TY - JOUR
T1 - Multiple roles for neurofibromin in skeletal development and growth
AU - Kolanczyk, Mateusz
AU - Kossler, Nadine
AU - Kühnisch, Jirko
AU - Lavitas, Liron
AU - Stricker, Sigmar
AU - Wilkening, Ulrich
AU - Manjubala, Inderchand
AU - Fratzl, Peter
AU - Spörle, Ralf
AU - Herrmann, Bernhard G.
AU - Parada, Luis F.
AU - Kornak, Uwe
AU - Mundlos, Stefan
N1 - Funding Information:
R.S. and B.H. would like to thank James Sharpe, Harris Morrison and Tim Mohun for their help with setting up the OPT equipment. We thank M. Giehl and D. Felsenberg for microCT scanning. The antibody MPIIIB101 developed by M. Solursh was obtained from the Developmental Studies Hybridoma Bank. We thank Victor Mautner, Universitätskli-nikum Hamburg, Germany, for providing us with an X-ray showing tibial bowing (Fig. 2B) in an NF1 patient. We acknowledge Monika Osswald and Kathrin Seidel for excellent technical assistance. S.M., M.K. and J.K. were supported by grants from the Deutsche Forschungsgemeinschaft and the US-Army grant DAMD17-03-1-0183.
PY - 2007/4/15
Y1 - 2007/4/15
N2 - Neurofibromatosis type 1 (NF1) is a prevalent genetic disorder primarily characterized by the formation of neurofibromas, café-au-lait spots and freckling. Skeletal abnormalities such as short stature or bowing/pseudarthrosis of the tibia are relatively common. To investigate the role of the neurofibromin in skeletal development, we crossed Nf1flox mice with Prx1Cre mice to inactivate Nf1 in undifferentiated mesenchymal cells of the developing limbs. Similar to NF1 affected individuals, Nf1Prx1 mice show bowing of the tibia and diminished growth. Tibial bowing is caused by decreased stability of the cortical bone due to a high degree of porosity, decreased stiffness and reduction in the mineral content as well as hyperosteoidosis. Accordingly, osteoblasts show an increase in proliferation and a decreased ability to differentiate and mineralize in vitro. The reduction in growth is due to lower proliferation rates and a differentiation defect of chondrocytes. Abnormal vascularization of skeletal tissues is likely to contribute to this pathology as it exerts a negative effect on cortical bone stability. Furthermore, Nf1 has an important role in the development of joints, as shown by fusion of the hip joints and other joint abnormalities, which are not observed in neurofibromatosis type I. Thus, neurofibromin has multiple essential roles in skeletal development and growth.
AB - Neurofibromatosis type 1 (NF1) is a prevalent genetic disorder primarily characterized by the formation of neurofibromas, café-au-lait spots and freckling. Skeletal abnormalities such as short stature or bowing/pseudarthrosis of the tibia are relatively common. To investigate the role of the neurofibromin in skeletal development, we crossed Nf1flox mice with Prx1Cre mice to inactivate Nf1 in undifferentiated mesenchymal cells of the developing limbs. Similar to NF1 affected individuals, Nf1Prx1 mice show bowing of the tibia and diminished growth. Tibial bowing is caused by decreased stability of the cortical bone due to a high degree of porosity, decreased stiffness and reduction in the mineral content as well as hyperosteoidosis. Accordingly, osteoblasts show an increase in proliferation and a decreased ability to differentiate and mineralize in vitro. The reduction in growth is due to lower proliferation rates and a differentiation defect of chondrocytes. Abnormal vascularization of skeletal tissues is likely to contribute to this pathology as it exerts a negative effect on cortical bone stability. Furthermore, Nf1 has an important role in the development of joints, as shown by fusion of the hip joints and other joint abnormalities, which are not observed in neurofibromatosis type I. Thus, neurofibromin has multiple essential roles in skeletal development and growth.
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U2 - 10.1093/hmg/ddm032
DO - 10.1093/hmg/ddm032
M3 - Article
C2 - 17317783
AN - SCOPUS:34447328431
SN - 0964-6906
VL - 16
SP - 874
EP - 886
JO - Human molecular genetics
JF - Human molecular genetics
IS - 8
ER -