The key royal jelly component 10-hydroxy-2-decenoic acid protects against bone loss by inhibiting NF-κB signaling downstream of FFAR4

Yosuke Tsuchiya,Mikihito Hayashi,Katashi Nagamatsu,Takehito Ono,Masaki Kamakura,Takanori Iwata,Tomoki Nakashima

doi:10.1074/jbc.ra120.013821

Yosuke Tsuchiya, Mikihito Hayashi + Show 5 more

Open Access

https://doi.org/10.1074/jbc.ra120.013821

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Abstract

The supplementation of royal jelly (RJ) is known to provide a variety of health benefits, including anti-inflammatory and anti-obesity effects. RJ treatment also reportedly protects against bone loss, but no single factor in RJ has yet been identified as an anti-osteoporosis agent. Here we fractionated RJ and identified 10-hydroxy-2-decenoic acid (10H2DA) as a key component involved in inhibiting osteoclastogenesis based on mass spectrometric analysis. We further demonstrated free fatty acid receptor 4 (FFAR4) as directly interacting with 10H2DA; binding of 10H2DA to FFAR4 on osteoclasts inhibited receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced activation of NF-κB signaling, thereby attenuating the induction of nuclear factor of activated T cells (NFAT) c1, a key transcription factor for osteoclastogenesis. Oral administration of 10H2DA attenuated bone resorption in ovariectomized mice. These results suggest a potential therapeutic approach of targeting osteoclast differentiation by the supplementation of RJ, and specifically 10H2DA, in cases of pathological bone loss such as occur in postmenopausal osteoporosis.

Highlights

Royal jelly (RJ), an essential food required by the queen honeybee, is a product secreted from the hypopharyngeal and mandibular glands of worker honeybees
Macrophage lineage precursor cells and their differentiation depends on receptor activator of nuclear factor-kB (NF-kB) ligand (RANKL) [3, 4] RANKL binding to RANK, a transmembrane molecule expressed on osteoclast precursor cells and mature osteoclasts, activates NF-kB, mitogen-activated protein kinases, and AP-1, leading to the activation of nuclear factor of activated T cell (NFAT) c1, a key transcription factor of osteoclast differentiation [3, 4]
We show that 10-hydroxy-2-decenoic acid (10H2DA), one of a group of unique medium-chain fatty acids present in RJ, is a potent inhibitor of RANKL-induced osteoclastogenesis

Summary

Introduction

Royal jelly (RJ), an essential food required by the queen honeybee, is a product secreted from the hypopharyngeal and mandibular glands of worker honeybees. The addition of RJ significantly inhibited the osteoclast differentiation induced by stimulation with macrophage-colony stimulating factor (M-CSF)/RANKL (Fig. 2A) and co-culture of bone marrow cells with calvarial osteoblastic cells (Fig. 2B) in a dose-dependent manner. We confirmed that the methanol-soluble fraction hardly contained any protein (Table S1) and this deproteinized fraction had similar inhibitory activity toward osteoclastogenesis as RJ itself (Fig. 3C).

Results

Conclusion