Citrus nobiletin suppresses bone loss in ovariectomized ddY mice
and collagen-induced arthritis in DBA/1J mice: Possible involvement of receptor
activator of NF-kappaB ligand (RANKL)-induced osteoclastogenesis
regulation
Affiliations: Division of Food Science and Biotechnology, Graduate
School of Agriculture, Kyoto University, Kyoto 606-8502, Japan | Department of Nutritional Science, Faculty of Applied
Bioscience, Tokyo University of Agriculture, Japan
Abstract: Bone resorption is known to accelerate during the onset of several
disorders, including osteoporosis (OP) and rheumatoid arthritis (RA). Some
epidemiological surveys have suggested that a high intake of vegetables and
fruits has an inverse relation to such disease incidence, though the number of
active constituents elucidated thus far is limited. In the present study, we
examined the efficacy of various food phytochemicals using two animal models.
First, female ddY mice were ovariectomized (OVX) or sham-operated (sham), after
which five different compounds (phenethyl isothiocyanate, zerumbone, auraptene,
1'-acetoxychavicol acetate, and nobiletin) were administered separately to OVX
mice with a mini-osmotic pump at doses of 0.25 or 0.5 mg/day for 4 weeks, with
17β-estradiol (E_{2}, 0.03μg/day) used as a positive
control. Nobiletin, in contrast to the other tested phytochemicals,
significantly (P<0.05) suppressed the reduction of whole bone mineral
density by 61%, which was comparable to or higher than the efficacy of
E_{2}. Next, nobiletin given as an i.p. administration at 20
mg/kg of body weight, but not 2 mg/kg, to male DBA/1J mice every 2 days for 12
days led to a marked decrease in type II collagen-induced arthritis by 45% (P
< 0.05). Furthermore, the flavonoid (4–50 μM) attenuated receptor
activator of nuclear factor kappaB ligand (RANKL)-induced osteoclastogenesis of
RAW264.7 cells, as detected by tartarate-resistant acid phosphatase activity
and microscopic observations. Of note, nobiletin also suppressed
RANKL-activated extracellular signal-regulated kinase1/2, c-Jun N-terminal
kinase1/2, and p38 mitogen-activated protein kinase activities, and thereby
regulated the promoter activation of nuclear factor kappaB (NFκB) and
activator protein-1, key transcription factors for differentiation. Together,
our results suggest that nobiletin is a promising phytochemical for the
prevention or treatment of osteoclastogenesis-related disorders, including OP
and RA, with reasonable action mechanisms.
