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

Nat Commun. 2022 Jul 8;13(1):3960. doi: 10.1038/s41467-022-31697-3.

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.

MeSH terms

  • Animals
  • Bone and Bones* / cytology
  • Bone and Bones* / metabolism
  • Cartilage* / cytology
  • Cartilage* / metabolism
  • Cell Differentiation / genetics
  • Chondrogenesis / genetics
  • Female
  • Mesenchymal Stem Cells* / cytology
  • Mesenchymal Stem Cells* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microtubule-Associated Proteins* / genetics
  • Osteogenesis / genetics
  • Protein Serine-Threonine Kinases* / genetics
  • Transforming Growth Factor beta / metabolism
  • Wnt Signaling Pathway

Substances

  • Microtubule-Associated Proteins
  • Transforming Growth Factor beta
  • Protein Serine-Threonine Kinases