DAPK1 Interacts with the p38 Isoform MAPK14, Preventing Its Nuclear Translocation and Stimulation of Bone Marrow Adipogenesis

Stem Cells. 2022 May 27;40(5):508-522. doi: 10.1093/stmcls/sxac013.

Abstract

Bone marrow (BM) adipose tissue (BMAT), a unique adipose depot, plays an important role in diseases such as osteoporosis and bone metastasis. Precise control of mesenchymal stem cell (MSC) differentiation is critical for BMAT formation and regeneration. Here, we show that death associated protein kinase 1 (DAPK1) negatively regulates BM adipogenesis in vitro and in vivo. Prx1creDapk1loxp/loxp mice showed more adipocytes in the femur than Dapk1loxp/loxp mice. Further mechanistic analyses revealed that DAPK1 inhibits p38 mitogen-activated protein kinase (MAPK) signaling in the nucleus by binding the p38 isoform MAPK14, decreasing p38 nuclear activity, which subsequently inhibits BM adipogenesis. The inhibitory effect of DAPK1 against MAPK14 was independent of its kinase activity. In addition, the decreased DAPK1 was observed in the BM-MSCs of ageing mice. Our results reveal a previously undescribed function for DAPK1 in the regulation of adipogenesis and may also reveal the underlying mechanism of BMAT formation in ageing.

Keywords: BMAT; DAPK1; MAPK14; MSCs; adipogenesis; ageing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipogenesis
  • Animals
  • Bone Marrow
  • Bone Marrow Cells
  • Cell Differentiation
  • Death-Associated Protein Kinases / genetics
  • Death-Associated Protein Kinases / metabolism
  • Death-Associated Protein Kinases / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Mesenchymal Stem Cells* / metabolism
  • Mice
  • Mitogen-Activated Protein Kinase 14* / metabolism
  • Protein Isoforms / metabolism

Substances

  • Protein Isoforms
  • Dapk1 protein, mouse
  • Death-Associated Protein Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase 14
  • mitogen-activated protein kinase 15, mouse