P aget disease is the most exaggerated example of abnormal bone remodeling, with the primary cellular abnormality in the osteoclast. Mutations in the p62 (sequestosome 1) gene occur in one-third of patients with familial Paget disease and in a minority of patients with sporadic Paget disease, with the P392L amino acid substitution being the most commonly observed mutation. However, it is unknown how p62^P392L mutation contributes to the development of this disease. To determine the effects of p62^P392L expression on osteoclasts in vitro and in vivo, we introduced either the p62^P392L or WT p62 gene into normal osteoclast precursors and targeted p62^P392L expression to the osteoclast lineage in transgenic mice. p62^P392L-transduced osteoclast precursors were hyperresponsive to receptor activator of NF-κB ligand (RANKL) and TNF-α and showed increased NF-κB signaling but did not demonstrate increased 1,25-(OH)₂D₃ responsivity, TAF_II-17 expression, or nuclear number per osteoclast. Mice expressing p62^P392L developed increased osteoclast numbers and progressive bone loss, but osteoblast numbers were not coordinately increased, as is seen in Paget disease. These results indicate that p62^P392L expression on osteoclasts is not sufficient to induce the full pagetic phenotype but suggest that p62 mutations cause a predisposition to the development of Paget disease by increasing the sensitivity of osteoclast precursors to osteoclastogenic cytokines.