Human Molecular Genetics Advance Access originally published online on September 2, 2008
Human Molecular Genetics 2008 17(23):3708-3719; doi:10.1093/hmg/ddn266
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A SQSTM1/p62 mutation linked to Paget’s disease increases the osteoclastogenic potential of the bone microenvironment
1 Department of Medicine/Hematology-Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15240, USA, 2 Department of Human and Molecular Genetics 3 Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA, 4 Regional Bone Center, Helen Hayes Hospital, West Haverstraw, NY 10993, USA, 5 Teijin Bio-Medical Research, Tokyo 191-8512, Japan, 6 Department of Pathology, Columbia University, College of Physician and Surgeons, New York, NY 10032, USA 7 Department of Medicine/Hematology-Oncology, VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA
* To whom correspondence should be addressed at: Department of Human and Molecular Genetics, Virginia Commonwealth University, PO Box 980033, Richmond, VA 23298-0033, USA. Tel: +1 8048285843; Fax: +1 8048285836; Email: jjwindle{at}vcu.edu
Received July 8, 2008; Accepted August 22, 2008
Paget’s disease of bone (PDB) is the second most common bone disease and is characterized by focal bone lesions which contain large numbers of abnormal osteoclasts (OCLs) and very active normal osteoblasts in a highly osteoclastogenic marrow microenvironment. The etiology of PDB is not well understood and both environmental and genetic causes have been implicated in its pathogenesis. Mutations in the SQSTM1/p62 gene have been identified in up to 30% of Paget’s patients. To determine if p62 mutation is sufficient to induce PDB, we generated mice harboring a mutation causing a P-to-L (proline-to-leucine) substitution at residue 394 (the murine equivalent of human p62P392L, the most common PDB-associated mutation). Bone marrow cultures from p62P394L mice formed increased numbers of OCLs in response to receptor activator of NF-
B ligand (RANKL), tumor necrosis factor 
(TNF-) or 1,25-(OH)2D3, similar to PDB patients. However, purified p62P394L OCL precursors depleted of stromal cells were no longer hyper-responsive to 1,25-(OH)2D3, suggesting effects of the p62P394L mutation on the marrow microenvironment in addition to direct effects on OCLs. Co-cultures of purified p62P394L stromal cells with either wild-type (WT) or p62P394L OCL precursors formed more OCLs than co-cultures containing WT stromal cells due to increased RANKL production by the mutant stromal cells. However, despite the enhanced osteoclastogenic potential of both OCL precursors and marrow stromal cells, the p62P394L mice had histologically normal bones. These results indicate that this PDB-associated p62 mutation is not sufficient to induce PDB and suggest that additional factors acting together with p62 mutation are necessary for the development of PDB in vivo.
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