title: Capturing the wide variety of impaired fracture healing phenotypes in Neurofibromatosis Type 1 with eight key factors: a computational study.
abstract: Congenital pseudarthrosis of the tibia (CPT) is a rare disease which normally presents itself during early childhood by anterolateral bowing of the tibia and spontaneous tibial fractures. Although the exact etiology of CPT is highly debated, 40-80% of CPT patients are carriers of a mutation in the Neurofibromatosis Type 1 (NF1) gene, which can potentially result in an altered phenotype of the skeletal cells and impaired bone healing. In this study we use a computational model of bone regeneration to examine the effect of the Nf1 mutation on bone fracture healing by altering the parameter values of eight key factors which describe the aberrant cellular behaviour of Nf1 haploinsufficient and Nf1 bi-allelically inactivated cells. We show that the computational model is able to predict the formation of a hamartoma as well as a wide variety of CPT phenotypes through different combinations of altered parameter values. A sensitivity analysis by "Design of Experiments" identified the impaired endochondral ossification process and increased infiltration of fibroblastic cells as key contributors to the degree of severity of CPT. Hence, the computational model results have added credibility to the experimental hypothesis of a genetic cause (i.e. Nf1 mutation) for CPT.
authors.affiliation: Biomechanics Section, KU Leuven, Celestijnenlaan 300 C, PB 2419, 3000 Leuven, Belgium.|Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, O&N 1, Herestraat 49, PB 813, 3000 Leuven, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Carlier
authors.affiliation: Department of Human Genetics, KU Leuven, O&N 1, Herestraat 49, PB 602, 3000 Leuven, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Brems
authors.affiliation: Department of Engineering Science, University of Oxford, Parks Road, Oxford OX1 3PJ, U.K.
authors.forename: J M A
authors.initials: JM
authors.lastname: Ashbourn
authors.affiliation: St Edmund Hall, University of Oxford, Queen's Lane, Oxford OX1 4AR, U.K.
authors.forename: I
authors.initials: I
authors.lastname: Nica
authors.affiliation: Department of Human Genetics, KU Leuven, O&N 1, Herestraat 49, PB 602, 3000 Leuven, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Legius
authors.affiliation: Biomechanics Section, KU Leuven, Celestijnenlaan 300 C, PB 2419, 3000 Leuven, Belgium.|Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, O&N 1, Herestraat 49, PB 813, 3000 Leuven, Belgium.|Biomechanics Research Unit, University of Liège, Chemin des Chevreuils 1 - BAT 52/3, 4000 Liege 1, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Geris
mesh_terms: D001861:Bone Regeneration / Q000235:genetics; D017102:Fracture Healing / Q000235:genetics*; D057895:Haploinsufficiency / Q000235:genetics; D006801:Humans; D008962:Models, Theoretical; D009456:Neurofibromatosis 1 / Q000235:genetics*; D010012:Osteogenesis / Q000235:genetics; D011542:Pseudarthrosis / Q000151:congenital* / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D013977:Tibia / Q000503:physiopathology*
references.citation: Am J Hum Genet. 2006 Jul;79(1):143-8
references.pmid: 16773574
references.citation: J Theor Biol. 2008 Nov 7;255(1):26-39
references.pmid: 18723028
references.citation: Orthop Traumatol Surg Res. 2011 Nov;97(7):750-61
references.pmid: 21996526
references.citation: Bone. 2009 Feb;44(2):243-50
references.pmid: 19061981
references.citation: Biomech Model Mechanobiol. 2011 Jun;10(3):383-95
references.pmid: 20827500
references.citation: Int Orthop. 2014 Sep;38(9):1771-8
references.pmid: 24984594
references.citation: Bone. 2010 Sep;47(3):583-90
references.pmid: 20541045
references.citation: Hum Mol Genet. 2013 Aug 1;22(15):3048-62
references.pmid: 23571107
references.citation: J Theor Biol. 2008 Jan 7;250(1):25-36
references.pmid: 18028963
references.citation: J Bone Miner Res. 2012 Jan;27(1):68-78
references.pmid: 21956219
references.citation: Am J Med Genet. 1997 May 16;70(2):138-43
references.pmid: 9128932
references.citation: BMC Med. 2008;6:21
references.pmid: 18671844
references.citation: J Theor Biol. 2015 Jan 21;365:247-64
references.pmid: 25452136
references.citation: Injury. 2005 Dec;36(12):1392-404
references.pmid: 16102764
references.citation: J Med Genet. 2015 Apr;52(4):256-61
references.pmid: 25612910
references.citation: J Bone Joint Surg Am. 2014 Jul 16;96(14 ):e117
references.pmid: 25031379
references.citation: Bone. 2011 Oct;49(4):591-9
references.pmid: 21782988
references.citation: J Orthop Trauma. 2003 Jan;17(1):11-21
references.pmid: 12499963
references.citation: Contemp Top Lab Anim Sci. 2002 Sep;41(5):21-6
references.pmid: 12213043
references.citation: J Invest Dermatol. 1999 Jun;112(6):835-42
references.pmid: 10383727
references.citation: J Pediatr Orthop. 2006 May-Jun;26(3):413-23
references.pmid: 16670560
references.citation: J Pediatr Orthop. 1986 Jan-Feb;6(1):72-88
references.pmid: 3079778
references.citation: J Cell Biochem. 2003 Apr 1;88(5):873-84
references.pmid: 12616527
references.citation: J Bone Joint Surg Am. 2008 Dec;90(12):2735-44
references.pmid: 19047720
references.citation: J Bone Miner Res. 1999 Nov;14(11):1805-15
references.pmid: 10571679
references.citation: Clin Orthop Surg. 2011 Sep;3(3):230-7
references.pmid: 21909471
references.citation: J Bone Miner Res. 2015 Jan;30(1):55-63
references.pmid: 25043591
references.citation: J Orthop Trauma. 2009 May-Jun;23(5 Suppl):S31-8
references.pmid: 19390374
references.citation: Bone. 2008 Apr;42(4):616-22
references.pmid: 18248783
references.citation: J Bone Miner Res. 2004 Jun;19(6):983-9
references.pmid: 15125795
references.citation: PLoS One. 2014;9(1):e86115
references.pmid: 24465906
references.citation: Wiley Interdiscip Rev Syst Biol Med. 2015 Jul-Aug;7(4):183-94
references.pmid: 25903383
references.citation: Clin Orthop Relat Res. 1982 Jun;(166):5-13
references.pmid: 7083685
references.citation: J Clin Invest. 2010 Mar;120(3):859-70
references.pmid: 20160346
references.citation: J Theor Biol. 2008 Mar 7;251(1):137-58
references.pmid: 18155732
references.citation: Acta Biomater. 2011 Oct;7(10):3573-85
references.pmid: 21723966
references.citation: Osteoporos Int. 2010 Jan;21(1):119-27
references.pmid: 19415373
references.citation: PLoS Comput Biol. 2012;8(10):e1002724
references.pmid: 23071433
references.citation: Hum Mol Genet. 2007 Apr 15;16(8):874-86
references.pmid: 17317783
references.citation: Muscle Nerve. 2012 Sep;46(3):394-9
references.pmid: 22907230