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 and Seong-Jin Kim ()
Additional contact information
Pyunggang Kim: GILO Foundation
Jinah Park: GILO Foundation
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
Seung-Jun Lee: Yonsei University College of Dentistry
Sun U. Song: SCM Lifescience Inc.
Kyung-Soon Park: CHA University
Mikako Tanaka: Niigata University Graduate School of Medical and Dental Sciences
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

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31697-3

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