Asiatic Acid Inhibits OVX-Induced Osteoporosis and Osteoclastogenesis Via Regulating RANKL-Mediated NF-κb and Nfatc1 Signaling Pathways.

Guoju Hong,Jennifer Tickner,Zhenqiu Chen,Lin Zhou,Xuguang Shi,Ping Sun,Xiaorui Han,Leilei Chen,Wei He,Jiake Xu

doi:10.3389/fphar.2020.00331

Abstract

Asiatic acid is a triterpenoid compound extracted from a medicinal plant Centella asiatica. It has been used as a highly efficient compound for the treatment of cancer and hyperlipidemia, as well as possessing potential antiinflammatory properties. However, its effects on bone metabolism and osteoporosis haven’t been reported. The purpose of our research were to reveal the biomolecular effects of asiatic acid on osteoclasts, and its underlying molecular mechanisms regulating its effects on receptor activator of NF-κB ligand (RANKL)-induced signaling pathways. We found that asiatic acid inhibited multinucleated tartrate-resistant acid phosphatase (TRAcP)-positive osteoclast differentiation and osteoclast induced bone loss. Real time PCR showed that asiatic acid reduced the expression of down-cascade target genes including Ctsk, Nfatc1, Calcr, and Atp6v0d2. Western blot and luciferase reporter gene assays revealed that asiatic acid inhibits RANKL mediated NF-κB and NFATc1 signalings. Further, in vivo study demonstrated asiatic acid attenuates estrogen deficiency-induced bone loss in ovariectomized mice. MicroCT and histology analyses revealed that osteoclast numbers were significantly suppressed in asiatic acid treated groups. Furthermore, serum levels of TRAcP and CTX-1 were downregulated in treated groups. Taken together, our data show that asiatic acid can inhibit osteoclastic formation and reduce OVX-induced bone resorption through RANKL-activated NF-κB or NFATc1 signaling, suggesting that asiatic acid may be a potential and effective natural compound for the therapy of excessive RANKL-related osteolytic diseases.

Highlights

Osteolytic disease is a pathologic condition characterized by the imbalance of two coordinating and opposite aspects, bone formation by osteoblastogenesis and bone resorption by osteoclastogenesis (Goltzman, 2001; Kular et al, 2012)
The results indicated that treatment with asiatic acid led to a dose-dependent inhibition of receptor activator of nuclear factor-kB (NF-kB) ligand (RANKL)-induced osteoclastogenesis. asiatic acid significantly reduced osteoclastogenesis at doses which were higher than 5 μM (Figures 1B, C)
Our results demonstrated that asiatic acid inhibited RANKLinduced osteoclastogenesis and osteoclast activity

Summary

Introduction

Osteolytic disease is a pathologic condition characterized by the imbalance of two coordinating and opposite aspects, bone formation by osteoblastogenesis and bone resorption by osteoclastogenesis (Goltzman, 2001; Kular et al, 2012). When osteoclast induced bone loss markedly exceeds the normal level, osteolytic disease occurs, which is manifested by bone mineral reduction and architectural deterioration in the skeletal system (Boyle et al, 2003; Caetano-Lopes et al, 2007). RANKL is necessary for osteoclast formation and bone mass resorption. RANKL binds with its receptor RANK and induces three key intracellular downstream signaling pathways; nuclear factor-kB (NF-kB), mitogen activated protein kinase (MAPK), and nuclear factor of activated T-cells (NFAT) (Baud’huin et al, 2007). Targeting RANKL-activated downstream signaling pathways to alter osteoclast number and function is a promising way for multiple natural compounds to attenuate enhanced bone resorption and bone loss as previously reported (Tanaka et al, 2005)

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