Abstract:

Chondrodysplasia is associated with gain-of-function mutations in FGFR3, which can cause dysfunction in growth plate cartilage and lead to short-limb dwarfism. The core molecular and cellular mechanisms remain unclear. In this study, an Fgfr3Ach knock-in mouse model was constructed, revealing that the renewal of resting zone chondrocytes was impaired, stem cell-like behavior was disrupted, and abnormal cell accumulation occurred; single-cell sequencing and functional experiments confirmed that CREB signaling interferes with the characteristics of resting zone chondrocytes. Inhibition of CREB can improve the pathological state of the growth plate and bone length, revealing the mechanism by which excessive FGFR3 signaling interferes with the renewal of resting zone chondrocytes through the CREB pathway.

01. Research Background

Achondroplasia is induced by gain-of-function mutations in FGFR3, which can cause abnormal growth plate cartilage function, thereby leading to short-limbed dwarfism. The key molecular and cellular regulatory mechanisms of this disease have not yet been clearly explained.

02

Main content

Focusing on the phenotype and functional changes of chondrocytes in the resting zone of growth plates, the process of excessive activation of FGFR3 regulating chondrocyte turnover in the resting zone through the CREB pathway was analyzed, and the effect of CREB inhibition on growth plate development and bone growth was verified.

03

Study design

A mouse model of Fgfr3Ach knock-in carrying achondroplasia pathogenic mutations was constructed. The renewal ability and stem cell-like behavior of chondrocytes in the resting zone were analyzed by EdU labeling and lineage tracking. Single-cell RNA sequencing and immunohistochemistry were used to identify cell clusters related to resting zone expansion. The regulatory role of CREB signal was clarified by pathway analysis and functional experiments. The model mice were treated with CREB inhibitor to detect its effect on the pathology of growth plates and bone length.

04

Result

In addition to the reported abnormal phenotype, Fgfr3Ach knock-in mice showed expansion of the resting zone of the growth plate. The renewal of chondrocytes in the resting zone is interrupted and the stem cell-like behavior is impaired, resulting in abnormal accumulation of cells in the resting zone. identified cell clusters corresponding to resting zone expansion; CREB signal disrupts the stem cell-like properties of chondrocytes in the resting zone and participates in the pathological process of dwarfism. Administration of CREB inhibitors restored the pathological state of growth plates and increased bone length.

05

Extended thinking

This study clarified the core regulatory role of FGFR3-CREB pathway on chondrocytes in the resting zone of growth plates, improved the understanding of cellular and molecular mechanisms of achondroplasia, and provided a new theoretical direction for the regulation of cartilage development and related skeletal development abnormalities in growth plates.

Original Source:

1. Journal: Nature Communications

2. Publication Date: 2026-02-26

3. DOI: 10.1038/s41467-026-69507-9

4. Authors: Nanao Horike, Seiya Oura, Saeko Koyamatsu, Noriko Tanaka, Yuki Iimori, Kaori Fujita, Takahiro Nemoto, Masahito Ikawa, Noriyuki Tsumaki