A SQSTM1/p62 mutation linked to Paget's disease increases the osteoclastogenic potential of the bone microenvironment

Yuko Hiruma, Noriyoshi Kurihara, Mark A. Subler, Hua Zhou, Christina S. Boykin, Heju Zhang, Seiichi Ishizuka, David W. Dempster, G. David Roodman, Jolene J. Windle

Research output: Contribution to journalArticle

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Abstract

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 p 62P394L, the most common PDB-associated mutation). Bone marrow cultures from p62P394L mice formed increased numbers of OCLs in response to receptor activator of NF-κB ligand (RANKL), tumor necrosis factor α (TNF-α) or 1α,25-(OH)2D3, similar to PDB patients. However, purified p62P394L OCL precursors depleted of stromal cells were no longer hyper-responsive to 1α,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.

Original languageEnglish (US)
Pages (from-to)3708-3719
Number of pages12
JournalHuman Molecular Genetics
Volume17
Issue number23
DOIs
StatePublished - 2008
Externally publishedYes

Fingerprint

Osteitis Deformans
Osteoclasts
Stromal Cells
Bone and Bones
Mutation
Bone Marrow
Coculture Techniques
Bone Diseases
Osteoblasts
Proline
Leucine
Tumor Necrosis Factor-alpha
Ligands

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

A SQSTM1/p62 mutation linked to Paget's disease increases the osteoclastogenic potential of the bone microenvironment. / Hiruma, Yuko; Kurihara, Noriyoshi; Subler, Mark A.; Zhou, Hua; Boykin, Christina S.; Zhang, Heju; Ishizuka, Seiichi; Dempster, David W.; Roodman, G. David; Windle, Jolene J.

In: Human Molecular Genetics, Vol. 17, No. 23, 2008, p. 3708-3719.

Research output: Contribution to journalArticle

Hiruma, Y, Kurihara, N, Subler, MA, Zhou, H, Boykin, CS, Zhang, H, Ishizuka, S, Dempster, DW, Roodman, GD & Windle, JJ 2008, 'A SQSTM1/p62 mutation linked to Paget's disease increases the osteoclastogenic potential of the bone microenvironment', Human Molecular Genetics, vol. 17, no. 23, pp. 3708-3719. https://doi.org/10.1093/hmg/ddn266
Hiruma, Yuko ; Kurihara, Noriyoshi ; Subler, Mark A. ; Zhou, Hua ; Boykin, Christina S. ; Zhang, Heju ; Ishizuka, Seiichi ; Dempster, David W. ; Roodman, G. David ; Windle, Jolene J. / A SQSTM1/p62 mutation linked to Paget's disease increases the osteoclastogenic potential of the bone microenvironment. In: Human Molecular Genetics. 2008 ; Vol. 17, No. 23. pp. 3708-3719.
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abstract = "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 p 62P394L, the most common PDB-associated mutation). Bone marrow cultures from p62P394L mice formed increased numbers of OCLs in response to receptor activator of NF-κB ligand (RANKL), tumor necrosis factor α (TNF-α) or 1α,25-(OH)2D3, similar to PDB patients. However, purified p62P394L OCL precursors depleted of stromal cells were no longer hyper-responsive to 1α,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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T1 - A SQSTM1/p62 mutation linked to Paget's disease increases the osteoclastogenic potential of the bone microenvironment

AU - Hiruma, Yuko

AU - Kurihara, Noriyoshi

AU - Subler, Mark A.

AU - Zhou, Hua

AU - Boykin, Christina S.

AU - Zhang, Heju

AU - Ishizuka, Seiichi

AU - Dempster, David W.

AU - Roodman, G. David

AU - Windle, Jolene J.

PY - 2008

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N2 - 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 p 62P394L, the most common PDB-associated mutation). Bone marrow cultures from p62P394L mice formed increased numbers of OCLs in response to receptor activator of NF-κB ligand (RANKL), tumor necrosis factor α (TNF-α) or 1α,25-(OH)2D3, similar to PDB patients. However, purified p62P394L OCL precursors depleted of stromal cells were no longer hyper-responsive to 1α,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.

AB - 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 p 62P394L, the most common PDB-associated mutation). Bone marrow cultures from p62P394L mice formed increased numbers of OCLs in response to receptor activator of NF-κB ligand (RANKL), tumor necrosis factor α (TNF-α) or 1α,25-(OH)2D3, similar to PDB patients. However, purified p62P394L OCL precursors depleted of stromal cells were no longer hyper-responsive to 1α,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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