Mutations Can't Go All The Way In Paget Disease

Paget disease is a bone disease that results in enlarged bones and causes bone pain, arthritis, deformities, and fractures. It mostly affects individuals over the age of 40 and has a hereditary component. One gene that is mutated in approximately one third of patients with hereditary Padget disease is p62 (sequestosome 1). However, it has not been clear whether mutations (such as the common p62P392L mutation) in this gene actually cause Paget disease.

In a study appearing online in advance of publication in the January print issue of the Journal of Clinical Investigation, Noriyoshi Kurihara and colleagues from the VA Pittsburgh Healthcare System show that expression of the p62P392L mutation causes abnormal development of human bone cells in vitro and mouse bone cells in vivo but does not cause a Padget-like disease in mice. Specifically, expression of p62P392L in the precursors of human bone cells known as osteoclasts (the cells that destroy bone) caused them to be more responsive to factors that drive osteoclast development. Similarly, expression of p62P392L in osteoclast-lineage cells in mice resulted in increased numbers of osteoclasts. Although increased numbers of osteoclasts is a feature of Paget disease, it is not the full range of characteristics. This study therefore suggests that although mutations in p62 predispose an individual to developing Paget disease, other factors are required for the full development of Paget disease.

TITLE: Mutation of the sequestosome 1 (p62) gene increases osteoclastogenesis but does not induce Paget disease

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JCI table of contents: Dec. 21, 2006

AUTHOR CONTACT:
Noriyoshi Kurihara
VA Pittsburgh Healthcare System and University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Contact: Karen Honey
Journal of Clinical Investigation