Abstract
Aconitum pseudo-laeve var. erectum (APE) has been widely shown in herbal medicine to have a therapeutic effect on inflammatory conditions. However, there has been no evidence on whether the extract of APE is involved in the biological bone metabolism process, particularly osteoclast-mediated bone resorption. In this study, we confirmed that the administration of APE could restore normal skeletal conditions in a murine model of lipopolysaccharide (LPS)-induced bone loss via a decrease in the receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio and osteoclast number. We then investigated the effect of APE on the RANKL-induced formation and function of osteoclasts to elucidate its underlying molecular mechanisms. APE suppressed the formation of tartrate-resistant acid phosphatase (TRAP)-positive cells, as well as the bone-resorbing activity of mature osteoclasts. Furthermore, APE attenuated nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and c-Fos without affecting any early signal pathway of osteoclastogenesis. Subsequently, APE significantly downregulated the expression of various genes exclusively expressed in osteoclasts. These results demonstrate that APE restores LPS-induced bone loss through a decrease of the serum RANKL/OPG ratio, and inhibits osteoclast differentiation and function, suggesting the promise of APE as a potential cure for various osteoclast-associated bone diseases.
Highlights
With a rapidly aging society, metabolic bone disorders including osteoporosis, periodontitis, Paget’s disease, and rheumatoid arthritis have become major health problems [1]
To determine the effect of Aconitum pseudo-laeve var. erectum (APE) on bone mass in vivo, we examined the effect of APE in murine models of LPS-mediated bone erosion
A greater reduction of bone mass was observed in the femurs of LPS-injected mice compared to the vehicle-treated mice, a partial recovery of bone density of both LPS- and APE-treated mice was observed in 3-dimensional visualization (Figure 1A)
Summary
With a rapidly aging society, metabolic bone disorders including osteoporosis, periodontitis, Paget’s disease, and rheumatoid arthritis have become major health problems [1]. Thereafter, the expression of osteoclast-specific marker genes—including osteoclast-associated receptor (OSCAR), tartrate-resistant acid phosphatase (TRAP), Atp6v0d2, cathepsin K, as well as, osteoclast stimulatory transmembrane protein (OC-STAMP), dendritic cell-specific transmembrane protein (DC-STAMP), calcitonin receptor (CTR), and matrix metallopeptidase 9 (MMP-9)—is induced to develop characteristic osteoclasts via interaction between c-Fos and NFATc1 [10,11,12,13,14,15]. Both c-Fos and NFATc1 were proven to have a critical role in osteoclast formation and differentiation. We demonstrated the inhibitory effect and mechanism of action of APE on RANKL-induced osteoclastogenesis, as well as the in vivo effect of APE in a murine model of lipopolysaccharide (LPS)-induced bone erosion
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