Abstract
Osteoporosis is a systemic metabolic bone disorder that is caused by an imbalance in the functions of osteoclasts and osteoblasts and is characterized by excessive bone resorption by osteoclasts. Targeting osteoclast differentiation and bone resorption is considered a good fundamental solution for overcoming bone diseases. β-boswellic acid (βBA) is a natural compound found in Boswellia serrata, which is an active ingredient with anti-inflammatory, anti-rheumatic, and anti-cancer effects. Here, we explored the anti-resorptive effect of βBA on osteoclastogenesis. βBA significantly inhibited the formation of tartrate-resistant acid phosphatase-positive osteoclasts induced by receptor activator of nuclear factor-B ligand (RANKL) and suppressed bone resorption without any cytotoxicity. Interestingly, βBA significantly inhibited the phosphorylation of IκB, Btk, and PLCγ2 and the degradation of IκB. Additionally, βBA strongly inhibited the mRNA and protein expression of c-Fos and NFATc1 induced by RANKL and subsequently attenuated the expression of osteoclast marker genes, such as OC-STAMP, DC-STAMP, β3-integrin, MMP9, ATP6v0d2, and CtsK. These results suggest that βBA is a potential therapeutic candidate for the treatment of excessive osteoclast-induced bone diseases such as osteoporosis.
Highlights
Bone is constantly formed by osteoblasts and resorbed by osteoclasts throughout its lifetime
Osteoclasts are multinucleated cells derived from hematopoietic precursor cells that are stimulated by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κ-B (RANKL)
We found that β-boswellic acid (βBA) inhibits osteoclast formation and bone resorption and downregulates nuclear factor of activated T cells 1 (NFATc1) expression via suppression of NF-κB and PLCγ2 signaling in vitro
Summary
Bone is constantly formed by osteoblasts and resorbed by osteoclasts throughout its lifetime. We found that βBA inhibits osteoclast formation and bone resorption and downregulates NFATc1 expression via suppression of NF-κB and PLCγ2 signaling in vitro. To determine the effect of βBA on osteoclast differentiation, bone marrow-derived macrophages (BMMs) were cultured with M-CSF (30 ng/mL) and RANKL (100 ng/mL) in the presence or absence of various concentrations of βBA (0, 5, 10, 20, and 30 μM) for 3 days. The resorption area was significantly decreased in both the hydroxyapatite plate and dentin slices in βBA compared to the control (Figure 2) These data suggest that βBA suppresses bone resorption without inducing cell death. ΒBA suppressed osteoclast differentiation via reduced nuclear translocation of NF-κB by inhibiting IκB degradation and Btk-PLCγ2 calcium signaling (Figure 3A). TTaakkeenn ttooggeetthheerr,, tthheesseerreessuullttssssuuggggeeststththataβt BβABAinhinibhiitbsitNs FNAFTAcT1ct1ratnrasncrsicprtiipotniodnudriunrgiRnAgNRKALN-iKnLd-uicnedducoesdteoocsltaesotcdlaisfftedreifnfteiraetniotniatainodn panredvepnretsveonsttesoocslatesot cmlaasttumraatitounraatniodnbaonnde breosnoerprteisoonrpbtyiobnlobcykibnlgocNkFin-κgBNaFn-dκBBtakn-PdLBCtγk2-PsLigCnγa2linsigg.nHaoliwnge.veHr,owweevcoeru,lwd enoctocuoldnfniromt cthoenfiefrfmectthoef eβfBfeActoonfoβsBteAobolnasotsatneodbalnasimt aanldstaundiym. aTlhsetruedfoyr.eT, hfuerrethfoerrer,efsueratrhcehrornestehaercehffoecnt tohfeβeBfAfecotnoofsβteBoAblaosntsocsoteuolbdlapsrtosvcidoue lmd oprreoivnisdieghmt oinretointhseigehftfeicnttooftihneheibffieticntgoof sintehoicbliatsintogogsetneeoscilsa,satnogdetnheesiesf,fiacnadcythoef βefBfiAcaicnyvoifvβoBcAouilndvsiuvgogceosut tldhesruagpgeeustticthpeortaepnetuiatli.c potential
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