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

Abstract

Paget 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) 2 D 3 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.

Measles virus nucleocapsid protein increases osteoblast differentiation in Paget’s disease

“…To determine whether ephrinB2 was increased in PD patients, we tested OCL precursors from PD patients who harbored the p62 P392L mutation and did or did not express MVNP (12,13,23). To circumvent the difficulty of obtaining marrow samples from PD patients, we assayed ephrinB2 expression in OCL precursors isolated from the peripheral blood of PD patients who we previously confirmed did or did not express MVNP in their marrow-derived OCLs and compared these OCL precursors with those from 2 age-matched controls.…”

SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone

“…However, several clinical and experimental observations raised the hypothesis that other genes and/or environmental triggers are necessary to cause the disease, at least in some cases. (2,20,21,23,(32)(33)(34) In this study we report the results of the largest SQSTM1 mutation screening performed to date in consecutive familial and sporadic PDB patients.…”

“…(19) This is in keeping with results from experimental animal models of PDB. (2,23,24) Marked geographic differences in the distribution of PDB also have been described, with a higher prevalence of the disease in populations of British descent. (25) Moreover, increased-prevalence areas have been described in different countries.…”

Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice

“…Furthermore, the Cyld -/-mice only had a weak increase in serum concentration of osteocalcin, an indicator of osteoblast activity (Supplemental Figure 1B). Thus, as seen with mice expressing a p62 mutant (18), the Cyld -/-mice have abnormalities predominantly in OCs, leading to osteoporosis.…”

“…Complete loss of p62 attenuates RANK signaling and osteoclastogenesis (14). On the other hand, mutations of p62 that disrupt its C-terminal ubiquitin association (UBA) domain cause aberrant RANK signaling and hyperproduction of OCs (3,(15)(16)(17)(18). Such genetic alterations of p62 are etiologically associated with development of Paget disease of bone (PDB), a severe bone disorder characterized by formation of giant OCs, excessive bone resorption, and irregular bone formation (15,19,20).…”