PSTPIP2 deficiency in mice causes osteopenia and increased differentiation of multipotent myeloid precursors into osteoclasts

Violeta Chitu, Viorel Nacu, Julia F. Charles, William M. Henne, Harvey T. McMahon, Sayan Nandi, Halley Ketchum, Renee Harris, Mary C. Nakamura, E. Richard Stanley

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Missense mutations that reduce or abrogate myeloid cell expression of the F-BAR domain protein, proline serine threonine phosphatase-interacting protein 2 (PSTPIP2), lead to autoinflammatory disease involving extramedullary hematopoiesis, skin and bone lesions. However, little is known about how PSTPIP2 regulates osteoclast development. Here we examined how PSTPIP2 deficiency causes osteopenia and bone lesions, using the mouse PSTPIP2 mutations, cmo, which fails to express PSTPIP2 and Lupo, in which PSTPIP2 is dysfunctional. In both models, serum levels of the pro-osteoclastogenic factor, MIP-1α, were elevated and CSF-1 receptor (CSF-1R)-dependent production of MIP-1α by macrophages was increased. Treatment of cmo mice with a dual specificity CSF-1R and c-Kit inhibitor, PLX3397, decreased circulating MIP-1α and ameliorated the extramedullary hematopoiesis, inflammation, and osteopenia, demonstrating that aberrant myelopoiesis drives disease. Purified osteoclast precursors from PSTPIP2-deficient mice exhibit increased osteoclastogenesis in vitro and were used to probe the structural requirements for PSTPIP2 suppression of osteoclast development. PSTPIP2 tyrosine phosphorylation and a functional F-BAR domain were essential for PSTPIP2 inhibition of TRAP expression and osteoclast precursor fusion, whereas interaction with PEST-type phosphatases was only required for suppression of TRAP expression. Thus, PSTPIP2 acts as a negative feedback regulator of CSF-1R signaling to suppress inflammation and osteoclastogenesis.

Original languageEnglish (US)
Pages (from-to)3126-3135
Number of pages10
JournalBlood
Volume120
Issue number15
DOIs
StatePublished - Oct 11 2012

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Protein Deficiency
Metabolic Bone Diseases
Phosphoprotein Phosphatases
Osteoclasts
Proline
Protein Phosphatase 2
Macrophage Colony-Stimulating Factor Receptors
Proteins
Extramedullary Hematopoiesis
Osteogenesis
Myelopoiesis
Inflammation
Bone
Bone and Bones
Myeloid Cells
Missense Mutation
Phosphorylation
Phosphoric Monoester Hydrolases
Macrophages
Skin

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

PSTPIP2 deficiency in mice causes osteopenia and increased differentiation of multipotent myeloid precursors into osteoclasts. / Chitu, Violeta; Nacu, Viorel; Charles, Julia F.; Henne, William M.; McMahon, Harvey T.; Nandi, Sayan; Ketchum, Halley; Harris, Renee; Nakamura, Mary C.; Stanley, E. Richard.

In: Blood, Vol. 120, No. 15, 11.10.2012, p. 3126-3135.

Research output: Contribution to journalArticle

Chitu, V, Nacu, V, Charles, JF, Henne, WM, McMahon, HT, Nandi, S, Ketchum, H, Harris, R, Nakamura, MC & Stanley, ER 2012, 'PSTPIP2 deficiency in mice causes osteopenia and increased differentiation of multipotent myeloid precursors into osteoclasts', Blood, vol. 120, no. 15, pp. 3126-3135. https://doi.org/10.1182/blood-2012-04-425595
Chitu, Violeta ; Nacu, Viorel ; Charles, Julia F. ; Henne, William M. ; McMahon, Harvey T. ; Nandi, Sayan ; Ketchum, Halley ; Harris, Renee ; Nakamura, Mary C. ; Stanley, E. Richard. / PSTPIP2 deficiency in mice causes osteopenia and increased differentiation of multipotent myeloid precursors into osteoclasts. In: Blood. 2012 ; Vol. 120, No. 15. pp. 3126-3135.
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AU - Chitu, Violeta

AU - Nacu, Viorel

AU - Charles, Julia F.

AU - Henne, William M.

AU - McMahon, Harvey T.

AU - Nandi, Sayan

AU - Ketchum, Halley

AU - Harris, Renee

AU - Nakamura, Mary C.

AU - Stanley, E. Richard

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