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Chondrocytes Promote Vascularization in Fracture Healing Through a FOXO1‐Dependent Mechanism
Author(s) -
Zhang Citong,
Feinberg Daniel,
Alharbi Mohammed,
Ding Zhenjiang,
Lu Chanyi,
O'Connor J Patrick,
Graves Dana T
Publication year - 2019
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.3610
Subject(s) - foxo1 , angiogenesis , endochondral ossification , vascular endothelial growth factor a , chondrocyte , bone healing , gene knockdown , microbiology and biotechnology , cartilage , biology , vascular endothelial growth factor , chemistry , cancer research , protein kinase b , signal transduction , cell culture , anatomy , genetics , vegf receptors
Chondrocytes play an essential role in fracture healing by producing cartilage, which forms an anlage for endochondral ossification that stabilizes the healing fracture callus. More recently it has been appreciated that chondrocytes have the capacity to produce factors that may affect the healing process. We examined the role of chondrocytes in angiogenesis during fracture healing and the role of the transcription factor forkhead box‐O 1 (FOXO1), which upregulates wound healing in soft tissue. Closed fractures were induced in experimental mice with lineage‐specific FOXO1 deletion by Cre recombinase under the control of a collagen‐2α1 promoter element (Col2α1Cre + FOXO1 L/L ) and Cre recombinase negative control littermates containing flanking loxP sites (Col2α1Cre – FOXO1 L/L ). Experimental mice had significantly reduced CD31 + new vessel formation. Deletion of FOXO1 in chondrocytes in vivo suppressed the expression of vascular endothelial growth factor‐A (VEGFA) at both the protein and mRNA levels. Overexpression of FOXO1 in chondrocytes in vitro increased VEGFA mRNA levels and VEGFA transcriptional activity whereas silencing FOXO1 reduced it. Moreover, FOXO1 interacted directly with the VEGFA promoter and a deacetylated FOXO1 mutant enhanced VEGFA expression whereas an acetylated FOXO1 mutant did not. Lastly, FOXO1 knockdown by siRNA significantly reduced the capacity of chondrocytes to stimulate microvascular endothelial cell tube formation in vitro. The results indicate that chondrocytes play a key role in angiogenesis which is FOXO1 dependent and that FOXO1 in chondrocytes regulates a potent angiogenic factor, VEGFA. These studies provide new insight into fracture healing given the important role of vessel formation in the fracture repair process. © 2018 American Society for Bone and Mineral Research.