Adaptor protein CrkII negatively regulates osteoblast differentiation and function through JNK phosphorylation

Exp Mol Med. 2019 Sep 25;51(9):1-10. doi: 10.1038/s12276-019-0314-3.

Abstract

The adaptor protein CrkII is involved in several biological activities, including mitogenesis, phagocytosis, and cytoskeleton reorganization. Previously, we demonstrated that CrkII plays an important role in osteoclast differentiation and function through Rac1 activation both in vitro and in vivo. In this study, we investigated whether CrkII also regulates the differentiation and function of another type of bone cells, osteoblasts. Overexpression of CrkII in primary osteoblasts inhibited bone morphogenetic protein (BMP) 2-induced osteoblast differentiation and function, whereas knockdown of CrkII expression exerted the opposite effect. Importantly, CrkII strongly enhanced c-Jun-N-terminal kinase (JNK) phosphorylation, and the CrkII overexpression-mediated attenuation of osteoblast differentiation and function was recovered by JNK inhibitor treatment. Furthermore, transgenic mice overexpressing CrkII under control of the alpha-1 type I collagen promoter exhibited a reduced bone mass phenotype. Together, these results indicate that CrkII negatively regulates osteoblast differentiation and function through JNK phosphorylation. Given that CrkII acts as a negative and positive regulator of osteoblast and osteoclast differentiation, respectively, the regulation of CrkII expression in bone cells may help to develop new strategies to enhance bone formation and inhibit bone resorption.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 2 / genetics
  • Bone Resorption / genetics*
  • Bone Resorption / pathology
  • Cell Differentiation / genetics
  • Collagen Type I
  • Collagen Type I, alpha 1 Chain
  • Humans
  • JNK Mitogen-Activated Protein Kinases / genetics
  • Mice
  • Mice, Transgenic
  • Neuropeptides / genetics*
  • Osteoblasts / metabolism
  • Osteoblasts / pathology
  • Osteoclasts / metabolism
  • Osteoclasts / pathology
  • Osteogenesis / genetics*
  • Phosphorylation
  • Proto-Oncogene Proteins c-crk / genetics*
  • Signal Transduction / genetics
  • rac1 GTP-Binding Protein / genetics*

Substances

  • Bmp2 protein, mouse
  • Bone Morphogenetic Protein 2
  • Collagen Type I
  • Collagen Type I, alpha 1 Chain
  • Neuropeptides
  • Proto-Oncogene Proteins c-crk
  • Rac1 protein, mouse
  • JNK Mitogen-Activated Protein Kinases
  • rac1 GTP-Binding Protein