Regulation of ER molecular chaperone prevents bone loss in a murine model for osteoporosis.
Endoplasmic reticulum (ER) stress response is important for protein maturation in the ER. Some murine models for bone diseases have provided significant insight into the possibility that pathogenesis of osteoporosis is related to ER stress response of osteoblasts. We examined a possible correlation between osteoporosis and ER stress response. Bone specimens from 8 osteoporosis patients and 8 disease-controls were used for immunohistochemical analysis. We found that ER molecular chaperones, such as BiP (immunoglobulin heavy-chain binding protein) and PDI (protein-disulfide isomerase) are down-regulated in osteoblasts from osteoporosis patients. Based on this result, we hypothesized that up-regulation of ER molecular chaperones in osteoblasts could restore decreased bone formation in osteoporosis. Therefore, we investigated whether treatment of murine model for osteoporosis with BIX (BiP inducer X), selective inducer BiP, could prevent bone loss. We found that oral administration of BIX effectively improves decline in bone formation through the activation of folding and secretion of bone matrix proteins. Considering these results together, BIX may be a potential therapeutic agent for the prevention of bone loss in osteoporosis patients.
Hino
Shin-ichiro
S
Division of Molecular and Cellular Biology, Department of Anatomy, Faculty of Medicine, University of Miyazaki, Kihara 5200, Kiyotake, Miyazaki, 889-1692, Japan.
Kondo
Shinichi
S
Yoshinaga
Kazuya
K
Saito
Atsushi
A
Murakami
Tomohiko
T
Kanemoto
Soshi
S
Sekiya
Hiroshi
H
Chihara
Kazuyasu
K
Aikawa
Yuji
Y
Hara
Hideaki
H
Kudo
Takashi
T
Sekimoto
Tomohisa
T
Funamoto
Taro
T
Chosa
Etsuo
E
Imaizumi
Kazunori
K
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000831:Animals, Newborn; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology; D053495:Osteopontin / Q000378:metabolism; D010024:Osteoporosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D013861:Thiocyanates / Q000008:administration & dosage / Q000627:therapeutic use*; D013997:Time Factors
C527742:1-(3,4-dihydroxyphenyl)-2-thiocyanate-ethanone; D050071:Bone Density Conservation Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D013861:Thiocyanates; D053495:Osteopontin; D019704:Protein Disulfide-Isomerases