A Qualitative Model of the Differentiation Network in Chondrocyte Maturation: A Holistic View of Chondrocyte Hypertrophy

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2016 Sep 1

PMID 27579819

Citations 14

Authors

Johan Kerkhofs

Jeroen Leijten

Johanna Bolander

Frank P Luyten

Janine N Post

Liesbet Geris

Affiliations

Soon will be listed here.

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.

Citing Articles

A multi-model approach identifies ALW-II-41-27 as a promising therapy for osteoarthritis-associated inflammation and endochondral ossification.

Ferrao Blanco M, Lesage R, Kops N, Fahy N, Bekedam F, Chavli A Heliyon. 2024; 10(23):e40871.

PMID: 39717596 PMC: 11664402. DOI: 10.1016/j.heliyon.2024.e40871.

Immune digital twins for complex human pathologies: applications, limitations, and challenges.

Niarakis A, Laubenbacher R, An G, Ilan Y, Fisher J, Flobak A NPJ Syst Biol Appl. 2024; 10(1):141.

PMID: 39616158 PMC: 11608242. DOI: 10.1038/s41540-024-00450-5.

Recent Advances in Liver Tissue Engineering as an Alternative and Complementary Approach for Liver Transplantation.

Nair D, Weiskirchen R Curr Issues Mol Biol. 2024; 46(1):262-278.

PMID: 38248320 PMC: 10814863. DOI: 10.3390/cimb46010018.

Lifelike Transformative Materials for Biohybrid Implants: Inspired by Nature, Driven by Technology.

Fernandez-Colino A, Kiessling F, Slabu I, De Laporte L, Akhyari P, Nagel S Adv Healthc Mater. 2023; 12(20):e2300991.

PMID: 37290055 PMC: 11469152. DOI: 10.1002/adhm.202300991.

Network-based modelling of mechano-inflammatory chondrocyte regulation in early osteoarthritis.

Segarra-Queralt M, Piella G, Noailly J Front Bioeng Biotechnol. 2023; 11:1006066.

PMID: 36815875 PMC: 9936426. DOI: 10.3389/fbioe.2023.1006066.

References

Qiao M, Shapiro P, Kumar R, Passaniti A . Insulin-like growth factor-1 regulates endogenous RUNX2 activity in endothelial cells through a phosphatidylinositol 3-kinase/ERK-dependent and Akt-independent signaling pathway. J Biol Chem. 2004; 279(41):42709-18. DOI: 10.1074/jbc.M404480200. View

Melas I, Chairakaki A, Chatzopoulou E, Messinis D, Katopodi T, Pliaka V . Modeling of signaling pathways in chondrocytes based on phosphoproteomic and cytokine release data. Osteoarthritis Cartilage. 2014; 22(3):509-18. DOI: 10.1016/j.joca.2014.01.001. View

Kang J, Alliston T, Delston R, Derynck R . Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3. EMBO J. 2005; 24(14):2543-55. PMC: 1176457. DOI: 10.1038/sj.emboj.7600729. View

Kerkhofs J, Roberts S, Luyten F, Van Oosterwyck H, Geris L . Relating the chondrocyte gene network to growth plate morphology: from genes to phenotype. PLoS One. 2012; 7(4):e34729. PMC: 3340393. DOI: 10.1371/journal.pone.0034729. View

Leijten J, Teixeira L, Landman E, van Blitterswijk C, Karperien M . Hypoxia inhibits hypertrophic differentiation and endochondral ossification in explanted tibiae. PLoS One. 2012; 7(11):e49896. PMC: 3503827. DOI: 10.1371/journal.pone.0049896. View

Cahan P, Li H, Morris S, Lummertz da Rocha E, Daley G, Collins J . CellNet: network biology applied to stem cell engineering. Cell. 2014; 158(4):903-915. PMC: 4233680. DOI: 10.1016/j.cell.2014.07.020. View

Wang X, Manner P, Horner A, Shum L, Tuan R, Nuckolls G . Regulation of MMP-13 expression by RUNX2 and FGF2 in osteoarthritic cartilage. Osteoarthritis Cartilage. 2004; 12(12):963-73. DOI: 10.1016/j.joca.2004.08.008. View

Kaiser M, Haag J, Soder S, Bau B, Aigner T . Bone morphogenetic protein and transforming growth factor beta inhibitory Smads 6 and 7 are expressed in human adult normal and osteoarthritic cartilage in vivo and are differentially regulated in vitro by interleukin-1beta. Arthritis Rheum. 2004; 50(11):3535-40. DOI: 10.1002/art.20750. View

Benya P, SHAFFER J . Dedifferentiated chondrocytes reexpress the differentiated collagen phenotype when cultured in agarose gels. Cell. 1982; 30(1):215-24. DOI: 10.1016/0092-8674(82)90027-7. View

10.

Mori Y, Saito T, Chang S, Kobayashi H, Ladel C, Guehring H . Identification of fibroblast growth factor-18 as a molecule to protect adult articular cartilage by gene expression profiling. J Biol Chem. 2014; 289(14):10192-200. PMC: 3974988. DOI: 10.1074/jbc.M113.524090. View

11.

Zhu M, Tang D, Wu Q, Hao S, Chen M, Xie C . Activation of beta-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice. J Bone Miner Res. 2008; 24(1):12-21. PMC: 2640321. DOI: 10.1359/jbmr.080901. View

12.

Studer D, Millan C, Ozturk E, Maniura-Weber K, Zenobi-Wong M . Molecular and biophysical mechanisms regulating hypertrophic differentiation in chondrocytes and mesenchymal stem cells. Eur Cell Mater. 2012; 24:118-35. DOI: 10.22203/ecm.v024a09. View

13.

Dy P, Wang W, Bhattaram P, Wang Q, Wang L, Ballock R . Sox9 directs hypertrophic maturation and blocks osteoblast differentiation of growth plate chondrocytes. Dev Cell. 2012; 22(3):597-609. PMC: 3306603. DOI: 10.1016/j.devcel.2011.12.024. View

14.

Luo J, Turner M . Evolving sensitivity balances Boolean Networks. PLoS One. 2012; 7(5):e36010. PMC: 3346810. DOI: 10.1371/journal.pone.0036010. View

15.

Zhong L, Huang X, Karperien M, Post J . The Regulatory Role of Signaling Crosstalk in Hypertrophy of MSCs and Human Articular Chondrocytes. Int J Mol Sci. 2015; 16(8):19225-47. PMC: 4581295. DOI: 10.3390/ijms160819225. View

16.

Dodou E, Verzi M, Anderson J, Xu S, Black B . Mef2c is a direct transcriptional target of ISL1 and GATA factors in the anterior heart field during mouse embryonic development. Development. 2004; 131(16):3931-42. DOI: 10.1242/dev.01256. View

17.

Pan Q, Yu Y, Chen Q, Li C, Wu H, Wan Y . Sox9, a key transcription factor of bone morphogenetic protein-2-induced chondrogenesis, is activated through BMP pathway and a CCAAT box in the proximal promoter. J Cell Physiol. 2008; 217(1):228-41. DOI: 10.1002/jcp.21496. View

18.

Bi W, Deng J, Zhang Z, Behringer R, de Crombrugghe B . Sox9 is required for cartilage formation. Nat Genet. 1999; 22(1):85-9. DOI: 10.1038/8792. View

19.

Fosang A, Beier F . Emerging Frontiers in cartilage and chondrocyte biology. Best Pract Res Clin Rheumatol. 2012; 25(6):751-66. DOI: 10.1016/j.berh.2011.11.010. View

20.

Peterson H, Dawud R, Garg A, Wang Y, Vilo J, Xenarios I . Qualitative modeling identifies IL-11 as a novel regulator in maintaining self-renewal in human pluripotent stem cells. Front Physiol. 2013; 4:303. PMC: 3809568. DOI: 10.3389/fphys.2013.00303. View