Abstract
The bone protective effects of carotenoids have been demonstrated in several studies, and the inhibition of RANKL-induced osteoclast differentiation by lycopene has also been demonstrated. We previously reported that carotenoid oxidation products are the active mediators in the activation of the transcription factor Nrf2 and the inhibition of the NF-κB transcription system by carotenoids. Here, we demonstrate that lycopene oxidation products are more potent than intact lycopene in inhibiting osteoclast differentiation. We analyzed the structure–activity relationship of a series of dialdehyde carotenoid derivatives (diapocarotene-dials) in inhibiting osteoclastogenesis. We found that the degree of inhibition depends on the electron density of the carbon atom that determines the reactivity of the conjugated double bond in reactions such as Michael addition to thiol groups in proteins. Moreover, the carotenoid derivatives attenuated the NF-κB signal through inhibition of IκB phosphorylation and NF-κB translocation to the nucleus. In addition, we show a synergistic inhibition of osteoclast differentiation by combinations of an active carotenoid derivative with the polyphenols curcumin and carnosic acid with combination index (CI) values < 1. Our findings suggest that carotenoid derivatives inhibit osteoclast differentiation, partially by inhibiting the NF-κB pathway. In addition, carotenoid derivatives can synergistically inhibit osteoclast differentiation with curcumin and carnosic acid.
Highlights
Several epidemiological studies imply that fruit and vegetable consumption decreases morbidity and has a beneficial effect on bone health [1,2,3]
Similar osteoclasts are seen in cells treated with RANKL and intact lycopene, in contrast to cells treated with RANKL and oxidized lycopene that showed no multinucleated osteoclasts, suggesting that the oxidized lycopene inhibited osteoclast differentiation
Since NFκB is involved in RANKL activation of osteoclast differentiation, and reduction of RANKL-induced ROS generation through activation of ARE/Nrf2 was suggested to inhibit this differentiation [35], we propose that the interaction of carotenoid derivatives with thiol groups in proteins critically involved in NFκB and ARE/Nrf2 pathways may be part of the mechanism for the inhibition of osteoclast differentiation by oxidized derivatives of lycopene and other carotenoids
Summary
Several epidemiological studies imply that fruit and vegetable consumption decreases morbidity and has a beneficial effect on bone health [1,2,3]. Carotenoids, a major group of micronutrients in a fruit and vegetable-rich diet, are fat soluble and pigmented phytochemicals produced by bacteria, fungi, algae, and plants [4]. From the more than 600 natural carotenoids that have been identified, nearly 50 are consumed by humans [5], whereas about 20 appear in human tissues and blood [6]. Β-carotene, lycopene, and lutein compose the major plasma carotenoids [7]. The sources of other carotenoids are more diverse; for example, β-carotene is rich in orange-yellow vegetables and fruits, but it is found in leafy vegetables. Humans appear to absorb carotenoids in a relatively non-specific fashion and, their plasma and tissue concentrations reflect their individual dietary habits [7]. The relative abundance of each of the five major carotenoids in the diet are similar to their distribution in plasma
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