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Chondrocyte-specific microRNA-140 regulates endochondral bone development and targets Dnpep to modulate bone

Yukio Nakamura1, Jennifer B Inloes, Takenobu Katagiri

  • 1Clinical Research Center, Murayama Medical Center, Tokyo 208-0011, Japan.

Molecular and Cellular Biology
|May 18, 2011
PubMed

Insights

MicroRNA-140 (Mir140) is crucial for skeletal development. Loss of Mir140 in mice leads to dwarfism and craniofacial issues due to altered bone growth and signaling.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Genetics

Background:

  • MicroRNAs (miRNAs) are vital regulators of biological processes.
  • Global miRNA reduction in chondrocytes causes skeletal dysplasia.
  • The role of individual miRNAs in chondrocytes remains largely unknown.

Purpose of the Study:

  • Investigate the physiological role of Mir140 in chondrocytes.
  • Determine the skeletal consequences of Mir140 loss in mice.
  • Identify downstream targets and pathways affected by Mir140 deficiency.

Main Methods:

  • Generated Mir140-null mice to study skeletal development.
  • Analyzed endochondral bone growth, chondrocyte differentiation, and craniofacial morphology.
  • Utilized Argonaute 2 (Ago2) immunoprecipitation followed by RNA sequencing to identify miRNA targets.
  • Assessed bone morphogenetic protein (BMP) signaling pathways.

Main Results:

  • Mir140-null mice exhibit dwarfism and craniofacial deformities due to growth defects.
  • Endochondral ossification is accelerated, with enhanced hypertrophic differentiation of chondrocytes.
  • Dnpep was identified as a direct target of Mir140, with its expression increased in Mir140-null chondrocytes.
  • Dnpep overexpression mildly antagonizes BMP signaling; Mir140 deficiency leads to reduced BMP signaling, reversed by Dnpep knockdown.

Conclusions:

  • Mir140 is essential for normal endochondral bone development.
  • Dysregulation of BMP signaling, mediated by Dnpep upregulation, contributes to skeletal defects in Mir140-null mice.
  • This study elucidates a novel miRNA-dependent mechanism regulating skeletal growth and BMP signaling.

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