TY - JOUR
T1 - Asfotase-α improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1
AU - de la Croix Ndong, Jean
AU - Makowski, Alexander J.
AU - Uppuganti, Sasidhar
AU - Vignaux, Guillaume
AU - Ono, Koichiro
AU - Perrien, Daniel S.
AU - Joubert, Simon
AU - Baglio, Serena R.
AU - Granchi, Donatella
AU - Stevenson, David A.
AU - Rios, Jonathan J.
AU - Nyman, Jeffry S.
AU - Elefteriou, Florent
PY - 2014
Y1 - 2014
N2 - 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 (PP i), a strong inhibitor of hydroxyapatite formation, and that a chronic extracellular signal-regulated kinase (ERK)-dependent increase in expression of genes promoting PP i 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 PP i breakdown, further contributing to PP i accumulation. The short stature and impaired bone mineralization and strength in mice lacking Nf1 in osteochondroprogenitors or osteoblasts can be corrected by asfotase- α enzyme therapy aimed at reducing PP i concentration. These results establish neurofibromin as an essential regulator of bone mineralization. They also suggest that altered PP i homeostasis contributes to the skeletal dysplasias associated with NF1 and that some of the NF1 skeletal conditions could be prevented pharmacologically. © 2014 Nature America, Inc.
AB - 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 (PP i), a strong inhibitor of hydroxyapatite formation, and that a chronic extracellular signal-regulated kinase (ERK)-dependent increase in expression of genes promoting PP i 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 PP i breakdown, further contributing to PP i accumulation. The short stature and impaired bone mineralization and strength in mice lacking Nf1 in osteochondroprogenitors or osteoblasts can be corrected by asfotase- α enzyme therapy aimed at reducing PP i concentration. These results establish neurofibromin as an essential regulator of bone mineralization. They also suggest that altered PP i homeostasis contributes to the skeletal dysplasias associated with NF1 and that some of the NF1 skeletal conditions could be prevented pharmacologically. © 2014 Nature America, Inc.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84907655164&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/24997609
UR - http://www.scopus.com/inward/record.url?scp=84907655164&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/nm.3583
DO - https://doi.org/10.1038/nm.3583
M3 - Article
C2 - 24997609
SN - 1078-8956
VL - 20
SP - 904
EP - 910
JO - Nature medicine
JF - Nature medicine
IS - 8
ER -