Neurofibromatosis type I (NF1) is a multisystem disease caused by mutations in the NF1-gene. The skeleton is frequently affected in NF1, and bone abnormalities are present in approx. 50% of patients. Some of the skeletal changes observed in NF1 patients can be attributed to the effect of nearby tumors. Many other defects, however, appear to be primary and intrinsic defects of the NF1 skeleton and include bone abnormalities such as macrocephaly, scoliosis, pseudo-arthrosis, short stature and bowing of the legs. In collaboration with Dr. Luis Parada (UT Southwestern, Dallas) we have generated mutant mice bearing a limb specific NF1 inactivation (Nf1Prx1). The mice provide us with a unique experimental model to address the question of NF1 role in bone development and homeostasis. An ongoing effort is focused on the characterization of the resulting achondroplasia phenotype as well as understanding its molecular pathomechanism.

In parallel we are studying the role of NF1 in the regulation of bone healing process. For that purpose we established a bone injury model in NF1Prx1 mouse. With help of this experimental model we were able to show that the high dose of systemically applied lovastatin, a cholesterol-lowering drug, improves bone healing in the Nf1 deficient limbs (The study was sponsored by the Drug Discovery Award from Children Tumor Foundation - New York). Ongoing effort is focused on understanding of the molecular mechanism of the delayed bone injury regeneration in the mouse model of NF1 tibial dysplasia.

References:

Kolanczyk M, Mautner V, Kossler N, Nguyen R, Kuhnisch J, Zemojtel T, Jamsheer A, Wegener E, Thurisch B, Tinschert S, Holtkamp N, Park SJ, Birch P, Kendler D, Harder A, Mundlos S, Kluwe L. MIA is a potential biomarker for tumor load in neurofibromatosis type 1. BMC Med. 2011 Jul 4;9(1):82.

Kossler N, Stricker S, Rödelsperger C, Robinson PN, Kim J, Dietrich C, Osswald M, Kühnisch J, Stevenson DA, Braun T, Mundlos S and Kolanczyk M. Neurofibromin (Nf1) is required for skeletal muscle development. Hum Mol Genet. 2011 Jul 15;20(14):2697-709. Epub 2011 Apr 9.

Kolanczyk M, Kossler N, Kuhnisch J, Lavitas L, Stricker S, Wilkening U, Manjubala I, Fratzl P, Sporle R, Herrmann BG, Parada LF, Kornak U, Mundlos S. Multiple roles for neurofibromin in skeletal development and growth. Hum Mol Genet. 2007 Apr 15;16(8):874-86.

Kolanczyk M, Kühnisch J, Kossler N, Osswald M, Stumpp S, Thurisch B, Kornak U, Mundlos S. Modelling neurofibromatosis type 1 tibial dysplasia and its treatment with lovastatin. BMC Med. 2008 Jul 31;6:21.