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.
Highlights
IntroductionRelevance of developmental biology to bone tissue engineering
Relevance of developmental biology to bone tissue engineeringIn bone tissue engineering (TE) strategies, progenitor cells are combined with a bioartificial scaffold and/or specific growth factors to initiate a process of new bone formation with the aim of addressing an unmet clinical need in treating large bone defects [1]
The gene network centres on the primordial transcription factors SOX9 and RUNX2 whose presence or absence is decisive for cell fate decisions
Summary
Relevance of developmental biology to bone tissue engineering. In bone tissue engineering (TE) strategies, progenitor cells are combined with a bioartificial scaffold and/or specific growth factors to initiate a process of new bone formation with the aim of addressing an unmet clinical need in treating large bone defects [1]. For TE constructs, an important obstacle for clinical translation lies in controlling the variability in the cell populations available for this approach. These populations are heterogeneous and may differ dramatically in behaviour in different individuals [2]. This work is part of Prometheus, the KU Leuven R&D division for skeletal tissue engineering (http://www.kuleuven.be/prometheus)
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