Excessive osteoclast activation by osteoblast paracrine factor RANKL is a major cause of the abnormal long bone phenotype in Apert syndrome model mice

J Cell Physiol. 2022 Apr;237(4):2155-2168. doi: 10.1002/jcp.30682. Epub 2022 Jan 20.

Abstract

The fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling pathway plays important roles in the development and growth of the skeleton. Apert syndrome caused by gain-of-function mutations of FGFR2 results in aberrant phenotypes of the skull, midface, and limbs. Although short limbs are representative features in patients with Apert syndrome, the causative mechanism for this limb defect has not been elucidated. Here we quantitatively confirmed decreases in the bone length, bone mineral density, and bone thickness in the Apert syndrome model of gene knock-in Fgfr2S252W/+ (EIIA-Fgfr2S252W/+ ) mice. Interestingly, despite these bone defects, histological analysis showed that the endochondral ossification process in the mutant mice was similar to that in wild-type mice. Tartrate-resistant acid phosphatase staining revealed that trabecular bone loss in mutant mice was associated with excessive osteoclast activity despite accelerated osteogenic differentiation. We investigated the osteoblast-osteoclast interaction and found that the increase in osteoclast activity was due to an increase in the Rankl level of osteoblasts in mutant mice and not enhanced osteoclastogenesis driven by the activation of FGFR2 signaling in bone marrow-derived macrophages. Consistently, Col1a1-Fgfr2S252W/+ mice, which had osteoblast-specific expression of Fgfr2 S252W, showed significant bone loss with a reduction of the bone length and excessive activity of osteoclasts was observed in the mutant mice. Taken together, the present study demonstrates that the imbalance in osteoblast and osteoclast coupling by abnormally increased Rankl expression in Fgfr2S252W/+ mutant osteoblasts is a major causative mechanism for bone loss and short long bones in Fgfr2S252W/+ mice.

Keywords: Apert syndrome; FGFR2; Rankl; long bone; osteoblast-osteoclast interaction.

MeSH terms

  • Acrocephalosyndactylia* / genetics
  • Acrocephalosyndactylia* / pathology
  • Animals
  • Cell Differentiation
  • Gene Knock-In Techniques
  • Humans
  • Mice
  • Osteoblasts / metabolism
  • Osteoclasts / metabolism
  • Osteogenesis / genetics
  • RANK Ligand / metabolism*
  • Receptor, Fibroblast Growth Factor, Type 2 / genetics
  • Receptor, Fibroblast Growth Factor, Type 2 / metabolism
  • Skull / pathology

Substances

  • RANK Ligand
  • Tnfsf11 protein, mouse
  • Fgfr2 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 2