The Paracrine Effect of Hyaluronic Acid-Treated Endothelial Cells Promotes BMP-2-Mediated Osteogenesis

Xiaojie Tong, Jin Chen, Renqin Wang, Dan Hou, Gang Wu, Chang Liu*, Janak Lal Pathak*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

The combination of hyaluronic acid (HA) and BMP-2 has been reported to promote bone regeneration. However, the interaction of endothelial cells and bone marrow mesenchymal stem cells (BMSCs) during HA + BMP-2 treatment is not fully understood. This study aimed to analyze the direct effect of HA, as well as the paracrine effect of HA-treated endothelial cells, on the BMP-2-mediated osteogenic differentiation of BMSCs. The angiogenic differentiation potential of HA at different molecular weights and different concentrations was tested. The direct effect of HA, as well as the indirect effect of HA-treated human umbilical cord endothelial cells (HUVECs, i.e., conditioned medium (CM)-based co-culture) on the BMP-2-mediated osteogenic differentiation of BMSCs was analyzed using alkaline phosphatase (ALP) staining and activity, alizarin red S (ARS) staining, and RT-qPCR of osteogenic markers. Angiogenic differentiation markers were also analyzed in HUVECs after treatment with HA + BMP-2. The bone regeneration potential of BMP-2 and HA + BMP-2 was analyzed in a rat ectopic model. We found that 1600 kDa HA at 300 µg/mL promoted tube formation by HUVECs in vitro and upregulated the mRNA expression of the angiogenic markers CD31, VEGF, and bFGF. HA inhibited, but conditioned medium from HA-treated HUVECs promoted, the BMP-2-mediated osteogenic differentiation of BMSCs, as indicated by the results of ALP staining and activity, ARS staining, and the mRNA expression of the osteogenic markers RUNX-2, ALP, COLI, and OPN. HA + BMP-2 (50 ng/mL) upregulated the expression of the angiogenesis-related genes VEGF and bFGF in HUVECs and bone regeneration in vivo compared to BMP-2 treatment. In conclusion, the paracrine effect of hyaluronic acid-treated endothelial cells promotes BMP-2-mediated osteogenesis, suggesting the application potential of HA + BMP-2 in bone tissue engineering.

Original languageEnglish
Article number1227
Pages (from-to)1-14
Number of pages14
JournalBioengineering
Volume10
Issue number10
Early online date20 Oct 2023
DOIs
Publication statusPublished - Oct 2023

Bibliographical note

This article belongs to the Special Issue: Biomaterials for Bone Repair and Regeneration.

Funding Information:
This research was funded by the National Natural Science Foundation of China (82150410451), the Guangzhou Science and Technology Plan Project (2023B03J1240), and the Research Program of Guangzhou Medical University (2014A32).

Publisher Copyright:
© 2023 by the authors.

Keywords

  • angiogenesis
  • bone morphogenetic protein-2
  • co-culture
  • hyaluronic acid
  • osteogenesis
  • paracrine

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