CCL7 is a protective factor secreted by mechanically loaded osteocytes

J Dent Res. 2014 Nov;93(11):1108-15. doi: 10.1177/0022034514553008. Epub 2014 Oct 1.

Abstract

In a search for factors up-regulated by mechanical strain in osteocytes, we discovered that chemokine (C-C motif) ligand 7 (CCL7), a chemotactic myokine, was highly expressed in MLO-Y4 osteocyte-like cells. Although MLO-Y4 cells secrete potent chemotactic factors for osteoclast precursors, CCL7 was not responsible for this activity. CCL7 was increased in osteocytes in response to tooth movement in vivo. Since mechanical loading plays a crucial role in maintaining osteocyte viability, CCL7 was tested for protective activity and found to be protective against cell death induced by dexamethasone and etoposide. CCL7 specific antibody partially, but in combination with indomethacin, completely abrogated the protective effects of fluid flow shear stress against dexamethasone-induced cell death. CCL7 activated the β-catenin pathway through phosphorylation of glycogen synthase kinase 3 (GSK-3), suggesting that this pathway is responsible for the observed protective effects. A related cytokine, CCL2, also produced by MLO-Y4 cells but not regulated by mechanical loading, proved to be more potent and protected against cell death induced by not only dexamethasone, but also by Tumor Necrosis Factor α (TNFα). Whereas osteocytes may produce CCL2 in constitutively low levels, a major function of mechanically induced CCL7 may be to selectively protect osteocytes in an autocrine manner against glucocorticoid-induced cell death.

Keywords: TNFα; cell death; chemokine; glucocorticoid; mechanical stress; tooth movement.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Antibodies / pharmacology
  • Autocrine Communication / physiology
  • Biomechanical Phenomena
  • Cell Death / drug effects
  • Cell Line
  • Cell Survival / physiology
  • Chemokine CCL2 / metabolism
  • Chemokine CCL7 / immunology
  • Chemokine CCL7 / metabolism*
  • Dexamethasone / pharmacology
  • Etoposide / pharmacology
  • Glucocorticoids / pharmacology
  • Glycogen Synthase Kinase 3 / drug effects
  • Indomethacin / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Osteoclasts / metabolism*
  • Phosphorylation
  • Protective Agents / metabolism*
  • Rheology
  • Stress, Mechanical
  • Tooth Movement Techniques / instrumentation
  • Topoisomerase II Inhibitors / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology
  • beta Catenin / drug effects

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Antibodies
  • Ccl2 protein, mouse
  • Ccl7 protein, mouse
  • Chemokine CCL2
  • Chemokine CCL7
  • Glucocorticoids
  • Protective Agents
  • Topoisomerase II Inhibitors
  • Tumor Necrosis Factor-alpha
  • beta Catenin
  • Etoposide
  • Dexamethasone
  • Glycogen Synthase Kinase 3
  • Indomethacin