Vitamin C-deficiency stimulates osteoclastogenesis with an increase in RANK expression.
The effects of vitamin C (VC) on osteoclastogenesis were studied in vivo using ascorbate-requiring Osteogenic Disorder Shionogi (ODS) rats and in vitro using bone marrow-derived monocyte/macrophage cells (BMMs). The results confirmed previous findings of increases in the number of osteoclasts and in bone resorption at 2 and 3 weeks, but not 1 week, of VC-deficiency in ODS rats. The mRNA and protein levels of receptor activator nuclear factor kappaB (RANK) ligand and osteoprotegerin, and the mRNA level of macrophage-colony stimulating factor (M-CSF) in the proximal tibia of VC-deficient rats did not differ from those in VC-supplemented control rats. However, the mRNA levels of RANK, c-fos and c-jun were significantly increased at as early as 1 week of VC-deficiency. These results suggested that VC-deficiency stimulated osteoclastogenesis by increasing RANK expression. The osteoclastic differentiation of BMMs was suppressed in the presence of VC. The suppressed osteoclastogenesis was associated with decreased levels of RANK, c-fos and c-jun. The pretreatment of BMMs with VC or PD 98059, a specific inhibitor of extracellular signal regulated kinase (ERK)-activating MEK1, decreased the expression of RANK induced by M-CSF. VC inhibited the M-CSF-induced activation of ERK. These results suggested that VC-deficiency increased osteoclastogenesis by increasing RANK expression mediated through the activation of ERK.
Hie
Mamiko
M
Department of Food Science and Nutrition, Nara Women's University, Nara 630, Japan.
Tsukamoto
Ikuyo
I
D000818:Animals; D001206:Ascorbic Acid Deficiency / Q000235:genetics*; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D004195:Disease Models, Animal; D005260:Female; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology; D009000:Monocytes / Q000166:cytology; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism*; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D016173:Macrophage Colony-Stimulating Factor