title: A Qualitative Model of the Differentiation Network in Chondrocyte Maturation: A Holistic View of Chondrocyte Hypertrophy.
abstract: Differentiation of chondrocytes towards hypertrophy is a natural process whose control is essential in endochondral bone formation. It is additionally thought to play a role in several pathophysiological processes, with osteoarthritis being a prominent example. We perform a dynamic analysis of a qualitative mathematical model of the regulatory network that directs this phenotypic switch to investigate the influence of the individual factors holistically. To estimate the stability of a SOX9 positive state (associated with resting/proliferation chondrocytes) versus a RUNX2 positive one (associated with hypertrophy) we employ two measures. The robustness of the state in canalisation (size of the attractor basin) is assessed by a Monte Carlo analysis and the sensitivity to perturbations is assessed by a perturbational analysis of the attractor. Through qualitative predictions, these measures allow for an in silico screening of the effect of the modelled factors on chondrocyte maintenance and hypertrophy. We show how discrepancies between experimental data and the model's results can be resolved by evaluating the dynamic plausibility of alternative network topologies. The findings are further supported by a literature study of proposed therapeutic targets in the case of osteoarthritis.
authors: Biomechanics Research Unit, University of Liège, Liège, Belgium.|Biomechanics section, KU Leuven, Leuven, Belgium.|Prometheus, the Leuven R&D division of skeletal tissue engineering, KU Leuven, Leuven, Belgium.
authors: Johan
authors: J
authors: Kerkhofs
authors: Prometheus, the Leuven R&D division of skeletal tissue engineering, KU Leuven, Leuven, Belgium.|Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium.
authors: Jeroen
authors: J
authors: Leijten
authors: Prometheus, the Leuven R&D division of skeletal tissue engineering, KU Leuven, Leuven, Belgium.|Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium.
authors: Johanna
authors: J
authors: Bolander
authors: Prometheus, the Leuven R&D division of skeletal tissue engineering, KU Leuven, Leuven, Belgium.|Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium.
authors: Frank P
authors: FP
authors: Luyten
authors: Developmental BioEngineering, MIRA Institute for biomedical technology and technical medicine, University of Twente, Enschede, The Netherlands.
authors: Janine N
authors: JN
authors: Post
authors: Biomechanics Research Unit, University of Liège, Liège, Belgium.|Biomechanics section, KU Leuven, Leuven, Belgium.|Prometheus, the Leuven R&D division of skeletal tissue engineering, KU Leuven, Leuven, Belgium.
authors: Liesbet
authors: L
authors: Geris
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology*; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008962:Models, Theoretical; D009010:Monte Carlo Method; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D055758:SOX9 Transcription Factor / Q000378:metabolism*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D055758:SOX9 Transcription Factor