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Apelin promotes RANKL‑mediated osteoclastogenesis by activating MAPK and NF‑κB pathways

  • Authors:
    • Yu-Han Wang
    • Yu-Ying Wu
    • Chun-Hao Tsai
    • Yi-Chin Fong
    • Chih-Yuan Ko
    • Hsien-Te Chen
    • Yat-Yin Law
    • Chih-Hsin Tang

  • View Affiliations / Copyright

    Affiliations: Department of Pharmacology, School of Medicine, China Medical University, Taichung 404328, Taiwan, R.O.C., Department of Orthopedics, Chung Shan Medical University Hospital, Taichung 402306, Taiwan, R.O.C., Department of Sports Medicine, College of Health Care, China Medical University, Taichung 402306, Taiwan, R.O.C., Department of Orthopedic Surgery, China Medical University Hospital, Taichung 404327, Taiwan, R.O.C.
    Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 41
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    Published online on: November 12, 2025
       https://doi.org/10.3892/mmr.2025.13751
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Abstract

The regulation of bone mass relies on a dynamic interplay between bone‑forming osteoblasts and bone‑resorbing osteoclasts. Imbalances in this regulatory system favor bone resorption and are implicated in the development of osteolytic disorders such as osteoporosis. Although current treatments targeting osteoclast activity are effective, safety concerns remain a notable limitation. As a multifunctional adipokine, apelin (APLN) serves a role in angiogenesis and metabolic regulation. However, to the best of our knowledge, its involvement in osteoclast differentiation has not yet been characterized. The present study thus examined the effects of APLN on osteoclastogenesis using a murine‑macrophage model stimulated with receptor activator of NF‑κB ligand (RANKL). The results revealed that APLN augmented RANKL‑induced osteoclast differentiation, promoting the formation of tartrate‑resistant acid phosphatase‑positive multinucleated cells and the development of organized F‑actin rings. Transcriptome analyses of a public dataset confirmed the temporal upregulation of osteoclast‑related genes under RANKL stimulation. It was further discovered that co‑treatment with APLN and RANKL significantly enhanced the expression of these osteoclast‑specific markers. APLN co‑treatment with RANKL upregulated the ERK, JNK, p38 and NF‑κB signaling pathways, and this activation was effectively attenuated by specific pathway inhibitors. In conclusion, these findings identified APLN as an enhancer of RANKL‑dependent osteoclast differentiation and signaling, suggesting that the modulation of APLN activity may provide a promising strategy for controlling excessive bone resorption in skeletal diseases.
View Figures

Figure 1

APLN promotes RANKL-induced osteoclast differentiation. RAW264.7 cells were treated with RANKL (50 ng/ml) in the presence or absence of APLN (1, 3 or 10 ng/ml) for 5 days. (A) Representative images of cells were stained with tartrate-resistant acid phosphatase to identify mature osteoclasts. (B) Quantification of the osteoclast area percentage using ImageJ software. Scale bar, 100 µm. *P<0.05 vs. RANKL-treated group. #P<0.05 vs. RANKL + APLN (10 ng/ml)-treated group. RANKL, receptor activator of NF-κB ligand; APLN, apelin.

Figure 2

APLN enhances F-actin ring formation in RANKL-treated RAW264.7 cells. (A) Immunofluorescence staining of F-actin (green, Alexa Fluor 488) and nuclei (blue, DAPI) in RAW264.7 cells treated with RANKL (50 ng/ml) and various concentrations of apelin (1, 3 or 10 ng/ml) for 5 days. Merged images are also shown. (B) Quantification of F-actin ring area relative to the RANKL-treated group. Scale bar, 100 µm. *P<0.05 vs. RANKL-treated group. RANKL, receptor activator of NF-κB ligand; APLN, apelin.

Figure 3

APLN enhances osteoclast marker gene expression under RANKL stimulation. (A) Heatmap analysis of osteoclast-related gene expression (ACP5, CTSK, MMP9 and NFATc1) from the GSE21639 dataset. RAW264.7 cells were treated with or without RANKL for 2 or 5 days. (B) Boxplot and UMAP analyses of the GSE21639 dataset. The boxplot shows consistent overall gene expression distributions across all samples without outliers, while the UMAP plot illustrates the clustering of samples according to experimental conditions (Control or RANKL treatment on days 2 and 5). These analyses were conducted to assess dataset quality and comparability prior to differential expression analysis. (C) Violin plot visualization of the transcript levels of each gene. Data were log2-transformed and grouped by treatment condition. (D) RAW264.7 cells were treated with RANKL (50 ng/ml) and increasing concentrations of APLN (1, 3 or 10 ng/ml) for 5 days. The mRNA expression of osteoclast markers was determined using reverse transcription-quantitative PCR. *P<0.05 vs. RANKL-treated group. UMAP, uniform manifold approximation and projection analyses; RANKL, receptor activator of NF-κB ligand; APLN, apelin; ACP5, acid phosphatase 5, tartrate resistant; CTSK, cathepsin K; MMP9, matrix metalloproteinase 9; NFATc1, nuclear factor of activated T-cells 1.

Figure 4

Transcriptome enrichment analysis identifies osteoclast-related signaling pathways activated by RANKL. DEGs were identified from the GSE21639 dataset by comparing RANKL-treated and control RAW264.7 cells on day 5 (|log2 fold change|>2, P<0.05). (A) Gene Ontology enrichment analysis of upregulated DEGs revealed significant enrichment in BP, CC and MF terms. (B) Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed the significant enrichment of the ‘NF-kappa B signaling pathway’ and ‘MAPK signaling pathway’. Adjusted P<0.05 was considered to indicate a significant difference. *P<0.05, **P<0.01 and ***P<0.001. DEGs, differentially expressed genes; BP, biological process; CC, cellular component; MF, molecular function; RANKL, receptor activator of NF-κB ligand.

Figure 5

APLN promotes osteoclast differentiation through activation of the MAPK pathway. (A) RAW264.7 cells were exposed to a control medium, RANKL (50 ng/ml) or RANKL + APLN (10 ng/ml) for 10 min. Cell lysates were subjected to western blot analysis to assess the phosphorylation of MAPK family members, including ERK, JNK and p38. (B) Signal intensities of p-ERK, p-JNK and p-p38 were semi-quantified using ImageJ software and normalized to their respective total protein levels. *P<0.05 vs. RANKL-treated group. (C) mRNA expression levels of osteoclast marker genes (ACP5, CTSK, MMP9 and NFATc1) were assessed using reverse transcription-quantitative PCR in cells treated with RANKL + APLN (10 ng/ml), either alone or in combination with MAPK inhibitors (FR180204 for ERK, SP600125 for JNK and SB203580 for p38). *P<0.05 vs. Control group; #P<0.05 vs. RANKL + APLN group. APLN, apelin; RANKL, receptor activator of NF-κB ligand; ACP5, acid phosphatase 5, tartrate resistant; CTSK, cathepsin K; MMP9, matrix metalloproteinase 9; NFATc1, nuclear factor of activated T-cells 1; p-, phosphorylated-; ERK/JNK/p38i, ERK/JNK/p38 inhibitor.

Figure 6

APLN enhances RANKL-induced activation of the NF-κB signaling pathway. (A) Western blot analysis of RAW264.7 cells treated with control medium, RANKL (50 ng/ml) or RANKL + APLN (10 ng/ml) for 10 min. Protein levels of p-IKK, p-IκB and p-p65 were detected to evaluate pathway activation. (B) Semi-quantification of p-IKK, p-IκB and p-p65 levels relative to their corresponding total proteins was performed using ImageJ software. (C) RAW264.7 cells were transfected with an NF-κB luciferase reporter construct and treated with RANKL (50 ng/ml) or RANKL + APLN (10 ng/ml) for 24 h. Luciferase activity was measured using cell lysates and reporter buffer mixed at a 1:1 ratio. NF-κB transcriptional activity is shown as the fold change relative to the RANKL-only group. *P<0.05 vs. RANKL-treated group. (D) Reverse transcription-quantitative PCR analysis of osteoclast marker genes (ACP5, CTSK, MMP9 and NFATc1) in cells treated with RANKL + APLN (10 ng/ml) with or without the NF-κBi PDTC (20 µM). *P<0.05 vs. Control group; #P<0.05 vs. RANKL + APLN group. APLN, apelin; RANKL, receptor activator of NF-κB ligand; ACP5, acid phosphatase 5, tartrate resistant; CTSK, cathepsin K; MMP9, matrix metalloproteinase 9; NFATc1, nuclear factor of activated T-cells 1; p-, phosphorylated-; NF-κBi, NF-κB inhibitor; PDTC, pyrrolidinedithiocarbamate ammonium.

Figure 7

APLN promotes RANKL-mediated osteoclastogenesis, and activates MAPK and NF-κB signaling pathways. APLN augmented RANKL-induced phosphorylation of ERK, JNK, p38 and NF-κB p65, leading to the increased expression of osteoclast marker genes and enhanced osteoclast differentiation and function. APLN, apelin; RANKL, receptor activator of NF-κB ligand; ACP5, acid phosphatase 5, tartrate resistant; CTSK, cathepsin K; MMP9, matrix metalloproteinase 9; NFATc1, nuclear factor of activated T-cells 1.
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Copy and paste a formatted citation
Spandidos Publications style
Wang Y, Wu Y, Tsai C, Fong Y, Ko C, Chen H, Law Y and Tang C: Apelin promotes RANKL‑mediated osteoclastogenesis by activating MAPK and NF‑&kappa;B pathways. Mol Med Rep 33: 41, 2026.
APA
Wang, Y., Wu, Y., Tsai, C., Fong, Y., Ko, C., Chen, H. ... Tang, C. (2026). Apelin promotes RANKL‑mediated osteoclastogenesis by activating MAPK and NF‑&kappa;B pathways. Molecular Medicine Reports, 33, 41. https://doi.org/10.3892/mmr.2025.13751
MLA
Wang, Y., Wu, Y., Tsai, C., Fong, Y., Ko, C., Chen, H., Law, Y., Tang, C."Apelin promotes RANKL‑mediated osteoclastogenesis by activating MAPK and NF‑&kappa;B pathways". Molecular Medicine Reports 33.1 (2026): 41.
Chicago
Wang, Y., Wu, Y., Tsai, C., Fong, Y., Ko, C., Chen, H., Law, Y., Tang, C."Apelin promotes RANKL‑mediated osteoclastogenesis by activating MAPK and NF‑&kappa;B pathways". Molecular Medicine Reports 33, no. 1 (2026): 41. https://doi.org/10.3892/mmr.2025.13751
Copy and paste a formatted citation
x
Spandidos Publications style
Wang Y, Wu Y, Tsai C, Fong Y, Ko C, Chen H, Law Y and Tang C: Apelin promotes RANKL‑mediated osteoclastogenesis by activating MAPK and NF‑&kappa;B pathways. Mol Med Rep 33: 41, 2026.
APA
Wang, Y., Wu, Y., Tsai, C., Fong, Y., Ko, C., Chen, H. ... Tang, C. (2026). Apelin promotes RANKL‑mediated osteoclastogenesis by activating MAPK and NF‑&kappa;B pathways. Molecular Medicine Reports, 33, 41. https://doi.org/10.3892/mmr.2025.13751
MLA
Wang, Y., Wu, Y., Tsai, C., Fong, Y., Ko, C., Chen, H., Law, Y., Tang, C."Apelin promotes RANKL‑mediated osteoclastogenesis by activating MAPK and NF‑&kappa;B pathways". Molecular Medicine Reports 33.1 (2026): 41.
Chicago
Wang, Y., Wu, Y., Tsai, C., Fong, Y., Ko, C., Chen, H., Law, Y., Tang, C."Apelin promotes RANKL‑mediated osteoclastogenesis by activating MAPK and NF‑&kappa;B pathways". Molecular Medicine Reports 33, no. 1 (2026): 41. https://doi.org/10.3892/mmr.2025.13751
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