期刊
NATURE MEDICINE
卷 20, 期 8, 页码 904-910出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3583
关键词
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资金
- Children's Tumor Foundation [2012-01-028]
- US National Institute of Arthritis and Musculoskeletal and Skin Diseases
- National Center for Research Resources of the US National Institutes of Health [5R01 AR055966, S10 RR027631]
- National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR001105]
- Pediatric Orthopaedic Society of North America
- Texas Scottish Rite Hospital for Children
- US Army Medical Research Acquisition Activity [W81XWH-11-1-0250]
Individuals with neurofibromatosis type-1 (NF1) can manifest focal skeletal dysplasias that remain extremely difficult to treat. NF1 is caused by mutations in the NF1 gene, which encodes the RAS GTPase-activating protein neurofibromin. We report here that ablation of Nf1 in bone-forming cells leads to supraphysiologic accumulation of pyrophosphate (PPi), a strong inhibitor of hydroxyapatite formation, and that a chronic extracellular signal-regulated kinase (ERK)-dependent increase in expression of genes promoting PPi synthesis and extracellular transport, namely Enpp1 and Ank, causes this phenotype. Nf1 ablation also prevents bone morphogenic protein-2 induced osteoprogenitor differentiation and, consequently, expression of alkaline phosphatase and PPi breakdown, further contributing to PPi accumulation. The short stature and impaired bone mineralization and strength in mice lacking Nf1 in osteochondroprogenitors or osteoblasts can be corrected by asfotase-alpha enzyme therapy aimed at reducing PPi concentration. These results establish neurofibromin as an essential regulator of bone mineralization. They also suggest that altered PPi homeostasis contributes to the skeletal dysplasias associated with NF1 and that some of the NF1 skeletal conditions could be prevented pharmacologically.
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