**1. Introduction**

Bones are a dynamic tissue that undergoes constant renewal and repair through bone remodeling. This process is characterized by the spatiotemporal coupling of osteoclastinduced bone resorption and osteoblast-induced bone formation. An imbalance between bone resorption and bone formation, especially excessive osteoclastic activity, is involved in the pathogenesis of osteoporosis, rheumatoid arthritis, multiple myeloma, and metastatic cancers [1,2]. Osteoclasts are multinucleated cells that are differentiated from hematopoietic precursor cells of monocyte or macrophage lineage by canonical stimulation with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) [3,4]. RANKL binds to its receptor on osteoclast precursors to activate the mitogen-activated protein kinase (MAPK) signaling pathway, and downstream transcription factors and osteoclast differentiation markers, including AP-1, NF-κB, and nuclear factor of activated T cells 1 (NFATc1) [2,5,6]. Some cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, can serve as noncanonical osteoclastogenic effectors in a RANKL-independent mechanism [7,8].

**Citation:** Ha, Y.-J.; Choi, Y.S.; Oh, Y.R.; Kang, E.H.; Khang, G.; Park, Y.-B.; Lee, Y.J. Fucoxanthin Suppresses Osteoclastogenesis via Modulation of MAP Kinase and Nrf2 Signaling. *Mar. Drugs* **2021**, *19*, 132. https://doi.org/10.3390/md19030132

Academic Editors: Masashi Hosokawa and Hayato Maeda

Received: 4 January 2021 Accepted: 23 February 2021 Published: 27 February 2021

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Fucoxanthin (FX) is an oxygenated carotenoid present in edible brown sea algae such as kombu (*Laminaria japonica*), wakame (*Undaria pinnatifida*), and arame (*Eisenia bicyclis*) [9]. Previous studies demonstrated that FX possesses antiobesity, antidiabetic, anti-inflammatory, anticancer, and hepatoprotective activities, in addition to its cerebrovascular protective effects [10–18]. Fruit carotenoids such as lycopene and cryptoxanthin were reported to inhibit osteoclastogenesis [19,20]. However, the effect and underlying mechanism of FX on osteoclastogenesis remain poorly understood.

There is interest in the effect of FX on osteoclast differentiation. Although FX exhibited a limited antiosteoresorptive effect in a ligature-induced periodontitis mouse model, FX administration significantly reduced the number of RANKL-positive osteoclasts [21]. Das et al. [22] showed that the treatment of osteoclast-like RAW264.7 cells with 2.5 μM FX inhibits RANKL-induced osteoclast differentiation through an induction of apoptosis. Despite this, an extremely high dose of FX did not produce significant side effects in animal models. Moreover, several studies demonstrated that FX inhibits apoptosis or promotes the survival of various nonmalignant cells at concentrations of up to 50 μM [23–26]. Taira et al. [27] reported FX-induced cytotoxicity in RAW264.7 cells at 20 μM. Therefore, the underlying mechanisms of FX effects on the canonical and noncanonical osteoclastogenic signaling pathways could not depend on cellular apoptosis and are ye<sup>t</sup> to be elucidated. In the present study, we investigated the effects of FX on RANKL-dependent and -independent osteoclast differentiation, and identified its molecular regulatory mechanisms.
