Abstract
ObjectiveCartilage is avascular and numerous studies have identified the presence of single anti- and pro-angiogenic factors in cartilage. To better understand the maintenance hyaline cartilage, we assessed the angiogenic potential of complete cartilage releasate with functional assays in vitro and in vivo.DesignWe evaluated the gene expression profile of angiogenesis-related factors in healthy adult human articular cartilage with a transcriptome-wide analysis generated by next-generation RNAseq. The effect on angiogenesis of the releasate of cartilage tissue was assessed with a chick chorioallantoic membrane (CAM) assay as well as human umbilical vein endothelial cell (HUVEC) migration and proliferation assays using conditioned media generated from tissue-engineered cartilage derived from human articular and nasal septum chondrocytes as well as explants from bovine articular cartilage and human nasal septum. Experiments were done with triplicate samples of cartilage from 3 different donors.ResultsRNAseq data of 3 healthy human articular cartilage donors revealed that the majority of known angiogenesis-related factors expressed in healthy adult articular cartilage are pro-angiogenic. The releasate from generated cartilage as well as from tissue explants, demonstrated at least a 3.1-fold increase in HUVEC proliferation and migration indicating a pro-angiogenic effect of cartilage. Finally, the CAM assay demonstrated that cartilage explants can indeed attract vessels; however, their ingrowth was not observed.ConclusionUsing multiple approaches, we show that cartilage releasate has an inherent pro-angiogenic capacity. It remains vessel free due to anti-invasive properties associated with the tissue itself.
Highlights
Cartilage is an avascular tissue and the absence of blood vessels is considered a key feature in the homeostasis of permanent cartilage.[1]
Of these 385 genes 63 genes were associated with the negative regulation of angiogenesis and 116 were known pro-angiogenic genes of which most are more highly expressed than d21 chondrogenic differentiated mesenchymal stem cells (MSCs)[26] (Fig. 1)
We demonstrated that the cartilage releasate is overall pro-angiogenic
Summary
Cartilage is an avascular tissue and the absence of blood vessels is considered a key feature in the homeostasis of permanent cartilage.[1] Healthy adult cartilage is often assumed to be anti-angiogenic in nature. It was shown that cartilage explants or tissue-engineered cartilage constructs from adult chondrocytes are not invaded by blood vessels and retains its stable cartilage phenotype when implanted subcutaneously in mice.[2,3] Eisenstein and colleagues have demonstrated that cartilage inhibits vessel invasion[4] due to factors that can be extracted from the tissue with guanidine hydrochloride.[5] Since components in this extracted fraction could be a useful tool against cancer (anti-invasion factors),[6,7] this further prompted search for specific proteins in cartilage that conferred the tissue with this anti-angiogenic capacity and led to the identification of proteins, such as chondromodulin and endostatin, that prevented vessel formation and invasion.[6,7,8,9,10,11,12,13].
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