Zanthoxylum piperitum alleviates the bone loss in osteoporosis via inhibition of RANKL-induced c-fos/NFATc1/NF-κB pathway

Phytomedicine. 2021 Jan:80:153397. doi: 10.1016/j.phymed.2020.153397. Epub 2020 Oct 22.

Abstract

Background: The fruit of Zanthoxylum piperitum (ZP) is an herbal medicine as well as a spice agent in Asia to treat carminative, stomachic, anthelmintic and degenerative diseases. Z. piperitum was reported to have anti-oxidant, anti-inflammatory, anti-osteoarthritic and osteosarcoma proliferation-control effects.

Purpose and study design: This study was conducted to determine the anti-osteoporotic effects and mechanisms of action of ZP.

Methods: Female ICR mice underwent ovariectomies (OVX) and were orally administered ZP at 1, 10 and 100 mg/kg for 6 weeks. The femoral and tibial bones were assessed by dual-energy X-ray absorptiometry and histology to analyze the bone mineral density (BMD) and the number of osteoclasts. Raw 264.7 cells were stimulated by 100 ng/ml receptor activator of nuclear factor-κB ligand (RANKL) for 7 days in the presence of ZP. RANKL-induced signaling molecules were analyzed in osteoclasts.

Results: The levels of femoral and tibial BMD were significantly increased by ZP administration. Serum biomarkers such as osteocalcin, calcium, alkaline phosphatase and bone-specific alkaline phosphatase concentrations were markedly recovered to normal levels in ZP-treated osteoporotic mice. In addition, the number of osteoclasts in the head, trochanter and body of the femur was obviously decreased in the ZP treatment groups. Moreover, ZP treated-cells showed a reduction in the number of TRAP-positive multinuclear cells in RANKL-stimulated Raw 264.7 cells. ZP decreased the RANKL-activated NFATc1 and c-fos, transcription factors of osteoclast formation. The nuclear translocation of NF-κB and phosphorylation of ERK42/44 were inhibited by the ZP treatment in RANKL-induced osteoclasts.

Conclusion: Collectively, ZP exerts its inhibitory effect against bone resorption by regulating RANKL-mediated c-fos/NFATc1/NF-κB in osteoclast. ZP may prove to be a therapeutic agent for osteoporosis.

Keywords: Bone mineral density; Osteoclast; Osteoporosis; RANKL; Zanthoxylum piperitum.

MeSH terms

  • Animals
  • Bone Density / drug effects
  • Bone Resorption / drug therapy
  • Bone Resorption / metabolism
  • Female
  • Mice
  • Mice, Inbred ICR
  • NF-kappa B / metabolism
  • NFATC Transcription Factors / metabolism
  • Osteoclasts / drug effects*
  • Osteoclasts / metabolism
  • Osteoporosis / drug therapy*
  • Osteoporosis / etiology
  • Osteoporosis / metabolism
  • Ovariectomy / adverse effects
  • Plant Extracts / pharmacology*
  • Proto-Oncogene Proteins c-fos / metabolism
  • RANK Ligand / metabolism
  • RAW 264.7 Cells
  • Zanthoxylum / chemistry*

Substances

  • NF-kappa B
  • NFATC Transcription Factors
  • Nfatc1 protein, mouse
  • Plant Extracts
  • Proto-Oncogene Proteins c-fos
  • RANK Ligand
  • Tnfsf11 protein, mouse