NFAT restricts osteochondroma formation from entheseal progenitors

Area of Science:

• Skeletal Biology
• Tumor Pathogenesis
• Molecular Mechanisms

Background:

• Osteochondromas are common benign bone tumors in children and adolescents.
• Their exact cause (pathogenesis) is not well understood.
• These tumors can cause pain, deformity, and dysfunction, with rare malignant transformation.

Purpose of the Study:

• To investigate the role of Nuclear Factor of Activated T cells (NFAT) in osteochondromagenesis.
• To identify the cellular origins and molecular mechanisms underlying osteochondroma formation.

Main Methods:

• Conditional gene deletion of NFATc1 and NFATc2 in specific progenitor cells in mice.
• Analysis of osteochondroma formation, size, and number.
• Investigation of NFATc1 and NFATc2 functions in proliferation, chondrogenesis, hypertrophy, and osteogenesis.

Main Results:

• Conditional deletion of NFATc1 in mesenchymal progenitors, Scx-expressing cells, or Aggrecan-expressing cells induced osteochondroma formation at entheses.
• Combined deletion of NFATc1 and NFATc2 resulted in larger and more numerous osteochondromas.
• Entheseal Aggrecan-expressing cells were identified as osteochondroma precursors.
• NFATc1 restricts precursor proliferation and chondrogenesis; NFATc2 inhibits chondrocyte hypertrophy and osteogenesis.

Conclusions:

• NFATc1 and NFATc2 individually and combinatorially suppress osteochondromagenesis.
• A novel mechanism involving entheseal NFAT-expressing cells in osteochondroma development is identified.
• Modulating NFAT activity presents a potential therapeutic strategy for skeletal disorders involving abnormal bone growth.