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 17beta-estradiol (E_{2}, 0.03 microg/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 microM) 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 (NFkappaB) 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.