Abstract
Osteoporosis is a debilitating skeletal disorder with an increased risk of low-energy fracture, which commonly occurs among postmenopausal women. Andrographolide (AP), a natural product isolated from Andrographis paniculata, has been found to have anti-inflammatory, anti-cancer, anti-asthmatic, and neuro-protective properties. However, its therapeutic effect on osteoporosis is unknown. In this study, an ovariectomy (OVX) mouse model was used to evaluate the therapeutic effects of AP on post-menopausal osteoporosis by using micro-computed tomography (micro-CT). Bone marrow-derived osteoclast culture was used to examine the inhibitory effect of AP on osteoclastogenesis. Real time PCR was employed to examine the effect of AP on the expression of osteoclast marker genes. The activities of transcriptional factors NF-κB and NFATc1 were evaluated using a luciferase reporter assay, and the IκBα protein level was analyzed by Western blot. We found that OVX mice treated with AP have greater bone volume (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N) compared to vehicle-treated OVX mice. AP inhibited RANKL-induced osteoclastogenesis, the expression of osteoclast marker genes including cathepsin K (Ctsk), TRACP (Acp5), and NFATc1, as well as the transcriptional activities of NF-κB and NFATc1. In conclusion, our results suggest that AP inhibits estrogen deficiency-induced bone loss in mice via the suppression of RANKL-induced osteoclastogensis and NF-κB and NFATc1 activities and, thus, might have therapeutic potential for osteoporosis.
Highlights
The maintenance of bone homeostasis involves two coordinated actions; namely bone formation and bone resorption
Osteoclasts become the key targets of commonly-used drugs in the treatment of osteoporosis and other osteoclast-related osteolytic iseases [24]
We demonstrated that AP effectively inhibits bone loss induced by OVX
Summary
The maintenance of bone homeostasis involves two coordinated actions; namely bone formation (by osteoblasts) and bone resorption (by osteoclasts). Macrophage colony-stimulating factor-1 (MCSF-1) is necessary for the proliferation and survival of osteoclast progenitor cells [4], the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) is a critical cytokine for osteoclast differentiation [5]. Andrographolide (AP) Inhibits Ovariectomy-Induced Bone Loss in Vivo trabecular bone mass in OVX mice was markedly reduced compared to sham-operated mice at seven weeks post-ovpoasrtimTeoecntooepxmaamuysi,anlewosthhteieocpheofrfweocsatisss. AP Suppresses RANKL-Induced Nuclear Factor of Activated T-Cells (NFATc1) Activation. AP inhibited RANKL-induced gene expression of Ctsk, TRACP (Acp5), and NFATc1. The transcriptional activity of NFAT was dramatically up-regulated by RANKL, but this effect was strongly inhibited by AP in a dose dependent manner (Figure 4D). The results showed that AP has no obvious effect on the ERK phosphorylation induced by RANKL (Figure 4E)
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