The p62 P392L Mutation Linked to Paget’s Disease Induces Activation of Human Osteoclasts

Mutations of the gene encoding p62/SQSTM1 have been described in Paget’s disease of bone (PDB), identifying p62 as an important player in osteoclast signaling. We investigated the phenotype of osteoclasts differentiated from peripheral blood monocytes obtained from healthy donors or PDB patients, al...

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Bibliographic Details
Published in:Molecular endocrinology (Baltimore, Md.) Md.), 2009-10, Vol.23 (10), p.1668-1680
Main Authors: Chamoux, Estelle, Couture, Julie, Bisson, Martine, Morissette, Jean, Brown, Jacques P, Roux, Sophie
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Aged
Aged, 80 and over
Amino Acid Substitution - drug effects
Amino Acid Substitution - genetics
Apoptosis - drug effects
Cells, Cultured
Female
Humans
Leukocytes, Mononuclear - drug effects
Leukocytes, Mononuclear - metabolism
Male
Middle Aged
Mutation - genetics
NF-kappa B - metabolism
Original Research
Osteitis Deformans - genetics
Osteitis Deformans - pathology
Osteoclasts - drug effects
Osteoclasts - enzymology
Osteoclasts - metabolism
Osteoclasts - pathology
Phenotype
Protein Binding - drug effects
Protein Kinase C - metabolism
RANK Ligand - pharmacology
Sequestosome-1 Protein
Signal Transduction - drug effects
Transfection
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Summary:Mutations of the gene encoding p62/SQSTM1 have been described in Paget’s disease of bone (PDB), identifying p62 as an important player in osteoclast signaling. We investigated the phenotype of osteoclasts differentiated from peripheral blood monocytes obtained from healthy donors or PDB patients, all genotyped for the presence of a mutation in the p62 ubiquitin-associated domain. The cohort included PDB patients carrying or not the p62 P392L mutation and healthy donors carrying or not this mutation. Osteoclasts from PDB patients were more numerous, contained more nuclei, were more resistant to apoptosis, and had a greater ability to resorb bone than their normal counterparts, regardless of whether the p62 mutation was present or not. A strong increase in p62 expression was observed in PDB osteoclasts. The presence of the p62P392L gene in cells from healthy carriers conferred a unique, intermediate osteoclast phenotype. In addition, we report that two survival-promoting kinases, protein kinase Cζ and phosphoinositide-dependent protein kinase 1, were associated with p62 in response to receptor activator of NF-κB ligand (RANKL) stimulation in controls and before RANKL was added in PDB osteoclasts. In transfected osteoclasts derived from cord blood monocytes, the p62 P392L mutation contributed to increased activation of kinases protein kinase Cζ/λ and phosphoinositide-dependent protein kinase 1, along with basal activation of NF-κB, independently of RANKL stimulation. These findings clearly indicate that the overexpression of p62 in PDB patients induces important shifts in the pathways activated by RANKL and up-regulates osteoclast functions. Moreover, the most-commonly reported p62 mutation, P392L, certainly contributes to the overactive state of osteoclasts in PDB. Over-expression of p62 and a p62 P392L mutation induce important shifts in the pathways activated by RANKL and up-regulate osteoclast functions in Paget’s disease of bone.
ISSN:0888-8809
1944-9917
DOI:10.1210/me.2009-0066