Abstract
Osteoclasts are large, multinucleated cells responsible for bone resorption and are induced in response to the regulatory activity of receptor activator of nuclear factor-kappa B ligand (RANKL). Excessive osteoclast activity causes pathological bone loss and destruction. Many studies have investigated molecules that specifically inhibit osteoclast activity by blocking RANKL signaling or bone resorption. In recent years, we screened compounds from commercial libraries to identify molecules capable of inhibiting RANKL-induced osteoclast differentiation. Consequently, we reported some compounds that are effective at attenuating osteoclast activity. In this study, we found that N-[2-(4-acetyl-1-piperazinyl)phenyl]-2-(3-methylphenoxy)acetamide (NAPMA) significantly inhibited the formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive cells from bone marrow-derived macrophages in a dose-dependent manner, without cytotoxic effects. NAPMA downregulated the expression of osteoclast-specific markers, such as c-Fos, NFATc1, DC-STAMP, cathepsin K, and MMP-9, at the transcript and protein levels. Accordingly, bone resorption and actin ring formation were decreased in response to NAPMA treatment. Furthermore, we demonstrated the protective effect of NAPMA against ovariectomy-induced bone loss using micro-CT and histological analysis. Collectively, the results showed that NAPMA inhibited osteoclast differentiation and attenuated bone resorption. It is thus a potential drug candidate for the treatment of osteoporosis and other bone diseases associated with excessive bone resorption.
Highlights
Bone homeostasis is a dynamic process that is important to maintain the balance between bone resorption by osteoclasts and bone formation by osteoblasts [1]
Owing to their structural similarity to NAPMA, we examined whether the inhibitory effect of NAPMA on receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclast differentiation was comparable with that of PPOA-N-Ac-2-Me or PPOA-N-Ac-2-Cl
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Summary
Bone homeostasis is a dynamic process that is important to maintain the balance between bone resorption by osteoclasts and bone formation by osteoblasts [1]. An imbalance caused by excessive osteoclast-induced bone resorption may lead to bone-destructive conditions, such as rheumatoid arthritis, osteoporosis, and lytic bone metastases [2]. Osteoclasts, which originate from hematopoietic cells of monocyte or macrophage lineage, undergo differentiation to form multinucleated cells (MNCs), which are responsible for bone resorption [3]. As osteoclasts are the primary bone resorptive cells, excessive osteoclast differentiation is strongly correlated with various bone diseases in humans. Excessive osteoclast-induced bone resorption may cause osteoporosis, rheumatoid arthritis, and osteoarthritis, and osteoclast dysfunction may cause osteopetrosis [4,5,6]. Osteoporosis is a disease characterized by the loss of bone mass, structural deterioration of bone tissue, and porous bones, all of which result in increased bone fragility [7]. There is a need to develop an effective treatment for osteoporosis based on the inhibition of excessive osteoclast activity
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