RRC ID |
62031
|
著者 |
Furuya Y, Inagaki A, Khan M, Mori K, Penninger JM, Nakamura M, Udagawa N, Aoki K, Ohya K, Uchida K, Yasuda H.
|
タイトル |
Stimulation of bone formation in cortical bone of mice treated with a receptor activator of nuclear factor-κB ligand (RANKL)-binding peptide that possesses osteoclastogenesis inhibitory activity.
|
ジャーナル |
J Biol Chem
|
Abstract |
To date, parathyroid hormone is the only clinically available bone anabolic drug. The major difficulty in the development of such drugs is the lack of clarification of the mechanisms regulating osteoblast differentiation and bone formation. Here, we report a peptide (W9) known to abrogate osteoclast differentiation in vivo via blocking receptor activator of nuclear factor-κB ligand (RANKL)-RANK signaling that we surprisingly found exhibits a bone anabolic effect in vivo. Subcutaneous administration of W9 three times/day for 5 days significantly augmented bone mineral density in mouse cortical bone. Histomorphometric analysis showed a decrease in osteoclastogenesis in the distal femoral metaphysis and a significant increase in bone formation in the femoral diaphysis. Our findings suggest that W9 exerts bone anabolic activity. To clarify the mechanisms involved in this activity, we investigated the effects of W9 on osteoblast differentiation/mineralization in MC3T3-E1 (E1) cells. W9 markedly increased alkaline phosphatase (a marker enzyme of osteoblasts) activity and mineralization as shown by alizarin red staining. Gene expression of several osteogenesis-related factors was increased in W9-treated E1 cells. Addition of W9 activated p38 MAPK and Smad1/5/8 in E1 cells, and W9 showed osteogenesis stimulatory activity synergistically with BMP-2 in vitro and ectopic bone formation. Knockdown of RANKL expression in E1 cells reduced the effect of W9. Furthermore, W9 showed a weak effect on RANKL-deficient osteoblasts in alkaline phosphatase assay. Taken together, our findings suggest that this peptide may be useful for the treatment of bone diseases, and W9 achieves its bone anabolic activity through RANKL on osteoblasts accompanied by production of several autocrine factors.
|
巻・号 |
288(8)
|
ページ |
5562-71
|
公開日 |
2013-2-22
|
DOI |
10.1074/jbc.M112.426080
|
PII |
S0021-9258(20)45058-6
|
PMID |
23319583
|
PMC |
PMC3581422
|
MeSH |
Alkaline Phosphatase / metabolism
Animals
Bone Morphogenetic Proteins / metabolism
Bone and Bones / metabolism*
Cell Line
Humans
Mesenchymal Stem Cells / cytology
Mice
Mice, Inbred C57BL
Models, Biological
Oligonucleotide Array Sequence Analysis
Osteoblasts / cytology
Osteoclasts / cytology*
Peptides / chemistry
Protein Binding
RANK Ligand / metabolism*
RNA Interference
Signal Transduction
|
IF |
4.238
|
リソース情報 |
ヒト・動物細胞 |
MC3T3-E1(RCB1126)
RAW 264(RCB0535)
L929 |