Abstract
BackgroundA decrease of bone mass is a major risk factor for fracture. Several natural products have traditionally been used as herbal medicines to prevent and/or treat bone disorders including osteoporosis. Praeruptorin A is isolated from the dry root extract of Peucedanum praeruptorum Dunn and has several biological activities, but its anti-osteoporotic activity has not been studied yet.Materials and MethodsThe effect of praeruptorin A on the differentiation of bone marrow–derived macrophages into osteoclasts was examined by phenotype assay and confirmed by real-time PCR and immunoblotting. The involvement of NFATc1 in the anti-osteoclastogenic action of praeruptorin A was evaluated by its lentiviral ectopic expression. Intracellular Ca2+ levels were also measured.ResultsPraeruptorin A inhibited the RANKL-stimulated osteoclast differentiation accompanied by inhibition of p38 and Akt signaling, which could be the reason for praeruptorin A-downregulated expression levels of c-Fos and NFATc1, transcription factors that regulate osteoclast-specific genes, as well as osteoclast fusion-related molecules. The anti-osteoclastogenic effect of praeruptorin A was rescued by overexpression of NFATc1. Praeruptorin A strongly prevented the RANKL-induced Ca2+ oscillation without any changes in the phosphorylation of PLCγ.ConclusionPraeruptorin A could exhibit its anti-osteoclastogenic activity by inhibiting p38/Akt-c-Fos-NFATc1 signaling and PLCγ-independent Ca2+ oscillation.
Highlights
Bone fracture is a public health problem because it occurs in patients with bone-related disorders including osteoporosis
Praeruptorin A inhibited the receptor activator of nuclear factor-kB ligand (RANKL)-stimulated osteoclast differentiation accompanied by inhibition of p38 and Akt signaling, which could be the reason for praeruptorin A-downregulated expression levels of c-Fos and NFATc1, transcription factors that regulate osteoclast-specific genes, as well as osteoclast fusion-related molecules
Praeruptorin A could exhibit its anti-osteoclastogenic activity by inhibiting p38/Akt-c-Fos-NFATc1 signaling and phospholipase Cc (PLCc)-independent Ca2+ oscillation
Summary
Bone fracture is a public health problem because it occurs in patients with bone-related disorders including osteoporosis. A method to pharmaceutically inhibit osteoclast differentiation is one of the therapeutic strategies for preventing and/or treating bone disorders and related fractures [5]. Osteoclast-targeting bisphosphonates have been widely used to treat patients with osteoporosis and/or prevent osteoporotic fracture. The orally available bisphosphonates principally inhibit the activation of osteoclasts by binding to hydroxyapatite [6], but recently bisphosphonate-related side effects including acute phase response, hypocalcaemia, secondary hyperparathyroidism, upper gastrointestinal tract problems, musculoskeletal pain, rental toxicity and osteonecrosis of the jaw have been reported [7]. Several natural products have traditionally been used as herbal medicines to prevent and/or treat bone disorders including osteoporosis. Praeruptorin A is isolated from the dry root extract of Peucedanum praeruptorum Dunn and has several biological activities, but its anti-osteoporotic activity has not been studied yet
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