Maslinic acid suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss by regulating RANKL-mediated NF-κB and MAPK signaling pathways

Sep 4, 2010Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

Maslinic acid may reduce bone loss after ovary removal by blocking signals that create bone-breaking cells

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Abstract

Maslinic acid inhibited RANKL-induced osteoclastogenesis in mouse cells in a dose-dependent manner.

Osteoclastogenesis-related gene expression decreased with maslinic acid treatment.
Maslinic acid suppressed actin ring formation during the early stages of osteoclast development.
In ovariectomized mice, maslinic acid administration prevented bone loss linked to increased osteoclast activity.
At the molecular level, maslinic acid reduced phosphorylation of key signaling proteins in the NF-κB and MAPK pathways.
Maslinic acid downregulated receptor activator NF-κB expression and inhibited its interaction with TRAF6.

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Activation of NF-κB and MAPK/activator protein 1 (AP-1) signaling pathways by receptor activator NF-κB ligand (RANKL) is essential for osteoclast activity. Targeting NF-κB and MAPK/AP-1 signaling to modulate osteoclast activity has been a promising strategy for osteoclast-related diseases. In this study we examined the effects of maslinic acid (MA), a pentacyclic triterpene acid that is widely present in dietary plants, on RANKL-induced osteoclastogenesis, osteoclast function, and signaling pathways by in vitro and in vivo assay systems. In mouse bone marrow monocytes (BMMs) and RAW264.7 cells, MA inhibited RANKL-induced osteoclastogenesis in a dose-dependent manner within nongrowth inhibitory concentration, and MA decreased osteoclastogenesis-related marker gene expression, including TRACP, MMP9, c-Src, CTR, and cathepsin K. Specifically, MA suppressed osteoclastogenesis and actin ring formation at early stage. In ovariectomized mice, administration of MA prevented ovariectomy-induced bone loss by inhibiting osteoclast activity. At molecular levels, MA abrogated the phosphorylation of MAPKs and AP-1 activity, inhibited the IκBα phosphorylation and degradation, blocked NF-κB/p65 phosphorylation, nuclear translocation, and DNA-binding activity by downregulating RANK expression and blocking RANK interaction with TRAF6. Together our data demonstrate that MA suppresses RANKL-induced osteoclastogenesis through NF-κB and MAPK/AP-1 signaling pathways and that MA is a promising agent in the treatment of osteoclast-related diseases such as osteoporosis.

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Maslinic acid suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss by regulating RANKL-mediated NF-κB and MAPK signaling pathways

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