D-chiro-inositol negatively regulates the formation of multinucleated osteoclasts by down-regulating NFATc1.
OBJECTIVE
Osteoclasts (OCs) are multinucleated giant cells that resorb bone matrix. Accelerated bone destruction by OCs might cause several metabolic bone-related diseases, such as osteoporosis and inflammatory bone loss. D-pinitol (3-O-methyl-D-chiro-inositol) is a prominent component of dietary legumes and is actively converted to D-chiro-inositol, which is a putative insulin-like mediator. In this study, we analyzed the effect of D-chiro-inositol on OC differentiation.


METHODS
To analyze the role of D-chiro-inositol on OC differentiation, we examined OC differentiation by the three types of osteoclastogenesis cultures with tartrate-resistant acid phosphatase (TRAP) staining and solution assay. Then, we carried out cell fusion assay with purified TRAP(+) mononuclear OC precursors. Finally, we analyzed the effect of D-chiro-inositol on OC maker expression in response to the regulation of nuclear factor of activated T cells c1 (NFATc1).


RESULTS
We demonstrated that D-chiro-inositol acts as an inhibitor of receptor activator of NF-κB ligand-induced OC differentiation. The formation of multinucleated OCs by cell-cell fusion is reduced by treatment with D-chiro-inositol in a dose-dependent manner. In addition, we demonstrated that D-chiro-inositol inhibits the expression of several osteoclastogenic genes by down-regulating NFATc1.


CONCLUSIONS
We have shown that D-chiro-inositol is negatively involved in osteoclastogenesis through the inhibition of multinucleated OC formation by cell-cell fusion. The expression of NFATc1 was significantly down-regulated by D-chiro-inositol in OCs and consequently, the expression of OC marker genes was significantly reduced. Hence, these results show that D-chiro-inositol might be a good candidate to treat inflammatory bone-related diseases or secondary osteoporosis in diabetes mellitus.
Department of Microbiology and Molecular Biology, Chungnam National University, 220 Gung-dong, Yuseong-gu, Daejeon, 305-764, Republic of Korea.
Jungeun
J
Yu
Seunga
S
Choi
Eui-Soon
ES
Park
Bongjin
B
Shin
Jiyeon
J
Yu
Seoung Hoon
SH
Lee
Masamichi
M
Takami
Jong Soon
JS
Kang
Hyungun
H
Meong
Jaerang
J
Rho
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002459:Cell Fusion; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects*; D015726:Giant Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007294:Inositol / Q000031:analogs & derivatives / Q000494:pharmacology*; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics* / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics* / Q000378:metabolism; D013237:Stereoisomerism
D015415:Biomarkers; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D007294:Inositol