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Culture of Murine Embryonic Metatarsals: A Physiological Model of Endochondral Ossification
Published on: December 3, 2016
FOXC1 and FOXC2 regulate growth plate chondrocyte maturation towards hypertrophy in the embryonic mouse limb skeleton
Asra Almubarak1, Qiuwan Zhang2, Cheng-Hai Zhang2
1Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2E1, Canada.
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.
Insights
Forkhead box transcription factors FOXC1 and FOXC2 are crucial for skeletal development. Ablating these genes in mice disrupts chondrocyte maturation and bone formation, leading to shorter limbs and malformed paws.
Area of Science:
- Developmental Biology
- Molecular Biology
- Genetics
Background:
- Forkhead box transcription factors FOXC1 and FOXC2 are expressed during skeletal development.
- Their specific roles in endochondral ossification are not fully understood.
Purpose of the Study:
- To investigate the function of FOXC1 and FOXC2 in limb skeletal progenitor cells during endochondral ossification.
- To elucidate the role of FOXC1 and FOXC2 in chondrocyte maturation and bone formation.
Main Methods:
- Utilized Prx1-cre and Col10a1-cre mouse models to conditionally ablate Foxc1 and Foxc2 in specific progenitor cell populations.
- Analyzed limb skeletal development, cartilage formation, mineralization, and chondrocyte maturation.
Main Results:
- Conditional ablation of Foxc1 and Foxc2 resulted in shorter limbs with severe disruption of cartilage formation and mineralization in the paws.
- Chondrocyte maturation was delayed, with reduced Indian hedgehog expression and a smaller hypertrophic zone.
- Targeting these factors in hypertrophic chondrocytes also led to an expanded hypertrophic zone and smaller primary ossification centers, with impaired osteoblast recruitment.
Conclusions:
- FOXC1 and FOXC2 are essential regulators of chondrocyte maturation towards hypertrophic chondrocyte formation.
- These transcription factors play critical roles in hypertrophic chondrocyte remodeling, primary ossification center formation, and osteoblast recruitment during skeletal development.
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