The growth plate's response to load is partially mediated by mechano-sensing via the chondrocytic primary cilium

Cell Mol Life Sci. 2015 Feb;72(3):597-615. doi: 10.1007/s00018-014-1690-4. Epub 2014 Aug 2.

Abstract

Mechanical load plays a significant role in bone and growth-plate development. Chondrocytes sense and respond to mechanical stimulation; however, the mechanisms by which those signals exert their effects are not fully understood. The primary cilium has been identified as a mechano-sensor in several cell types, including renal epithelial cells and endothelium, and accumulating evidence connects it to mechano-transduction in chondrocytes. In the growth plate, the primary cilium is involved in several regulatory pathways, such as the non-canonical Wnt and Indian Hedgehog. Moreover, it mediates cell shape, orientation, growth, and differentiation in the growth plate. In this work, we show that mechanical load enhances ciliogenesis in the growth plate. This leads to alterations in the expression and localization of key members of the Ihh-PTHrP loop resulting in decreased proliferation and an abnormal switch from proliferation to differentiation, together with abnormal chondrocyte morphology and organization. Moreover, we use the chondrogenic cell line ATDC5, a model for growth-plate chondrocytes, to understand the mechanisms mediating the participation of the primary cilium, and in particular KIF3A, in the cell's response to mechanical stimulation. We show that this key component of the cilium mediates gene expression in response to mechanical stimulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Biomechanical Phenomena
  • Cell Differentiation / physiology
  • Cell Proliferation / physiology
  • Chickens
  • Chondrocytes / physiology*
  • Chondrocytes / ultrastructure
  • Cilia / physiology*
  • DNA Primers / genetics
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Growth Plate / physiology*
  • Hedgehog Proteins / metabolism
  • Immunohistochemistry
  • In Situ Hybridization
  • Mechanotransduction, Cellular / physiology*
  • Microscopy, Electron, Scanning
  • Parathyroid Hormone-Related Protein / metabolism
  • Physical Stimulation
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • DNA Primers
  • Hedgehog Proteins
  • Parathyroid Hormone-Related Protein