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

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 Jang; Hyun Yi Kim; Seung Jun Lee; Sun U. Song; Kyung Soon Park; Mikako Tanaka; Hayato Ohshima; Jin Won Cho; Fumihiro Sugiyama; Satoru Takahashi; Han Sung Jung; Seong Jin Kim

doi:10.1038/s41467-022-31697-3

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

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 Jang, Hyun Yi Kim, Seung Jun Lee, Sun U. Song, Kyung Soon Park, Mikako Tanaka, Hayato Ohshima, Jin Won ChoFumihiro Sugiyama, Satoru Takahashi, Han Sung Jung, Seong Jin Kim

Research output: Contribution to journal › Article › peer-review

31 Citations (Scopus)

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.

Original language	English
Article number	3960
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-31697-3
Publication status	Published - 2022 Dec

Bibliographical note

Publisher Copyright:
© 2022, The Author(s).

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-022-31697-3

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Kim, P., Park, J., Lee, D. J., Mizuno, S., Shinohara, M., Hong, C. P., Jeong, Y., Yun, R., Park, H., Park, S., Yang, K. M., Lee, M. J., Jang, S. P., Kim, H. Y., Lee, S. J., Song, S. U., Park, K. S., Tanaka, M., Ohshima, H., ... Kim, S. J. (2022). Mast4 determines the cell fate of MSCs for bone and cartilage development. Nature communications, 13(1), Article 3960. https://doi.org/10.1038/s41467-022-31697-3

@article{378e400ed51e447fb105065ed4d7ca00,

title = "Mast4 determines the cell fate of MSCs for bone and cartilage development",

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.",

author = "Pyunggang Kim and Jinah Park and Lee, {Dong Joon} and Seiya Mizuno and Masahiro Shinohara and Hong, {Chang Pyo} and Yealeen Jeong and Rebecca Yun and Hyeyeon Park and Sujin Park and Yang, {Kyung Min} and Lee, {Min Jung} and Jang, {Seung Pil} and Kim, {Hyun Yi} and Lee, {Seung Jun} and Song, {Sun U.} and Park, {Kyung Soon} and Mikako Tanaka and Hayato Ohshima and Cho, {Jin Won} and Fumihiro Sugiyama and Satoru Takahashi and Jung, {Han Sung} and Kim, {Seong Jin}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-31697-3",

language = "English",

volume = "13",

journal = "Nature communications",

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Kim, P, Park, J, Lee, DJ, Mizuno, S, Shinohara, M, Hong, CP, Jeong, Y, Yun, R, Park, H, Park, S, Yang, KM, Lee, MJ, Jang, SP, Kim, HY, Lee, SJ, Song, SU, Park, KS, Tanaka, M, Ohshima, H, Cho, JW, Sugiyama, F, Takahashi, S, Jung, HS & Kim, SJ 2022, 'Mast4 determines the cell fate of MSCs for bone and cartilage development', Nature communications, vol. 13, no. 1, 3960. https://doi.org/10.1038/s41467-022-31697-3

TY - JOUR

T1 - Mast4 determines the cell fate of MSCs for bone and cartilage development

AU - Kim, Pyunggang

AU - Park, Jinah

AU - Lee, Dong Joon

AU - Mizuno, Seiya

AU - Shinohara, Masahiro

AU - Hong, Chang Pyo

AU - Jeong, Yealeen

AU - Yun, Rebecca

AU - Park, Hyeyeon

AU - Park, Sujin

AU - Yang, Kyung Min

AU - Lee, Min Jung

AU - Jang, Seung Pil

AU - Kim, Hyun Yi

AU - Lee, Seung Jun

AU - Song, Sun U.

AU - Park, Kyung Soon

AU - Tanaka, Mikako

AU - Ohshima, Hayato

AU - Cho, Jin Won

AU - Sugiyama, Fumihiro

AU - Takahashi, Satoru

AU - Jung, Han Sung

AU - Kim, Seong Jin

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-022-31697-3

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AN - SCOPUS:85133717739

SN - 2041-1723

VL - 13

JO - Nature communications

JF - Nature communications

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ER -

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

Abstract

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