TAOK3 is a MAP3K contributing to osteoblast differentiation and skeletal mineralization

Biochem Biophys Res Commun. 2020 Oct 22;531(4):497-502. doi: 10.1016/j.bbrc.2020.07.060. Epub 2020 Aug 14.

Abstract

Current anabolic drugs to treat osteoporosis and other disorders of low bone mass all have important limitations in terms of toxicity, contraindications, or poor efficacy in certain contexts. Addressing these limitations will require a better understanding of the molecular pathways, such as the mitogen activated protein kinase (MAPK) pathways, that govern osteoblast differentiation and, thereby, skeletal mineralization. Whereas MAP3Ks functioning in the extracellular signal-regulated kinases (ERK) and p38 pathways have been identified in osteoblasts, MAP3Ks mediating proximal activation of the c-Jun N-terminal kinase (JNK) pathway have yet to be identified. Here, we demonstrate that thousand-and-one kinase 3 (TAOK3, MAP3K18) functions as an upstream activator of the JNK pathway in osteoblasts both in vitro and in vivo. Taok3-deficient osteoblasts displayed defective JNK pathway activation and a marked decrease in osteoblast differentiation markers and defective mineralization, which was also confirmed using TAOK3 deficient osteoblasts derived from human MSCs. Additionally, reduced expression of Taok3 in a murine model resulted in osteopenia that phenocopies aspects of the Jnk1-associated skeletal phenotype such as occipital hypomineralization. Thus, in vitro and in vivo evidence supports TAOK3 as a proximal activator of the JNK pathway in osteoblasts that plays a critical role in skeletal mineralization.

Keywords: Bone; JNK; MAPK; Osteoblasts; TAOK3.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcification, Physiologic / physiology*
  • Cell Differentiation*
  • Cells, Cultured
  • Femur / cytology
  • Femur / diagnostic imaging
  • Gene Expression
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Signaling System / physiology
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mitogen-Activated Protein Kinase 8 / genetics
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Osteoblasts / cytology*
  • Osteoblasts / physiology
  • Phenotype
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • X-Ray Microtomography

Substances

  • Protein Serine-Threonine Kinases
  • TAOK3 protein, human
  • Mitogen-Activated Protein Kinase 8
  • MAP Kinase Kinase Kinases