title: Heat shock protein 60 causes osteoclastic bone resorption via toll-like receptor-2 in estrogen deficiency.
abstract: 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)-1beta and tumor necrosis factor (TNF)-alpha in T cell and osteoclasts (OCs) lineages, IL-1beta 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(2)) 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-1beta- and TNF-alpha. HSP60 upregulated the expression levels of toll-like receptor (TLR)-2 in bone marrow macrophage (BMMvarphi), 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.
authors.affiliation: Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap 2-Dong, Songpa-Gu, Seoul 138-736, Republic of Korea.
authors.forename: Jung-Min
authors.initials: JM
authors.lastname: Koh
authors.forename: Young-Sun
authors.initials: YS
authors.lastname: Lee
authors.forename: Yang Soon
authors.initials: YS
authors.lastname: Kim
authors.forename: Su-Hye
authors.initials: SH
authors.lastname: Park
authors.forename: Seung Hun
authors.initials: SH
authors.lastname: Lee
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
authors.forename: Ki-Up
authors.initials: KU
authors.lastname: Lee
authors.forename: Ghi Su
authors.initials: GS
authors.lastname: Kim
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D001862:Bone Resorption / Q000378:metabolism* / Q000473:pathology*; D018834:Chaperonin 60 / Q000378:metabolism*; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010012:Osteogenesis / Q000187:drug effects; D010052:Ovariectomy; D020543:Proteome / Q000032:analysis; D053245:RANK Ligand / Q000494:pharmacology; D051381:Rats; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D018834:Chaperonin 60; D004967:Estrogens; D053583:Interleukin-1beta; D020543:Proteome; D053245:RANK Ligand; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha