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Natural polyamines inhibit the migration of preosteoclasts by attenuating Ca2+-PYK2-Src-NFATc1 signaling pathways

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Abstract

Natural polyamines have numerous biological activities. Several studies have reported their beneficial role in bone metabolism, but their mode of action is not fully understood. Bone diseases such as osteoporosis, which is characterized by impaired bone structure and low bone mass, are caused by an increased number of osteoclasts and/or overactivation of osteoclastogenesis. Osteoclast differentiation is a multi-complex procedure involving the following sequential steps: differentiation–migration–fusion–resorption. In this study, we found that putrescine, spermidine or spermine inhibited the RANKL-mediated migration of preosteoclasts. Furthermore, the RANKL-mediated activation of the Src-PYK2 signaling axis and of transcription factors such as NF-κB and NFATc1 was prevented by each polyamine. Anti-osteoclastogenic and anti-migration activities of polyamines were confirmed by evaluating their potential to downregulate the mRNA expression levels of osteoclastogenesis-related genes such as OSCAR, TRAP, cathepsin K and c-Src, and genes related to fusion and/or migration of preosteoclasts. Moreover, ATP-mediated elevation of cytosolic free Ca2+ concentration ([Ca2+]i) was strongly inhibited by each polyamine, indicating the involvement of [Ca2+]i in the anti-fusion activities of polyamines. In conclusion, polyamines could exhibit anti-osteoclastogenic activity by inhibiting the migration of preosteoclasts via the Ca2+-PYK2-Src-NFATc1 signaling axis.

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Acknowledgments

This work was supported by the Korea Research Institute of Chemical Technology project’s grant (SI-1304) and the Inter-ER Cooperation Projects (R0002019) of Korea Institute for Advancement of Technology, which were funded by the Korea Ministry of Knowledge Economy.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Research Institute of Basic Science, Sunchon National University, Suncheon, 540-742, Republic of Korea

    Jeong-Tae Yeon

  2. Laboratory of Translational Therapeutics, Pharmacology Research Center, Division of Drug Discovery, Korea Research Institute of Chemical Technology, Daejeon, 305-600, Republic of Korea

    Byung Jun Ryu, Sik-Won Choi & Seong Hwan Kim

  3. Pharmacology Research Center, Division of Drug Discovery, Korea Research Institute of Chemical Technology, Daejeon, 305-600, Republic of Korea

    Jin-Chul Heo

  4. Department of Pharmacy, Sunchon National University, Suncheon, 540-742, Republic of Korea

    Kwang-Jin Kim & Young-Jin Son

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  1. Jeong-Tae Yeon
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Correspondence to Young-Jin Son or Seong Hwan Kim.

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Yeon, JT., Ryu, B.J., Choi, SW. et al. Natural polyamines inhibit the migration of preosteoclasts by attenuating Ca2+-PYK2-Src-NFATc1 signaling pathways. Amino Acids 46, 2605–2614 (2014). https://doi.org/10.1007/s00726-014-1797-9

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