Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
23
pubmed:dateCreated
2008-11-10
pubmed:abstractText
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 p62(P392L), the most common PDB-associated mutation). Bone marrow cultures from p62(P394L) mice formed increased numbers of OCLs in response to receptor activator of NF-kappaB ligand (RANKL), tumor necrosis factor alpha (TNF-alpha) or 1alpha,25-(OH)(2)D(3), similar to PDB patients. However, purified p62(P394L) OCL precursors depleted of stromal cells were no longer hyper-responsive to 1alpha,25-(OH)(2)D(3), suggesting effects of the p62(P394L) mutation on the marrow microenvironment in addition to direct effects on OCLs. Co-cultures of purified p62(P394L) stromal cells with either wild-type (WT) or p62(P394L) 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 p62(P394L) 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.
pubmed:grant
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-10703924, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-10862799, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-10962353, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-11127193, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-11231972, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-11771661, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-11992264, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-12374763, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-12929942, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-15187244, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-15493999, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-15690073, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-16104845, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-16491293, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-16600214, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-17032166, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-17174552, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-17187080, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-17903332, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-17907922, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-18379713, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-18543015, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-2068956, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-2318982, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-2718781, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-3455637, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-3680930, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-729966, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-7426075, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-7608263, http://linkedlifedata.com/resource/pubmed/commentcorrection/18765443-7610939
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
1460-2083
pubmed:author
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
17
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3708-19
pubmed:dateRevised
2010-9-21
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
A SQSTM1/p62 mutation linked to Paget's disease increases the osteoclastogenic potential of the bone microenvironment.
pubmed:affiliation
Department of Medicine/Hematology-Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15240, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural