Formin 1 and Filamin B Physically Interact to Coordinate Chondrocyte Proliferation and Differentiation in the Growth Plate

Hum Mol Genet. 2014 Sep 1;23(17):4663-73. doi: 10.1093/hmg/ddu186. Epub 2014 Apr 23.


Filamin B (FlnB) is an actin-binding protein thought to transduce signals from various membrane receptors and intracellular proteins onto the actin cytoskeleton. Formin1 (Fmn1) is an actin-nucleating protein, implicated in actin assembly and intracellular signaling. Human mutations in FLNB cause several skeletal disorders associated with dwarfism and early bone fusion. Mouse mutations in Fmn1 cause aberrant fusion of carpal digits. We report here that FlnB and Fmn1 physically interact, are co-expressed in chondrocytes in the growth plate and share overlapping expression in the cell cytoplasm and nucleus. Loss of FlnB leads to a dramatic decrease in Fmn1 expression at the hypertrophic-to-ossification border. Loss of Fmn1-FlnB in mice leads to a more severe reduction in body size, weight and growth plate length, than observed in mice following knockout of either gene alone. Shortening of the long bone is associated with a decrease in chondrocyte proliferation and an overall delay in ossification in the double-knockout mice. In contrast to FlnB null, Fmn1 loss results in a decrease in the width of the prehypertrophic zone. Loss of both proteins, however, causes an overall decrease in the width of the proliferation zone and an increase in the differentiated hypertrophic zone. The current findings suggest that Fmn1 and FlnB have shared and independent functions. FlnB loss promotes prehypertrophic differentiation whereas Fmn1 leads to a delay. Both proteins, however, regulate chondrocyte proliferation, and FlnB may regulate Fmn1 function at the hypertrophic-to-ossification border, thereby explaining the overall delay in ossification.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcification, Physiologic
  • Cell Differentiation*
  • Cell Proliferation
  • Chondrocytes / metabolism*
  • Chondrocytes / pathology*
  • Fetal Proteins / deficiency
  • Fetal Proteins / metabolism*
  • Filamins / deficiency
  • Filamins / metabolism*
  • Formins
  • Growth Plate / metabolism*
  • Growth Plate / pathology*
  • Humans
  • Hypertrophy
  • Mice, Knockout
  • Microfilament Proteins / deficiency
  • Microfilament Proteins / metabolism*
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Protein Transport
  • Receptor, Parathyroid Hormone, Type 1 / metabolism


  • Fetal Proteins
  • Filamins
  • Formins
  • Microfilament Proteins
  • Nuclear Proteins
  • Receptor, Parathyroid Hormone, Type 1