Objective. SH3 domain-binding protein 2 (SH3BP2) is a signaling adapter protein that regulates the immune and skeletal systems. The present study was undertaken to investigate the role of SH3BP2 in arthritis using 2 experimental mouse models, i.e., human tumor necrosis factor alpha-transgenic (hTNF-Tg) mice and mice with collagen-induced arthritis (CIA). Methods. First, Sh3bp2(-/-) and wild-type (Sh3bp2(+/+)) mice were crossed with hTNF-Tg mice. Inflammation and bone loss were examined by clinical inspection and histologic and micro-computed tomography analysis, and osteoclastogenesis was evaluated using primary bone marrow-derived macrophage colony-stimulating factor-dependent macrophages (BMMs). Second, CIA was induced in Sh3bp2(-/-) and Sh3bp2(+/+) mice, and the incidence and severity of arthritis were evaluated. Anti-mouse type II collagen (CII) antibody levels were measured by enzyme-linked immunosorbent assay, and lymph node cell responses to CII were determined. Results. SH3BP2 deficiency did not alter the severity of joint swelling but did suppress bone erosion in the hTNF-Tg mouse model. Bone loss at the talus and tibia was prevented in Sh3bp2(-/-)/hTNF-Tg mice compared to Sh3bp2(+/+)/hTNF-Tg mice. RANKL- and TNF alpha-induced osteoclastogenesis was suppressed in Sh3bp2(-/-) mouse BMM cultures. NF-ATc1 nuclear localization in response to TNF alpha was decreased in Sh3bp2(-/-) mouse BMMs compared to Sh3bp2(+/+) mouse BMMs. In the CIA model, SH3BP2 deficiency suppressed the incidence of arthritis and this was associated with decreased anti-CII antibody production, while antigen-specific T cell responses in lymph nodes were not significantly different between Sh3bp2(+/+) and Sh3bp2(-/-) mice. Conclusion. SH3BP2 deficiency prevents loss of bone via impaired osteoclastogenesis in the hTNF-Tg mouse model and suppresses the induction of arthritis via decreased autoantibody production in the CIA model. Therefore, SH3BP2 could potentially be a therapeutic target in rheumatoid arthritis.
机构:
Univ Barcelona, Fac Med, Biochem Unit, E-08036 Barcelona, Spain
Inst Invest Biomed August Pi & Sunyer, Lab Immunoallergia Resp Clin & Expt, Barcelona 08036, SpainUniv Barcelona, Fac Med, Biochem Unit, E-08036 Barcelona, Spain
Ainsua-Enrich, Erola
Alvarez-Errico, Damiana
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Univ Barcelona, Fac Med, Biochem Unit, E-08036 Barcelona, Spain
Inst Invest Biomed August Pi & Sunyer, Lab Immunoallergia Resp Clin & Expt, Barcelona 08036, SpainUniv Barcelona, Fac Med, Biochem Unit, E-08036 Barcelona, Spain
Alvarez-Errico, Damiana
Gilfillan, Alasdair M.
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NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USAUniv Barcelona, Fac Med, Biochem Unit, E-08036 Barcelona, Spain
Gilfillan, Alasdair M.
Picado, Cesar
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Inst Invest Biomed August Pi & Sunyer, Lab Immunoallergia Resp Clin & Expt, Barcelona 08036, Spain
Networking Res Ctr Resp Dis, Inst Hlth Carlos 3, Madrid 28029, SpainUniv Barcelona, Fac Med, Biochem Unit, E-08036 Barcelona, Spain
Picado, Cesar
Sayos, Joan
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Autonomous Univ Barcelona, Immunobiol Grp, Mol Biol & Biochem Res Ctr Nanomed, Vall Hebron Hosp,Nanomed Program,Res Inst, E-08035 Barcelona, Spain
Networking Res Ctr Bioengn Biomat & Nanomed, Inst Hlth Carlos 3, Madrid 28029, SpainUniv Barcelona, Fac Med, Biochem Unit, E-08036 Barcelona, Spain
机构:
Univ Barcelona, Fac Med, Biochem Unit, E-08036 Barcelona, Spain
Inst Invest Biomed August Pi & Sunyer, Lab Immunoallergia Resp Clin & Expt, Barcelona 08036, SpainUniv Barcelona, Fac Med, Biochem Unit, E-08036 Barcelona, Spain
机构:
Beth Israel Deaconess Med Ctr, Orthoped Biomech Lab RN115, Ctr Adv Orthoped Studies, Boston, MA 02215 USA
Harvard Univ, Sch Med, Boston, MA 02215 USABeth Israel Deaconess Med Ctr, Orthoped Biomech Lab RN115, Ctr Adv Orthoped Studies, Boston, MA 02215 USA
Bouxsein, Mary L.
Boyd, Stephen K.
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Univ Calgary, Dept Mech Engn, Schulich Sch Engn, Calgary, AB T2N 1N4, CanadaBeth Israel Deaconess Med Ctr, Orthoped Biomech Lab RN115, Ctr Adv Orthoped Studies, Boston, MA 02215 USA
Boyd, Stephen K.
Christiansen, Blaine A.
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h-index: 0
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Harvard Univ, Sch Med, Boston, MA 02215 USABeth Israel Deaconess Med Ctr, Orthoped Biomech Lab RN115, Ctr Adv Orthoped Studies, Boston, MA 02215 USA
Christiansen, Blaine A.
Guldberg, Robert E.
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Georgia Inst Technol, George W Woodruff Sch Mech Engn, Parker H Petit Inst Bioengn & Biosci, Atlanta, GA 30332 USABeth Israel Deaconess Med Ctr, Orthoped Biomech Lab RN115, Ctr Adv Orthoped Studies, Boston, MA 02215 USA
Guldberg, Robert E.
Jepsen, Karl J.
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Mt Sinai Sch Med, Dept Orthopaed, New York, NY USABeth Israel Deaconess Med Ctr, Orthoped Biomech Lab RN115, Ctr Adv Orthoped Studies, Boston, MA 02215 USA
Jepsen, Karl J.
Mueller, Ralph
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Swiss Fed Inst Technol, Inst Biomech, Zurich, SwitzerlandBeth Israel Deaconess Med Ctr, Orthoped Biomech Lab RN115, Ctr Adv Orthoped Studies, Boston, MA 02215 USA
机构:
Univ Barcelona, Fac Med, Biochem Unit, E-08036 Barcelona, Spain
Inst Invest Biomed August Pi & Sunyer, Lab Immunoallergia Resp Clin & Expt, Barcelona 08036, SpainUniv Barcelona, Fac Med, Biochem Unit, E-08036 Barcelona, Spain
Ainsua-Enrich, Erola
Alvarez-Errico, Damiana
论文数: 0引用数: 0
h-index: 0
机构:
Univ Barcelona, Fac Med, Biochem Unit, E-08036 Barcelona, Spain
Inst Invest Biomed August Pi & Sunyer, Lab Immunoallergia Resp Clin & Expt, Barcelona 08036, SpainUniv Barcelona, Fac Med, Biochem Unit, E-08036 Barcelona, Spain
Alvarez-Errico, Damiana
Gilfillan, Alasdair M.
论文数: 0引用数: 0
h-index: 0
机构:
NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USAUniv Barcelona, Fac Med, Biochem Unit, E-08036 Barcelona, Spain
Gilfillan, Alasdair M.
Picado, Cesar
论文数: 0引用数: 0
h-index: 0
机构:
Inst Invest Biomed August Pi & Sunyer, Lab Immunoallergia Resp Clin & Expt, Barcelona 08036, Spain
Networking Res Ctr Resp Dis, Inst Hlth Carlos 3, Madrid 28029, SpainUniv Barcelona, Fac Med, Biochem Unit, E-08036 Barcelona, Spain
Picado, Cesar
Sayos, Joan
论文数: 0引用数: 0
h-index: 0
机构:
Autonomous Univ Barcelona, Immunobiol Grp, Mol Biol & Biochem Res Ctr Nanomed, Vall Hebron Hosp,Nanomed Program,Res Inst, E-08035 Barcelona, Spain
Networking Res Ctr Bioengn Biomat & Nanomed, Inst Hlth Carlos 3, Madrid 28029, SpainUniv Barcelona, Fac Med, Biochem Unit, E-08036 Barcelona, Spain
机构:
Univ Barcelona, Fac Med, Biochem Unit, E-08036 Barcelona, Spain
Inst Invest Biomed August Pi & Sunyer, Lab Immunoallergia Resp Clin & Expt, Barcelona 08036, SpainUniv Barcelona, Fac Med, Biochem Unit, E-08036 Barcelona, Spain
机构:
Beth Israel Deaconess Med Ctr, Orthoped Biomech Lab RN115, Ctr Adv Orthoped Studies, Boston, MA 02215 USA
Harvard Univ, Sch Med, Boston, MA 02215 USABeth Israel Deaconess Med Ctr, Orthoped Biomech Lab RN115, Ctr Adv Orthoped Studies, Boston, MA 02215 USA
Bouxsein, Mary L.
Boyd, Stephen K.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Calgary, Dept Mech Engn, Schulich Sch Engn, Calgary, AB T2N 1N4, CanadaBeth Israel Deaconess Med Ctr, Orthoped Biomech Lab RN115, Ctr Adv Orthoped Studies, Boston, MA 02215 USA
Boyd, Stephen K.
Christiansen, Blaine A.
论文数: 0引用数: 0
h-index: 0
机构:
Harvard Univ, Sch Med, Boston, MA 02215 USABeth Israel Deaconess Med Ctr, Orthoped Biomech Lab RN115, Ctr Adv Orthoped Studies, Boston, MA 02215 USA
Christiansen, Blaine A.
Guldberg, Robert E.
论文数: 0引用数: 0
h-index: 0
机构:
Georgia Inst Technol, George W Woodruff Sch Mech Engn, Parker H Petit Inst Bioengn & Biosci, Atlanta, GA 30332 USABeth Israel Deaconess Med Ctr, Orthoped Biomech Lab RN115, Ctr Adv Orthoped Studies, Boston, MA 02215 USA
Guldberg, Robert E.
Jepsen, Karl J.
论文数: 0引用数: 0
h-index: 0
机构:
Mt Sinai Sch Med, Dept Orthopaed, New York, NY USABeth Israel Deaconess Med Ctr, Orthoped Biomech Lab RN115, Ctr Adv Orthoped Studies, Boston, MA 02215 USA
Jepsen, Karl J.
Mueller, Ralph
论文数: 0引用数: 0
h-index: 0
机构:
Swiss Fed Inst Technol, Inst Biomech, Zurich, SwitzerlandBeth Israel Deaconess Med Ctr, Orthoped Biomech Lab RN115, Ctr Adv Orthoped Studies, Boston, MA 02215 USA