VEGF Secretion Drives Bone Formation in Classical MAP2K1+ Melorheostosis

Area of Science:

• Cellular and Molecular Biology
• Skeletal Biology
• Regenerative Medicine

Background:

• Melorheostosis is a rare bone disorder characterized by excessive bone growth, pain, and deformity.
• Somatic mutations in MAP2K1, encoding MEK1 protein, are implicated in most melorheostosis cases.
• Current treatments are lacking, and understanding the disease mechanism is hindered by limited access to affected tissues.

Purpose of the Study:

• To establish a cellular model of melorheostosis using patient-derived induced pluripotent stem cells (iPSCs).
• To investigate the molecular mechanisms underlying the excessive bone formation in melorheostosis.
• To identify potential therapeutic targets for melorheostosis.

Main Methods:

• Reprogramming patient skin fibroblasts with MAP2K1 mutations into iPSCs.
• Differentiating iPSCs into mesenchymal stem cells (iMSCs) and then into osteoblasts.
• Analyzing MEK1 activity, vascular endothelial growth factor (VEGF) secretion, proliferation, and mineralization in iMSCs and osteoblasts.
• Investigating the role of VEGF by administering or blocking it with bevacizumab.

Main Results:

• Patient-derived iPSCs and iMSCs retained the MAP2K1 mutation and exhibited elevated MEK1 activity.
• Mutation-bearing iMSCs showed increased VEGF secretion, proliferation, and collagen production.
• iMSC-derived osteoblasts displayed enhanced mineralization and VEGF secretion.
• VEGF administration increased mineralization in unaffected cells, while bevacizumab reduced mineralization in affected cells.

Conclusions:

• Patient-derived iPSCs successfully model melorheostosis, recapitulating key disease features.
• Increased bone formation in melorheostosis is partly driven by abundant VEGF secretion.
• Targeting VEGF presents a promising therapeutic strategy for melorheostosis.
• iPSCs hold potential for studying other rare bone diseases.