Abstract
Excessive osteoclast differentiation and/or function plays a pivotal role in the pathogenesis of bone diseases such as osteoporosis and rheumatoid arthritis. Here, we examined whether fucoidan, a sulfated polysaccharide present in brown algae, attenuates receptor activator of nuclear factor-κB ligand (RANKL)-stimulated osteoclastogenesis in vitro and lipopolysaccharide (LPS)-induced bone resorption in vivo, and investigated the molecular mechanisms involved. Our results indicated that fucoidan significantly inhibited osteoclast differentiation in RANKL-stimulated macrophages and the bone resorbing activity of osteoclasts. The effects of fucoidan may be mediated by regulation of Akt/GSK3β/PTEN signaling and suppression of the increase in intracellular Ca2+ level and calcineurin activity, thereby inhibiting the translocation of nuclear factor-activated T cells c1 (NFATc1) into the nucleus. However, fucoidan-mediated NFATc1 inactivation was greatly reversed by kenpaullone, a GSK3β inhibitor. In addition, using microcomputer tomography (micro-CT) scanning and bone histomorphometry, we found that fucoidan treatment markedly prevented LPS-induced bone erosion in mice. Collectively, we demonstrated that fucoidan was capable of inhibiting osteoclast differentiation and inflammatory bone loss, which may be modulated by regulation of Akt/GSK3β/PTEN/NFATc1 and Ca2+/calcineurin signaling cascades. These findings suggest that fucoidan may be a potential agent for the treatment of osteoclast-related bone diseases.
Highlights
Bone homeostasis is largely controlled by the balance of the actions of bone-resorbing osteoclasts and bone-forming osteoblasts
RANKL-induced osteoclast differentiation from RAW 264.7 macrophages accompanied by elevation of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear osteoclasts and their activities were significantly reduced by fucoidan in a dose-dependent manner (Figure 1A)
Fucoidan was proven to be a potent inhibitor on RANKL-induced osteoclastogenesis via regulation of Akt/GSK3β/Phosphatase and tensin homolog (PTEN) and calcium/calcineurin cascades, thereby inhibiting nuclear factor-activated T cells c1 (NFATc1) activation
Summary
Bone homeostasis is largely controlled by the balance of the actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Mar. Drugs 2019, 17, 345 of nuclear factor-κB (RANKL) has been regarded as an important stimulator for osteoclast differentiation from the monocytes/macrophage lineage [2]. GSK3β-mediated phosphorylation of PTEN at Thr 366 site activates PTEN, and inhibits the PI3K/Akt pathway. Under RANKL stimulation, the PI3K/Akt cascade is activated, leading to inactivation of GSK3β and PTEN, leading to osteoclastogenesis [13]. These findings highlight the importance of Akt/GSK3β/PTEN/NFATc1 and calcium/calcineurin/NFATc1 signaling pathways in the regulation of RANKL-induced osteoclast differentiation. We further investigated the molecular mechanisms by which fucoidan affects osteoclast differentiation and inflammatory bone loss, especially focusing on the alterations in Akt/GSK3β/PTEN/NFATc1 and calcium/calcineurin signaling pathways
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have