Abstract
Pathological osteolysis is commonly associated with osteoporosis, bone tumors, osteonecrosis, and chronic inflammation. It involves excessive resorption of bone matrix by activated osteoclasts. Suppressing receptor activator of NF-κB ligand (RANKL) signaling pathways has been proposed to be a good target for inhibiting osteoclast differentiation and bone resorption. Bajijiasu—a natural compound derived from Morinda officinalis F. C. How—has previously been shown to have anti-oxidative stress property; however, its effect and molecular mechanism of action on osteoclastogenesis and bone resorption remains unclear. In the present study, we found that Bajijiasu dose-dependently inhibited RANKL-induced osteoclast formation and bone resorption from 0.1 mM, and reached half maximal inhibitory effects (IC50) at 0.4 mM without toxicity. Expression of RANKL-induced osteoclast specific marker genes including cathepsin K (Ctsk), nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), tartrate resistant acid phosphatase (TRAcP), vacuolar-type H+-ATPase V0 subunit D2 (V-ATPase d2), and (matrix metalloproteinase-2 (MMP2) was inhibited by Bajijiasu treatment. Luciferase reporter gene studies showed that Bajijiasu could significantly reduce the expression and transcriptional activity of NFAT as well as RANKL-induced NF-κB activation in a dose-dependent manner. Further, Bajijiasu was found to decrease the RANKL-induced phosphorylation of extracellular signal-regulated kinases (ERK), inhibitor of κB-α (IκB-α), NFAT, and V-ATPase d2. Taken together, this study revealed Bajijiasu could attenuate osteoclast formation and bone resorption by mediating RANKL signaling pathways, indicative of a potential effect of Bajijiasu on osteolytic bone diseases.
Highlights
Osteolytic bone diseases result from the unbalanced activities of osteoblast-induced bone formation and osteoclast-induced bone resorption [1]
Stimulation and differentiation of osteoclasts is modulated by the receptor activator of nuclear factor-κB (NF-κB) (RANK) ligand (RANKL), which is an essential cytokine in bone metabolic processes [4]
Due to the imbalance between osteoblast and osteoclast activity, is paErxticceuslsairvlye cbhoanreacrteersiosrtipctiionno, sdteuoelyttoicthboeniemdbiasleaansecse, binectwluedeinngoostseteoobplaosrtosaisn,dboonsteeotuclmasotrsa,catinvdity, is poasrtteiocnuelacrrolysisc.hWarhaecntecroinstsiicdienrinogsttehoelymtoiclebcounlaer mdiescehaasnesis,minsculunddeinrlgyionsgteoostpeoorlyotsiicsd, ibsoenaseestu, emxcoersss,ivaend osteboonneecrroessoisr.pWtiohneniscoofntseindecraiunsgedthbeymionlcerceualsaerdmReAchNaKnLismlesveulns daenrdlysinugbsoesqtueoenlyttiecndhiasnecaesmese,netxocefsistisve bone resorption is often caused by increased RANKL levels and subsequent enhancement of its related downstream genes; this pathway has been confirmed as a useful target for treatment of osteolytic bone diseases [19,20]
Summary
Osteolytic bone diseases result from the unbalanced activities of osteoblast-induced bone formation and osteoclast-induced bone resorption [1]. The interaction of RANKL and RANK directly activates a cascade of intracellular molecular events, leading to osteoclast formation and activation. RANKL-activated pathways include NF-κB, mitogen-activated protein kinases (MAPK) including extracellular signal-regulated kinases (ERK), PI3K (phosphatidylinositol-3-kinase) and ionic calcium and calcium/calmodulin-dependent kinase [5]. These sequential molecular events can result in the induction of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) [6]. We have focused on compound discovery through screening natural herbs to identify novel inhibitors of osteoclast formation and function, and determining their associated pharmacological intervention pathways [8,9]
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