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Mast4 determines the cell fate of MSCs for bone and cartilage development

Author

Listed:
  • Pyunggang Kim

    (GILO Foundation
    CHA University)

  • Jinah Park

    (GILO Foundation
    Amoris Bio Inc)

  • Dong-Joon Lee

    (Yonsei University College of Dentistry)

  • Seiya Mizuno

    (University of Tsukuba)

  • Masahiro Shinohara

    (National Rehabilitation Center for Persons with Disabilities)

  • Chang Pyo Hong

    (Theragen Bio Co., Ltd)

  • Yealeen Jeong

    (GILO Foundation)

  • Rebecca Yun

    (GILO Foundation)

  • Hyeyeon Park

    (GILO Foundation)

  • Sujin Park

    (GILO Foundation)

  • Kyung-Min Yang

    (Medpacto Inc.)

  • Min-Jung Lee

    (Yonsei University College of Dentistry)

  • Seung Pil Jang

    (Soo Hospital)

  • Hyun-Yi Kim

    (Yonsei University College of Dentistry
    NGeneS Inc.)

  • Seung-Jun Lee

    (Yonsei University College of Dentistry)

  • Sun U. Song

    (SCM Lifescience Inc.
    Inha University College of Medicine)

  • Kyung-Soon Park

    (CHA University)

  • Mikako Tanaka

    (Niigata University Graduate School of Medical and Dental Sciences
    Meirin College)

  • Hayato Ohshima

    (Niigata University Graduate School of Medical and Dental Sciences)

  • Jin Won Cho

    (Yonsei University)

  • Fumihiro Sugiyama

    (University of Tsukuba)

  • Satoru Takahashi

    (University of Tsukuba)

  • Han-Sung Jung

    (Yonsei University College of Dentistry)

  • Seong-Jin Kim

    (GILO Foundation
    Medpacto Inc.
    TheragenEtex Co.)

Abstract

Mesenchymal stromal cells (MSCs) differentiation into different lineages is precisely controlled by signaling pathways. Given that protein kinases play a crucial role in signal transduction, here we show that Microtubule Associated Serine/Threonine Kinase Family Member 4 (Mast4) serves as an important mediator of TGF-β and Wnt signal transduction in regulating chondro-osteogenic differentiation of MSCs. Suppression of Mast4 by TGF-β1 led to increased Sox9 stability by blocking Mast4-induced Sox9 serine 494 phosphorylation and subsequent proteasomal degradation, ultimately enhancing chondrogenesis of MSCs. On the other hand, Mast4 protein, which stability was enhanced by Wnt-mediated inhibition of GSK-3β and subsequent Smurf1 recruitment, promoted β-catenin nuclear localization and Runx2 activity, increasing osteogenesis of MSCs. Consistently, Mast4−/− mice demonstrated excessive cartilage synthesis, while exhibiting osteoporotic phenotype. Interestingly, Mast4 depletion in MSCs facilitated cartilage formation and regeneration in vivo. Altogether, our findings uncover essential roles of Mast4 in determining the fate of MSC development into cartilage or bone.

Suggested Citation

  • Pyunggang Kim & Jinah Park & Dong-Joon Lee & Seiya Mizuno & Masahiro Shinohara & Chang Pyo Hong & Yealeen Jeong & Rebecca Yun & Hyeyeon Park & Sujin Park & Kyung-Min Yang & Min-Jung Lee & Seung Pil Ja, 2022. "Mast4 determines the cell fate of MSCs for bone and cartilage development," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31697-3
    DOI: 10.1038/s41467-022-31697-3
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    References listed on IDEAS

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    1. Derrek P. Hibar & Hieab H. H. Adams & Neda Jahanshad & Ganesh Chauhan & Jason L. Stein & Edith Hofer & Miguel E. Renteria & Joshua C. Bis & Alejandro Arias-Vasquez & M. Kamran Ikram & Sylvane Desriviè, 2017. "Novel genetic loci associated with hippocampal volume," Nature Communications, Nature, vol. 8(1), pages 1-12, April.
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