# Excess FGFR3 signaling in achondroplasia disrupts turnover of resting zone chondrocytes via CREB signaling

## TL;DR

This study shows that overactive FGFR3 signaling in achondroplasia disrupts cartilage cell function and suggests CREB as a potential treatment target.

## Contribution

The study identifies CREB signaling as a novel mediator of FGFR3 effects in achondroplasia.

## Key findings

- Excess FGFR3 signaling disrupts resting zone chondrocyte turnover and stem cell-like behavior.
- CREB signaling contributes to dwarfism by impairing resting zone chondrocyte properties.
- CREB inhibitor 666-15 restores growth plate pathology and bone length in a mouse model.

## Abstract

Achondroplasia, associated with gain-of-function mutations in FGFR3, causes growth plate cartilage dysfunction, resulting in short-limb dwarfism. However, its precise molecular and cellular mechanisms remain unclear. To address this, we aimed to generate knock-in mice (Fgfr3Ach) harboring the achondroplasia mutation (p.Gly380Arg). In addition to previously reported abnormalities, we observe an expansion of the resting zone. EdU labeling and lineage tracing analyses indicate that disruption of turnover and impairment of stem cell-like behavior of resting zone chondrocytes results in accumulation of cells in the resting zone. Single-cell RNA-seq and immunohistochemical analysis identify a cell cluster that corresponds to the expanded resting zone. Pathway analysis and functional experiments reveal that CREB disrupts stem cell-like properties in resting zone chondrocytes and contributes to dwarfism. Administration of CREB inhibitor 666-15 restores growth plate pathology and bone length. These findings demonstrate that excess FGFR3 signaling disrupts resting zone chondrocyte properties and suggest potential therapeutic targets for achondroplasia.

Achondroplasia, associated with FGFR3 gain-of-function mutations, is a chondrodysplasia characterized by short-limb dwarfism. Here, Horike et al. discover that excess FGFR3 signaling is mediated by CREB and disrupts resting zone chondrocyte properties in a knock-in mouse model harboring the achondroplasia mutation.