SH3BP2 gain-of-function mutation exacerbates inflammation and bone loss in a murine collagen-induced arthritis model

Tomoyuki Mukai, Richard Gallant, Shu Ishida, Teruhito Yoshitaka, Mizuho Kittaka, Keiichiro Nishida, David A. Fox, Yoshitaka Morita, Yasuyoshi Ueki

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Objective: SH3BP2 is a signaling adapter protein which regulates immune and skeletal systems. Gain-of-function mutations in SH3BP2 cause cherubism, characterized by jawbone destruction. This study was aimed to examine the role of SH3BP2 in inflammatory bone loss using a collagen-induced arthritis (CIA) model. Methods: CIA was induced in wild-type (Sh3bpsup2+/+/sup) and heterozygous P416R SH3BP2 cherubism mutant knock-in (Sh3bp2supKI/+/sup) mice, an SH3BP2 gain-of-function model. Severity of the arthritis was determined by assessing the paw swelling and histological analyses of the joints. Micro-CT analysis was used to determine the levels of bone loss. Inflammation and osteoclastogenesis in the joints were evaluated by quantitating the gene expression of inflammatory cytokines and osteoclast markers. Furthermore, involvement of the T- and B-cell responses was determined by draining lymph node cell culture and measurement of the serum anti-mouse type II collagen antibody levels, respectively. Finally, roles of the SH3BP2 mutation in macrophage activation and osteoclastogenesis were determined by evaluating the TNF-α production levels and osteoclast formation in bone marrow-derived M-CSF-dependent macrophage (BMM) cultures. Results: Sh3bp2supKI/+/sup mice exhibited more severe inflammation and bone loss, accompanying an increased number of osteoclasts. The mRNA levels for TNF-α and osteoclast marker genes were higher in the joints of Sh3bp2KI/+ mice. Lymph node cell culture showed that lymphocyte proliferation and IFN-γ and IL-17 production were comparable between Sh3bp2sup+/+/sup and Sh3bp2supKI/+/sup cells. Serum anti-type II collagen antibody levels were comparable between Sh3bp2 sup+/+/sup and Sh3bp2supKI/+/sup mice. In vitro experiments showed that TNF-α production in Sh3bp2supKI/+/sup BMMs is elevated compared with Sh3bp2sup+/+/sup BMMs and that RANKL-induced osteoclastogenesis is enhanced in Sh3bp2supKI/+/sup BMMs associated with increased NFATc1 nuclear localization. Conclusion: Gain-of-function of SH3BP2 augments inflammation and bone loss in the CIA model through increased macrophage activation and osteoclast formation. Therefore, modulation of the SH3BP2 expression may have therapeutic potential for the treatment of rheumatoid arthritis.

Original languageEnglish (US)
Article numbere105518
JournalPLoS ONE
Volume9
Issue number8
DOIs
StatePublished - Aug 21 2014
Externally publishedYes

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Osteitis
osteoclasts
Experimental Arthritis
arthritis
Osteoclasts
collagen
Bone
Collagen
inflammation
bones
Macrophages
Cherubism
Mutation
Cell culture
Osteogenesis
joints (animal)
mice
macrophage activation
Collagen Type II
Macrophage Activation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

SH3BP2 gain-of-function mutation exacerbates inflammation and bone loss in a murine collagen-induced arthritis model. / Mukai, Tomoyuki; Gallant, Richard; Ishida, Shu; Yoshitaka, Teruhito; Kittaka, Mizuho; Nishida, Keiichiro; Fox, David A.; Morita, Yoshitaka; Ueki, Yasuyoshi.

In: PLoS ONE, Vol. 9, No. 8, e105518, 21.08.2014.

Research output: Contribution to journalArticle

Mukai, T, Gallant, R, Ishida, S, Yoshitaka, T, Kittaka, M, Nishida, K, Fox, DA, Morita, Y & Ueki, Y 2014, 'SH3BP2 gain-of-function mutation exacerbates inflammation and bone loss in a murine collagen-induced arthritis model', PLoS ONE, vol. 9, no. 8, e105518. https://doi.org/10.1371/journal.pone.0105518
Mukai, Tomoyuki ; Gallant, Richard ; Ishida, Shu ; Yoshitaka, Teruhito ; Kittaka, Mizuho ; Nishida, Keiichiro ; Fox, David A. ; Morita, Yoshitaka ; Ueki, Yasuyoshi. / SH3BP2 gain-of-function mutation exacerbates inflammation and bone loss in a murine collagen-induced arthritis model. In: PLoS ONE. 2014 ; Vol. 9, No. 8.
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abstract = "Objective: SH3BP2 is a signaling adapter protein which regulates immune and skeletal systems. Gain-of-function mutations in SH3BP2 cause cherubism, characterized by jawbone destruction. This study was aimed to examine the role of SH3BP2 in inflammatory bone loss using a collagen-induced arthritis (CIA) model. Methods: CIA was induced in wild-type (Sh3bpsup2+/+/sup) and heterozygous P416R SH3BP2 cherubism mutant knock-in (Sh3bp2supKI/+/sup) mice, an SH3BP2 gain-of-function model. Severity of the arthritis was determined by assessing the paw swelling and histological analyses of the joints. Micro-CT analysis was used to determine the levels of bone loss. Inflammation and osteoclastogenesis in the joints were evaluated by quantitating the gene expression of inflammatory cytokines and osteoclast markers. Furthermore, involvement of the T- and B-cell responses was determined by draining lymph node cell culture and measurement of the serum anti-mouse type II collagen antibody levels, respectively. Finally, roles of the SH3BP2 mutation in macrophage activation and osteoclastogenesis were determined by evaluating the TNF-α production levels and osteoclast formation in bone marrow-derived M-CSF-dependent macrophage (BMM) cultures. Results: Sh3bp2supKI/+/sup mice exhibited more severe inflammation and bone loss, accompanying an increased number of osteoclasts. The mRNA levels for TNF-α and osteoclast marker genes were higher in the joints of Sh3bp2KI/+ mice. Lymph node cell culture showed that lymphocyte proliferation and IFN-γ and IL-17 production were comparable between Sh3bp2sup+/+/sup and Sh3bp2supKI/+/sup cells. Serum anti-type II collagen antibody levels were comparable between Sh3bp2 sup+/+/sup and Sh3bp2supKI/+/sup mice. In vitro experiments showed that TNF-α production in Sh3bp2supKI/+/sup BMMs is elevated compared with Sh3bp2sup+/+/sup BMMs and that RANKL-induced osteoclastogenesis is enhanced in Sh3bp2supKI/+/sup BMMs associated with increased NFATc1 nuclear localization. Conclusion: Gain-of-function of SH3BP2 augments inflammation and bone loss in the CIA model through increased macrophage activation and osteoclast formation. Therefore, modulation of the SH3BP2 expression may have therapeutic potential for the treatment of rheumatoid arthritis.",
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AU - Mukai, Tomoyuki

AU - Gallant, Richard

AU - Ishida, Shu

AU - Yoshitaka, Teruhito

AU - Kittaka, Mizuho

AU - Nishida, Keiichiro

AU - Fox, David A.

AU - Morita, Yoshitaka

AU - Ueki, Yasuyoshi

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N2 - Objective: SH3BP2 is a signaling adapter protein which regulates immune and skeletal systems. Gain-of-function mutations in SH3BP2 cause cherubism, characterized by jawbone destruction. This study was aimed to examine the role of SH3BP2 in inflammatory bone loss using a collagen-induced arthritis (CIA) model. Methods: CIA was induced in wild-type (Sh3bpsup2+/+/sup) and heterozygous P416R SH3BP2 cherubism mutant knock-in (Sh3bp2supKI/+/sup) mice, an SH3BP2 gain-of-function model. Severity of the arthritis was determined by assessing the paw swelling and histological analyses of the joints. Micro-CT analysis was used to determine the levels of bone loss. Inflammation and osteoclastogenesis in the joints were evaluated by quantitating the gene expression of inflammatory cytokines and osteoclast markers. Furthermore, involvement of the T- and B-cell responses was determined by draining lymph node cell culture and measurement of the serum anti-mouse type II collagen antibody levels, respectively. Finally, roles of the SH3BP2 mutation in macrophage activation and osteoclastogenesis were determined by evaluating the TNF-α production levels and osteoclast formation in bone marrow-derived M-CSF-dependent macrophage (BMM) cultures. Results: Sh3bp2supKI/+/sup mice exhibited more severe inflammation and bone loss, accompanying an increased number of osteoclasts. The mRNA levels for TNF-α and osteoclast marker genes were higher in the joints of Sh3bp2KI/+ mice. Lymph node cell culture showed that lymphocyte proliferation and IFN-γ and IL-17 production were comparable between Sh3bp2sup+/+/sup and Sh3bp2supKI/+/sup cells. Serum anti-type II collagen antibody levels were comparable between Sh3bp2 sup+/+/sup and Sh3bp2supKI/+/sup mice. In vitro experiments showed that TNF-α production in Sh3bp2supKI/+/sup BMMs is elevated compared with Sh3bp2sup+/+/sup BMMs and that RANKL-induced osteoclastogenesis is enhanced in Sh3bp2supKI/+/sup BMMs associated with increased NFATc1 nuclear localization. Conclusion: Gain-of-function of SH3BP2 augments inflammation and bone loss in the CIA model through increased macrophage activation and osteoclast formation. Therefore, modulation of the SH3BP2 expression may have therapeutic potential for the treatment of rheumatoid arthritis.

AB - Objective: SH3BP2 is a signaling adapter protein which regulates immune and skeletal systems. Gain-of-function mutations in SH3BP2 cause cherubism, characterized by jawbone destruction. This study was aimed to examine the role of SH3BP2 in inflammatory bone loss using a collagen-induced arthritis (CIA) model. Methods: CIA was induced in wild-type (Sh3bpsup2+/+/sup) and heterozygous P416R SH3BP2 cherubism mutant knock-in (Sh3bp2supKI/+/sup) mice, an SH3BP2 gain-of-function model. Severity of the arthritis was determined by assessing the paw swelling and histological analyses of the joints. Micro-CT analysis was used to determine the levels of bone loss. Inflammation and osteoclastogenesis in the joints were evaluated by quantitating the gene expression of inflammatory cytokines and osteoclast markers. Furthermore, involvement of the T- and B-cell responses was determined by draining lymph node cell culture and measurement of the serum anti-mouse type II collagen antibody levels, respectively. Finally, roles of the SH3BP2 mutation in macrophage activation and osteoclastogenesis were determined by evaluating the TNF-α production levels and osteoclast formation in bone marrow-derived M-CSF-dependent macrophage (BMM) cultures. Results: Sh3bp2supKI/+/sup mice exhibited more severe inflammation and bone loss, accompanying an increased number of osteoclasts. The mRNA levels for TNF-α and osteoclast marker genes were higher in the joints of Sh3bp2KI/+ mice. Lymph node cell culture showed that lymphocyte proliferation and IFN-γ and IL-17 production were comparable between Sh3bp2sup+/+/sup and Sh3bp2supKI/+/sup cells. Serum anti-type II collagen antibody levels were comparable between Sh3bp2 sup+/+/sup and Sh3bp2supKI/+/sup mice. In vitro experiments showed that TNF-α production in Sh3bp2supKI/+/sup BMMs is elevated compared with Sh3bp2sup+/+/sup BMMs and that RANKL-induced osteoclastogenesis is enhanced in Sh3bp2supKI/+/sup BMMs associated with increased NFATc1 nuclear localization. Conclusion: Gain-of-function of SH3BP2 augments inflammation and bone loss in the CIA model through increased macrophage activation and osteoclast formation. Therefore, modulation of the SH3BP2 expression may have therapeutic potential for the treatment of rheumatoid arthritis.

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