Journal
BONE
Volume 45, Issue 4, Pages 650-660Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.bone.2009.06.007
Keywords
Estrogen deficiency; Heat shock protein 60; Osteoclast; Toll-like receptor 2
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Funding
- Korean Ministry of Education, Science and Technology [FPROSBI-170]
- Ministry for Health, Welfare and Family Affairs [A080256]
- Asan Institute for Life Sciences, Seoul, Korea [2008-347]
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Estrogen deficiency leads to marked increases in osteoclastic bone resorption, but the exact mechanism is unclear. Proteomic analysis was performed on the femur and tibia of ovariectomy (OVX) and sham-operated Sprague-Dawley rats using two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) mass spectrometer (MS). Among the nine proteins differentially expressed between OVX and sham-operated rats, heat shock protein 60 (HSP60) was upregulated by 2.6-fold in the bones of OVX rats, and the plasma concentration of HSP60 was also significantly increased in OVX rats. Estrogen deficiency increases in secretions of interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha in T cell and osteoclasts (OCs) lineages, IL-1 beta and TNF-alpha stimulated the production and secretion of HSP60 from OCs lineages. IL-1 receptor antagonist (ra), TNF-blocking antibody (Ab), and estradiol (E,) significantly suppressed the OVX-induced increase in plasma concentrations of HSP60 in mice. HSP60 potentiated OC formation and bone resorption, and pretreatment with HSP60-blocking Ab markedly reduced the potentiation of OC formation and bone resorption by IL-1 beta- and TNF-alpha. HSP60 upregulated the expression levels of toll-like receptor (TLR)-2 in bone marrow macrophage (BMM phi), and pretreatment with a TLR-2-blocking Ab almost completely inhibited HSP60- or cytokine-induced potentiation of OC formation and/or bone resorption. In conclusion, HSP60 and TLR-2 are novel mediators Of estrogen-deficiency-induced bone loss. (c) 2009 Elsevier Inc. All rights reserved.
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