PDF(Pubmed)
Abstract：
The Forkhead box transcription factors FOXC1 and FOXC2 are expressed in condensing mesenchyme cells at the onset of endochondral ossification. We used the Prx1-cre mouse to ablate Foxc1 and Foxc2 in limb skeletal progenitor cells. Prx1-cre;Foxc1Δ/Δ;Foxc2Δ/Δ limbs were shorter than controls, with worsening phenotypes in distal structures. Cartilage formation and mineralization was severely disrupted in the paws. The radius and tibia were malformed, whereas the fibula and ulna remained unmineralized. Chondrocyte maturation was delayed, with fewer Indian hedgehog-expressing, prehypertrophic chondrocytes forming and a smaller hypertrophic chondrocyte zone. Later, progression out of chondrocyte hypertrophy was slowed, leading to an accumulation of COLX-expressing hypertrophic chondrocytes and formation of a smaller primary ossification center with fewer osteoblast progenitor cells populating this region. Targeting Foxc1 and Foxc2 in hypertrophic chondrocytes with Col10a1-cre also resulted in an expanded hypertrophic chondrocyte zone and smaller primary ossification center. Our findings suggest that FOXC1 and FOXC2 direct chondrocyte maturation towards hypertrophic chondrocyte formation. At later stages, FOXC1 and FOXC2 regulate function in hypertrophic chondrocyte remodeling to allow primary ossification center formation and osteoblast recruitment.
摘要：
在软骨内骨化开始时，叉头盒转录因子Foxc1和Foxc2在缩合间充质细胞中表达。我们使用Prx1-cre小鼠在肢体骨骼祖细胞中消融Foxc1和Foxc2。Prx1-cre；Foxc1Δ/Δ；Foxc2Δ/Δ四肢短于对照组，远端结构表型恶化。软骨形成和矿化在爪子中被严重破坏。桡骨和胫骨畸形,腓骨和尺骨仍未矿化。软骨细胞的成熟随着印度Hedgehog表达的减少而延迟，肥大前软骨细胞形成和较小的肥大软骨细胞区。稍后，软骨细胞肥大的进展减慢，导致表达COLX的肥大软骨细胞区积累，并形成较小的原代骨化中心，该区域的成骨细胞祖细胞数量较少。用Col10a1-cre靶向肥大软骨细胞中的Foxc1和Foxc2也导致肥大软骨细胞区扩大和原发性骨化中心变小。我们的发现表明Foxc1和Foxc2指导软骨细胞向肥大软骨细胞形成成熟。在以后的阶段,Foxc1和Foxc2调节肥大软骨细胞重塑中的功能，以允许原发性骨化中心形成和成骨细胞募集。
