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

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 observed an expansion of the resting zone. EdU labeling and lineage tracing analysis revealed disrupted stem cell properties of resting zone chondrocytes, preventing self-renewal, limiting cell divisions and migration toward the primary ossification center. Single-cell RNA-seq and immunohistochemical analysis identified a cell cluster that corresponded to the expanded resting zone. Pathway analysis and functional experiments revealed that CREB disrupts stem cell properties in resting zone chondrocytes and contributes to dwarfism. Administration of CREB inhibitor 666-15 restored growth plate pathology and bone length. These findings demonstrate that how excess FGFR3 signaling disrupts resting zone chondrocyte properties and suggest potential therapeutic targets for achondroplasia.

ORGANISM(S): Mus

PROVIDER: GSE275171 | GEO | 2025/12/21

REPOSITORIES: GEO

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Project description:Articular and growth plate cartilage have comparable structures consisting of three distinct layers of chondrocytes, suggesting similar differentiation programs and therefore similar gene expression profiles. To address this hypothesis and to explore transcriptional changes that occur during the onset of articular and growth plate cartilage divergence, we used microdissection of 10-day-old rat proximal tibial epiphyses, microarray analysis, and bioinformatics to compare gene expression profiles in individual layers of articular and growth plate cartilage. We found that many genes that were spatially upregulated in intermediate/deep zone of articular cartilage were also spatially upregulated in resting zone of growth plate cartilage (overlap greater than expected by chance, P < 0.001). Interestingly, superficial zone of articular cartilage showed an expression profile with similarities to both proliferative and hypertrophic zones of growth plate cartilage (P < 0.001 each). Additionally, significant numbers of known proliferative zone markers (3 out of 6) and hypertrophic zone markers (27 out of 126) were spatially upregulated in superficial zone compared to intermediate/deep zone (more than expected by chance, P < 0.001 each). In conclusion, we provide evidence that intermediate/deep zone of articular cartilage has a gene expression profile more similar to resting zone of growth plate cartilage, whereas superficial zone has a gene expression profile more similar to proliferative and hypertrophic zones. 10-day-old rat proximal tibial epiphyses were manually microdissected into articular cartilage superficial (SZ) and intermediate/deep (IDZ) zones and growth plate cartilage resting zone (RZ) for total RNA extraction and hybridization on Affymetrix microarrays. We used 10-day-old animals because, at this age, the secondary ossification center has recently begun to form and divides the epiphysis into articular cartilage distally and growth plate cartilage more centrally. The 4 SZ samples were taken from animals 5-8, respectively, whereas the 4 IDZ and 4 RZ samples were each taken from animals 1-2, 3-4, 5-6, and 7-8, respectively.

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

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