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An LGR4 agonist activates the GSK‑3β pathway to inhibit RANK‑RANKL signaling during osteoclastogenesis in bone marrow‑derived macrophages

  • Authors:
    • Yuria Jang
    • Hyeonjoon Lee
    • Yongjin Cho
    • Eunseo Choi
    • Suenghwan Jo
    • Hong Moon Sohn
    • Beom Chang Kim
    • Young Jong Ko
    • Wonbong Lim
  • View Affiliations / Copyright

    Affiliations: Laboratory of Orthopedic Research, Chosun University Hospital, Gwangju 61452, Republic of Korea, Department of Physics, Chosun University, Gwangju 61452, Republic of Korea
    Copyright: © Jang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 10
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    Published online on: December 5, 2023
       https://doi.org/10.3892/ijmm.2023.5334
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Abstract

The binding between receptor‑activated nuclear factor‑κB (RANK) and the RANK ligand (RANKL) during osteoclast development is an important target for drugs that treat osteoporosis. The leucine‑rich repeat‑containing G‑protein‑coupled receptor 4 (LGR4) acts as a negative regulator of RANK‑RANKL that suppresses canonical RANK signaling during osteoclast differentiation. Therefore, LGR4 agonists may be useful in inhibiting osteoclastogenesis and effectively treating osteoporosis. In the present study, bone marrow‑derived macrophages and a mouse model of RANKL‑induced bone loss were used to investigate the effect of mutant RANKL (MT RANKL), which was previously developed based on the crystal structure of the RANKL complex. In the present study, the binding affinity of wild‑type (WT) RANKL and MT RANKL to RANK and LGR4 was determined using microscale thermophoresis analysis, and the effect of the ligands on the AKT‑glycogen synthase kinase‑3β (GSK‑3β)‑nuclear factor of activated T cells, cytoplasmic, calcineurin‑dependent 1 (NFATc1) signaling cascade was investigated using western blotting and confocal microscopy. In addition, the expression of LGR4 and the colocalization of LGR4 with MT RANKL were analyzed in a mouse model of RANKL‑induced bone loss. The results showed that in osteoclast precursor cells, MT RANKL bound with high affinity to LGR4 and increased GSK‑3β phosphorylation independently of AKT, resulting in the inhibition of NFATc1 nuclear translocation. In the mouse model, MT RANKL colocalized with LGR4 and inhibited bone resorption. These results indicated that MT RANKL may inhibit RANKL‑induced osteoclastogenesis through an LGR4‑dependent pathway and this could be exploited to develop new therapies for osteoporosis.
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Copy and paste a formatted citation
Spandidos Publications style
Jang Y, Lee H, Cho Y, Choi E, Jo S, Sohn HM, Kim BC, Ko YJ and Lim W: An LGR4 agonist activates the GSK‑3β pathway to inhibit RANK‑RANKL signaling during osteoclastogenesis in bone marrow‑derived macrophages. Int J Mol Med 53: 10, 2024.
APA
Jang, Y., Lee, H., Cho, Y., Choi, E., Jo, S., Sohn, H.M. ... Lim, W. (2024). An LGR4 agonist activates the GSK‑3β pathway to inhibit RANK‑RANKL signaling during osteoclastogenesis in bone marrow‑derived macrophages. International Journal of Molecular Medicine, 53, 10. https://doi.org/10.3892/ijmm.2023.5334
MLA
Jang, Y., Lee, H., Cho, Y., Choi, E., Jo, S., Sohn, H. M., Kim, B. C., Ko, Y. J., Lim, W."An LGR4 agonist activates the GSK‑3β pathway to inhibit RANK‑RANKL signaling during osteoclastogenesis in bone marrow‑derived macrophages". International Journal of Molecular Medicine 53.1 (2024): 10.
Chicago
Jang, Y., Lee, H., Cho, Y., Choi, E., Jo, S., Sohn, H. M., Kim, B. C., Ko, Y. J., Lim, W."An LGR4 agonist activates the GSK‑3β pathway to inhibit RANK‑RANKL signaling during osteoclastogenesis in bone marrow‑derived macrophages". International Journal of Molecular Medicine 53, no. 1 (2024): 10. https://doi.org/10.3892/ijmm.2023.5334
Copy and paste a formatted citation
x
Spandidos Publications style
Jang Y, Lee H, Cho Y, Choi E, Jo S, Sohn HM, Kim BC, Ko YJ and Lim W: An LGR4 agonist activates the GSK‑3β pathway to inhibit RANK‑RANKL signaling during osteoclastogenesis in bone marrow‑derived macrophages. Int J Mol Med 53: 10, 2024.
APA
Jang, Y., Lee, H., Cho, Y., Choi, E., Jo, S., Sohn, H.M. ... Lim, W. (2024). An LGR4 agonist activates the GSK‑3β pathway to inhibit RANK‑RANKL signaling during osteoclastogenesis in bone marrow‑derived macrophages. International Journal of Molecular Medicine, 53, 10. https://doi.org/10.3892/ijmm.2023.5334
MLA
Jang, Y., Lee, H., Cho, Y., Choi, E., Jo, S., Sohn, H. M., Kim, B. C., Ko, Y. J., Lim, W."An LGR4 agonist activates the GSK‑3β pathway to inhibit RANK‑RANKL signaling during osteoclastogenesis in bone marrow‑derived macrophages". International Journal of Molecular Medicine 53.1 (2024): 10.
Chicago
Jang, Y., Lee, H., Cho, Y., Choi, E., Jo, S., Sohn, H. M., Kim, B. C., Ko, Y. J., Lim, W."An LGR4 agonist activates the GSK‑3β pathway to inhibit RANK‑RANKL signaling during osteoclastogenesis in bone marrow‑derived macrophages". International Journal of Molecular Medicine 53, no. 1 (2024): 10. https://doi.org/10.3892/ijmm.2023.5334
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