticleDOI
Osteoclasts: more than ‘bone eaters’
TL;DR: This work considers how osteoclast signals may contribute to bone formation by osteoblasts and to the pathology of bone lesions such as fibrous dysplasia and giant cell tumors and reviews the interaction of osteoclasts with the hematopoietic system, including the stem cell niche and adaptive immune cells.
References
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Journal ArticleDOI
Osteoprotegerin Ligand Is a Cytokine that Regulates Osteoclast Differentiation and Activation
David L. Lacey,Emma Timms,Hong-Lin Tan,Michael J. Kelley,Colin R. Dunstan,Tim Burgess,Robin Elliott,Anne Colombero,Gary Elliott,S. Scully,Hailing Hsu,John K. Sullivan,Nessa Hawkins,E. Davy,C. Capparelli,Alana Eli,Yi-xin Qian,Steve Kaufman,Ildiko Sarosi,Victoria Shalhoub,Giorgio Senaldi,Jane Guo,John M. Delaney,William J. Boyle +23 more
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TL;DR: The past five years have witnessed important insights into osteoclast formation and function and many of these discoveries have been made through genetic experiments that involved the rare hereditary disorder osteopetrosis.
Journal ArticleDOI
Genetic diagnosis by whole exome capture and massively parallel DNA sequencing
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The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption.
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