Spatiotemporal distribution of thrombospondin-4 and -5 in cartilage during endochondral bone formation and repair

E. Andrés Sastre, K. Maly, M. Zhu, J. Witte-Bouma, D. Trompet, A. M. Böhm, B. Brachvogel, C. A. van Nieuwenhoven, C. Maes, G. J.V.M. van Osch, F. Zaucke, E. Farrell*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)

Abstract

During skeletal development most bones are first formed as cartilage templates, which are gradually replaced by bone. If later in life those bones break, temporary cartilage structures emerge to bridge the fractured ends, guiding the regenerative process. This bone formation process, known as endochondral ossification (EO), has been widely studied for its potential to reveal factors that might be used to treat patients with large bone defects. The extracellular matrix of cartilage consists of different types of collagens, proteoglycans and a variety of non-collagenous proteins that organise the collagen fibers in complex networks. Thrombospondin-5, also known as cartilage oligomeric matrix protein (TSP-5/COMP) is abundant in cartilage, where it has been described to enhance collagen fibrillogenesis and to interact with a variety of growth factors, matrix proteins and cellular receptors. However, very little is known about the skeletal distribution of its homologue thrombospondin-4 (TSP-4). In our study, we compared the spatiotemporal expression of TSP-5 and TSP-4 during postnatal bone formation and fracture healing. Our results indicate that in both these settings, TSP-5 distributes across all layers of the transient cartilage, while the localisation of TSP-4 is restricted to the population of hypertrophic chondrocytes. Furthermore, in fractured bones we observed TSP-4 sparsely distributed in the periosteum, while TSP-5 was absent. Last, we analysed the chemoattractant effects of the two proteins on endothelial cells and bone marrow stem cells and hypothesised that, of the two thrombospondins, only TSP-4 might promote blood vessel invasion during ossification. We conclude that TSP-4 is a novel factor involved in bone formation. These findings reveal TSP-4 as an attractive candidate to be evaluated for bone tissue engineering purposes.

Original languageEnglish
Article number115999
JournalBone
Volume150
DOIs
Publication statusPublished - Sep 2021

Bibliographical note

Funding Information:
This project has received funding from the European Union's Horizon 2020 Research and Innovation programme under Marie Sklodowska-Curie grant agreement No. 721432. This work was performed within the framework of the Erasmus Postgraduate School Molecular Medicine and Medical Delta Regenerative Medicine 4D program. CM acknowledges funding by the Research Foundation Flanders (FWO #G0B5219N) and KU Leuven (#C14/18/105). DT was supported by a FWO PhD fellowship for Strategic Basic Research (SB). We also would like to thank N. Kops (Erasmus MC) for the support with the histological methodology.

Funding Information:
This project has received funding from the European Union's Horizon 2020 Research and Innovation programme under Marie Sklodowska-Curie grant agreement No. 721432 . This work was performed within the framework of the Erasmus Postgraduate School Molecular Medicine and Medical Delta Regenerative Medicine 4D program. CM acknowledges funding by the Research Foundation Flanders (FWO # G0B5219N ) and KU Leuven (# C14/18/105 ). DT was supported by a FWO PhD fellowship for Strategic Basic Research (SB). We also would like to thank N. Kops (Erasmus MC) for the support with the histological methodology.

Publisher Copyright:
© 2021 The Author(s)

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