Rosmarinic acid exerts an antiosteoporotic effect in the RANKL-induced mouse model of bone loss by promotion of osteoblastic differentiation and inhibition of osteoclastic differentiation.
METHODS
Bone homeostasis is ensured by the balance between bone formation and resorption. Thus, control of the recruitment, proliferation, and differentiation of bone cells is essential to maintain bone mass. The aim of this study was to elucidate the effects of rosmarinic acid as a potential therapeutic agent on bone metabolism using bone cells and a mouse model.


RESULTS
Rosmarinic acid increased alkaline phosphatase activity and induced mineralization in osteoblasts. Addition of rosmarinic acid to cultures of calvarial osteoblastic cells prepared from T-cell factor/β-catenin TOP-GAL mutant mice strongly induced the expression of LacZ and promoted stabilization of β-catenin in the cytoplasm of ST2 cells, suggesting that rosmarinic acid affects the canonical Wnt signaling pathway. Moreover, rosmarinic acid inhibited not only osteoclast formation in cocultures of mouse bone marrow cells and osteoblasts, but also receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastic differentiation in bone marrow-derived macrophages. RANKL-induced p38 mitogen-activated protein kinase and the expression of nuclear factor of activated T cell, c-Jun, and c-Fos were inhibited by rosmarinic acid in bone marrow macrophages. Finally, we confirmed that rosmarinic acid improved bone mass in a soluble RANKL-induced bone loss mouse model.


CONCLUSIONS
Rosmarinic acid has dual regulatory effects on bone metabolism and may control the bone functions by controlling osteoblastic and osteoclastic differentiation.
Division of Bio-Imaging, Proteo-Science Center (PROS), Ehime University, Ehime, Japan; Section of Oral Pathology, Graduate School of Medicine and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Research Institute for Biological Functions, Chubu University, Aichi, Japan.
Ji-Won
JW
Lee
Midori
M
Asai
Sang-Kyung
SK
Jeon
Tadahiro
T
Iimura
Takayuki
T
Yonezawa
Byung-Yoon
BY
Cha
Je-Tae
JT
Woo
Akira
A
Yamaguchi
D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects; D001862:Bone Resorption / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology*; D018920:Coculture Techniques; D053630:Depsides / Q000494:pharmacology*; D004195:Disease Models, Animal; D008297:Male; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D053245:RANK Ligand / Q000633:toxicity; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000097123:Rosmarinic Acid
D002934:Cinnamates; D053630:Depsides; D053245:RANK Ligand; D060509:Wnt3A Protein; D051176:beta Catenin; D000097123:Rosmarinic Acid; C495267:CTNNB1 protein, mouse; C555511:Wnt3a protein, mouse
Osteoblast; Osteoclast; Rosmarinic acid; Wnt; β-Catenin