Inhibitory Effect of Purpurogallin on Osteoclast Differentiation in Vitro through the Downregulation of c-Fos and NFATc1

Abstract

Purpurogallin, a benzotropolone-containing natural compound, has been reported to exhibit numerous biological and pharmacological functions, such as antioxidant, anticancer, and anti-inflammatory effects. In this study, we enzymatically synthesized purpurogallin from pyrogallol and investigated its role in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. Purpurogallin attenuated the formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts from bone marrow macrophages (BMMs) without causing cytotoxicity, and suppressed upregulation of osteoclast-specific markers, including TRAP (Acp5), cathepsin K (Ctsk), and dendritic cell-specific transmembrane protein (Dcstamp). However, purpurogallin did not affect the bone resorbing function of mature osteoclasts evident by the resorption pit assay. Activation of mitogen-activated protein kinases, Akt and IkB pathways in RANK signaling were not altered by purpurogallin, whereas the expression of c-Fos and NFATc1, key transcriptional regulators in osteoclastogenesis, was dramatically inhibited by purpurogallin. Purpurogallin also significantly reduced the expression level of B lymphocyte-induced maturation protein-1 (Blimp1) gene (Prdm1). Further, downregulation of Blimp1 led to forced expression of anti-osteoclastogenic genes, including interferon regulatory factor-8 (Irf8) and B-cell lymphoma 6 (Bcl6) genes. Taken together, our data suggested that purpurogallin inhibits osteoclast differentiation via downregulation of c-Fos and NFATc1.

Macrophage migration inhibitory factor (MIF) inhibitor 4‐IPP suppresses osteoclast formation and promotes osteoblast differentiation through the inhibition of the NF‐κB signaling pathway

“…As a result, p65 was sequestered in the cytoplasm and prevented from translocating to the nucleus to induce transcription of osteoclastic genes such as NFATc1, c-Fos, and DC-STAMP. Genes involved in mature osteoclastic bone resorption such as CTSK, TRAP, and TCIRG1 (a3 subunit of vacuolar-ATPase proton pump), which are under the transcriptional control of NFATc1 (52,53), were subsequently affected. Previous findings have shown that MIF interacts with TXNIP, abrogating its inhibitory effect on NF-kB activity (28).…”

Effect of echinalkamide identified from Echinacea purpurea (L.) Moench on the inhibition of osteoclastogenesis and bone resorption

“…Activation is carried out at the protein level through phosphorylation processes including mitogen-activated protein kinases (MAPKs) and Phosphatidyl-inositol-3-kinase (PI3K)/Akt pathway 60,61 . Many studies have revealed that MAPKs can be stimulated by RANKL stimulation and are associated with osteoclastogenesis [62][63][64][65] . RANKL stimulated ERK, JNK, and p38 through activation of MEK1/2, MKK7, and MKK6 to induce activation of their downsignal targets such as c-Fos, AP-1 transcription Figure 6.…”

Purpurogallin Protects Keratinocytes from Damage and Apoptosis Induced by Ultraviolet B Radiation and Particulate Matter 2.5

“…Purpurogallin (PG), a natural phenol, suppressed delayed vasospasm, and protected cardiac and kidney cells (Zeng et al ., 1992; Wu et al ., 1996; Chang et al ., 2014). Additionally, PG reduced inflammation in BV2 microglia cells and osteolytic diseases and showed antioxidant effects by scavenging hydroxyl radicals (Prasad and Laxdal, 1994; Park et al ., 2013; Kim et al ., 2018).…”