Heat shock protein 60 causes osteoclastic bone resorption via toll-like receptor-2 in estrogen deficiency.
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.
Koh
Jung-Min
JM
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.
Lee
Young-Sun
YS
Kim
Yang Soon
YS
Park
Su-Hye
SH
Lee
Seung Hun
SH
Kim
Hong-Hee
HH
Lee
Myung-Shik
MS
Lee
Ki-Up
KU
Kim
Ghi Su
GS
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
D018834:Chaperonin 60; D004967:Estrogens; D053583:Interleukin-1beta; D020543:Proteome; D053245:RANK Ligand; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha