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Effect of cadmium on Rho GTPases signal transduction during osteoclast differentiation

Shuangjiang He1,2,3, Kanglei Zhang1,2,3, Ying Cao1,2,3

  • 1College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, China.

Environmental Toxicology
|March 8, 2022
PubMed

Insights

Cadmium exposure impacts osteoclast differentiation by altering Rho GTPase signaling. Understanding these changes may reveal new therapeutic targets for cadmium-induced bone diseases.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Toxicology

Background:

  • Osteoclasts are critical cells in bone metabolism and are targets for cadmium (Cd)-induced bone diseases.
  • Rho GTPases are vital regulators of osteoclast differentiation and bone resorption.
  • Identifying therapeutic targets for Cd-induced bone diseases is crucial.

Purpose of the Study:

  • To investigate the role of Rho GTPases in osteoclast differentiation under cadmium influence.
  • To elucidate signal transduction pathways affected by cadmium in osteoclasts.
  • To identify potential therapeutic targets for cadmium-induced bone pathologies.

Main Methods:

  • Exposure of osteoclastic precursor cells and mature osteoclasts to varying concentrations of cadmium (10 nM to 5 μM).
  • Analysis of cell morphology, migration, and fusion.
  • Quantitative assessment of mRNA and protein levels of Rho GTPases (Cdc42, RhoQ, Rac1, Rac2, RhoU, RhoB, RhoA) and downstream effectors (ROCK1, ROCK2, ARP2/3, p-cofilin).
  • In vivo studies using bone marrow cells from cadmium-exposed mice.

Main Results:

  • Low cadmium concentration (10 nM) promoted osteoclast precursor migration and upregulated Cdc42, RhoQ, ROCK1/2, while downregulating ARP2/3.
  • Higher cadmium concentrations (2-5 μM) inhibited migration, reduced ROCK1/2 and ARP2/3 levels, and affected p-cofilin and various Rho GTPase mRNAs.
  • Cadmium exposure in vivo increased the levels of Rho GTPases and their mRNAs in bone marrow cells.
  • Cadmium significantly altered osteoclast differentiation and Rho GTPase expression.

Conclusions:

  • Cadmium significantly impacts osteoclast differentiation and function through modulation of Rho GTPase signaling pathways.
  • Altered expression of Rho GTPases (Cdc42, RhoQ, Rac1, Rac2, RhoU, RhoB, RhoA) and their downstream targets are key mechanisms in cadmium-induced bone toxicity.
  • Rho GTPases represent potential therapeutic targets for mitigating cadmium-induced bone diseases.
Keywords:
RAW264.7 cellsRho GTPasebonecadmiumcytoskeletonosteoclasts

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