This proposal seeks to investigate a novel biologic mechanism behind the pathogenesis of craniosynostosis. Craniosynostosis is a debilitating pediatric condition in which adjacent cranial bones become prematurely fused. This pediatric abnormality can lead to abnormal skull and facial shapes, blindness, seizures and cognitive deficits. The primary treatment modality for craniosynostosis is surgery, therefore even with appropriately early diagnosis severely affected patients suffer high morbidity. Previous studies demonstrated that craniosynostosis is associated with genetic mutations in Fibroblast Growth Factor (FGF) receptors, Twist, TCF12, Msx2, Efnb1 and Gli3; and that the pathogenesis of craniosynososis can include defective boundary formation/maintenance, lineage commitment, proliferation and/or apoptosis of cranial bone and suture cells. Despite these important advancements, a pharmaceutical treatment option for craniosynostosis has not yet been realized. We recently reported that the tissue non-specific alkaline phosphatase (TNAP/Alpl) null mouse model of hypophosphatasia exhibits craniofacial bone hypomineralization in combination with craniosynostosis and an abnormal craniofacial skeletal shape. We also previously showed that FGF signaling inhibits expression of TNAP in cranial cells and tissues. Together, these results prompt us to hypothesize that aberrant FGF signaling influences craniofacial skeletal development and contribute to some forms of craniosynostosis via decreased TNAP expression. Inadequate TNAP enzyme levels decrease phosphate (Pi) and increase pyrophosphate (PPi) at the extracellular membrane. These changes inhibit hydroxyapatite mineralization and also locally modulate gene expression, cellular apoptosis and proliferation. Here we propose to utilize genetic and pharmacologic approaches to determine the degree to which TNAP influences FGFR-associated craniosynostosis and associated craniofacial skeletal abnormalities. We will also more clearly define mechanisms by which TNAP influences craniofacial skeletal development and craniosynostosis. Of clinical significance, our data suggests that enzyme replacement strategies currently used to treat hypophosphatasia patients could be used to prevent and/or diminish the severity of craniosynostosis. These treatments could decrease craniosynostosis severity and normalize craniofacial shape defects to a greater extent than surgery alone, greatly improving patient quality of life.
Craniosynostosis is a debilitating pediatric condition in which adjacent cranial bones become prematurely fused. Craniosynostosis can lead to high intracranial pressure, abnormal skull and facial shapes, airway impairments, obstructive sleep apnea, brain abnormalities, blindness, deafness, seizures and death. Craniosynostosis has a relatively high incidence of approximately 1 in 2500 live births, and current treatment options are limited to surgery, genetic counseling, dental, medical and social support. Notably, even with an early and accurate diagnosis, craniosynostosis can cause high morbidity. For example, some patients require multiple surgeries throughout childhood to relieve high intracranial pressure, treat recurring craniosynostosis, and normalize skull and facial shapes. Surgical approaches also do not fully correct abnormal skull and facial shapes, which contribute to social challenges. Studies of mouse models of craniosynostosis indicate that the pathogenesis can include defective boundary formation/maintenance, lineage commitment, proliferation and/or apoptosis of cranial bone and suture cells. Despite these important advancements, a pharmaceutical treatment option for craniosynostosis has not yet been realized. We hypothesize that tissue non-specific alkaline phosphatase (TNAP/Alpl) enzyme is an important additional mediator of craniosynostosis. Of clinical significance, our data suggests that enzyme replacement strategies currently used to treat hypophosphatasia patients lacking TNAP, could be used to prevent and/or diminish the severity of craniosynostosis. These treatments could decrease craniosynostosis severity and normalize craniofacial shape defects to a greater extent than surgery alone, greatly improving patient quality of life. In addition, results will allow us identiy novel targets for treatment. Greater understanding of mechanisms underlying craniofacial skeletal development and tissue mineralization will also enhance the development of future therapies for craniofacial tissue regeneration.
