(2<i>S</i>)-2′-Methoxykurarinone Inhibits Osteoclastogenesis and Bone Resorption through Down-Regulation of RANKL Signaling

Abstract

(2S)-2′-Methoxykurarinone (MK), a compound isolated from the roots of Sophora flavescens, has various physiological properties, such as anti-inflammatory, antipyretic, antidiabetic, and antineoplastic effects. However, the effect of S. flavescens-derived MK on osteoclastogenesis remains unknown. Therefore, we examined the effect and mechanism of action of MK on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and bone resorption. MK inhibited osteoclast differentiation in bone marrow cell-osteoblast cocultures but did not affect the RANKL-to-osteoprotegerin ratio induced by osteoclastogenic factors in osteoblasts. MK also inhibited RANKL-induced osteoclast differentiation from bone marrow macrophages in a dose-dependent manner, without cytotoxicity. Pretreatment with MK significantly suppressed the Akt, p38, c-Jun N terminal kinase (JNK), c-Fos, and nuclear factor of activated T cells c1 (NFATc1) pathways and inhibited the bone-resorbing activity of mature osteoclasts. These results collectively suggest that MK inhibits osteoclast differentiation and bone resorption through RANKL-induced mitogen-activated protein kinases (MAPKs) and c-Fos-NFATc1 signaling pathways. Key words (2S)-2′-methoxykurarinone; bone resorption; osteoclast; osteoporosis; receptor activator of nuclear factor-κB ligand (RANKL)Osteoclasts, which originate from hematopoietic cells of the monocyte macrophage lineage, play a crucial role in bone remodeling.1,2) The bone loss in many important skeletal disorders, such as osteoporosis, rheumatoid arthritis, and bone metastases, occurs mainly because of increased osteoclast activity.3,4) Bone formation is regulated by osteoblasts, which also express the receptor activator of nuclear factor kappa-B ligand (RANKL), which has been identified as a member of the tumor necrosis factor (TNF) superfamily and regulates osteoclast differentiation through cell-to-cell contact.3,4) Osteoblasts and stromal cells also produce a soluble decoy receptor for RANKL, osteoprotegerin (OPG), which inhibits osteoclast formation by interrupting the interaction between RANKL and RANK, resulting in an increase in bone density and bone volume.1,2) Several osteoclastogenic factors, such as 1,25-dihydroxyvitamin D 3 (VitD 3 ) and proinflammatory cytokines, can stimulate osteoclast formation by up-regulating the ratio of RANKL to OPG in osteoblasts or stromal cells.

Molecular signaling mechanisms behind polyphenol-induced bone anabolism

“…On the other hand, inhibition of RANKL and IL-1-induced osteoclast differentiation, through the inhibition of Akt phosphorylation, has also been reported following treatment with (2S)-2′-Methoxykurarinone prenylflavonoid (Kim et al 2014 ).…”

“…Several works report the anti-inflammatory effects of polyphenols, being exerted through targeting MAPKs pathway (Fig. 5 ): EGCG plays a role against inflammatory cytokines, which favor bone resorption, by inhibiting, at a dose of 30 μM, endothelin1 and platelet-derived growth factor BB-induced IL-6 synthesis, through diminishing the phosphorylation levels of MEK1/2 and Raf-1 at a point upstream of ERK1/2 MAPK (Tokuda et al 2007a ) and through downregulating the stress-activated protein kinase (SAPK)/JNK pathway (Takai et al 2008 ); (2S)-2′-Methoxykurarinone, a compound isolated from the root of Sophora flavescens , inhibits, at the dose of 20 μM, IL-1-induced differentiation of osteoclasts through the inhibition of p38 and JNK phosphorylation (Kim et al 2014 ), while icariin, at nM concentrations, decreases PGE 2 production by suppressing activation of p38 and JNK pathways (Hsieh et al 2011 ).…”

Carvacrol Inhibits Osteoclastogenesis and Negatively Regulates the Survival of Mature Osteoclasts

“…13) Accumulating lines of evidence suggest that several natural compounds may have potential anabolic effects on bone. 14,15) Carvacrol (5-isopropyl-2-methylphenol), is a monoterpenic phenol found in oregano and thyme. 16) Essential oils containing carvacrol have been widely used in various traditional medicines.…”

Harpagoside Inhibits RANKL-Induced Osteoclastogenesis via Syk-Btk-PLCγ2-Ca2+ Signaling Pathway and Prevents Inflammation-Mediated Bone Loss

“…Various medicinal compounds prepared from crude plant extracts that act on osteoclast differentiation and functions have been reported to have therapeutic benefits with few side effects in the treatment or prevention of bone diseases. − To identify novel compounds that can function as antiresorptive agents, several natural compounds were screened by analyzing TRAP staining. Harpagoside (HAR, Figure A) is an iridoid glycoside isolated from Harpagophytum procumbens (devil’s claw) that has been used to treat pain, arthritis, fever, ulcers, and boils in Southern Africa and has been described as an anti-inflammatory and analgesic agent. , We found that HAR suppressed RANKL-mediated osteoclast differentiation from bone marrow macrophages (BMMs).…”