Abstract
Osteoclasts are poly-nuclear cells that resorb mineral components from old or damaged bone tissue. Primary mononuclear cells are activated by receptor activator of nuclear factor kappa-Β ligand (RANKL) and differentiate into large multinucleated cells. Dysregulation of osteoclast differentiation can lead to pathological bone loss and destruction. Many studies have focused on the development of new molecules to regulate RANKL-mediated signaling. In this study, N-[2-(4-acetyl-1-piperazinyl)phenyl]-2-(2-chlorophenoxy) acetamide (PPOA-N-Ac-2-Cl) led to a significant decrease in the formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive cells in a dose-dependent manner, without inducing significant cytotoxicity. PPOA-N-Ac-2-Cl affected the expression of osteoclast-specific marker genes, such as TRAF6, c-fos, DC-STAMP, NFATc1, MMP9, CtsK, and TRAP (Acp5), during RANKL-mediated osteoclastogenesis. Moreover, PPOA-N-Ac-2-Cl significantly attenuated the protein levels of CtsK, a critical protease involved in bone resorption. Accordingly, bone resorption activity and F-actin ring formation decreased in the presence of PPOA-N-Ac-2-Cl. In conclusion, this study shows that PPOA-N-Ac-2-Cl acts as an inhibitor of osteoclast differentiation and may serve as a potential candidate agent for the treatment of osteoclast-related bone diseases by virtue of attenuating bone resorption.
Highlights
Bone homeostasis is finely regulated by osteoblasts that form bone and osteoclasts that absorb bone
Evidence has shown that NF-κB, c-Src, and mitogen-activated protein kinases (MAPKs)-mediated signaling pathways are critical for osteoclast differentiation and require intermediate cytokines, such as receptor activator of nuclear factor kappa-B ligand (RANKL), interleukin-1 (IL-1), and tumor necrosis factor alpha (TNF-α) [4]
We investigated whether PPOA derivatives could attenuate RANKL-induced osteoclast differentiation in vitro and examined the molecular mechanisms underlying the inhibitory effects of PPOA-N-Ac-2-Cl during osteoclastogenesis
Summary
Bone homeostasis is finely regulated by osteoblasts that form bone and osteoclasts that absorb bone. Phosphoinositide 3-kinase (PI3k)/Akt plays an important role in the differentiation and function of osteoclast [6,7] Activation of these signaling pathways induces nuclear factor of activated T-cells cytoplasmic (NFATc1), which eventually triggers the expression of osteoclast-specific genes, such as tartrate-resistant acid phosphatase (TRAP), dendritic cell-specific transmembrane protein (DC-STAMP), matrix metalloproteinase- 9 (MMP-9), and cathepsin K (CtsK) [8]. PPOA-N-Ac-2-Cl attenuated bone resorption during osteoclastogenesis in a dose-dependent manner; further, it suppressed the expression levels of osteoclast-related marker genes, such as TRAF6, c-fos, DC-STAMP, ATP6v0d2, NFATc1, MMP9, CtsK, and Acp. PPOA-N-Ac-2-Cl attenuated bone resorption during osteoclastogenesis in a dose-dependent manner; further, it suppressed the expression levels of osteoclast-related marker genes, such as TRAF6, c-fos, DC-STAMP, ATP6v0d2, NFATc1, MMP9, CtsK, and Acp5 These results suggest that PPOA-N-Ac-2-Cl inhibits osteoclast formation and bone resorption, indicating its potential as a candidate agent for the treatment of bone resorption-related diseases
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