Biglycan potentially regulates angiogenesis during fracture repair by altering expression and function of endostatin

Abstract

The small proteoglycan biglycan (Bgn) is highly expressed in the organic matrix of bone and plays a role in bone formation. Previous work implicated Bgn in vessel growth during bone healing (1). By infusing barium sulfate (BaSO4) into WT and Bgn-deficient mice we discovered the positive effect of Bgn in modulating angiogenesis during fracture healing. Using micro-computed tomography angiography we found significant differences in the vessel size and volume among other parameters. To further understand the mechanistic basis for this, we explored the relationship between Bgn and the anti-angiogenic protein endostatin. Immunohistochemistry (IHC) showed co-localization of Bgn and endostatin in regions of bone formation, with increased endostatin staining in Bgn-KO compared to WT at 14 days post-fracture. To further elucidate the relationship between Bgn and endostatin, an endothelial cell tube formation assay was used. This study showed that endothelial cells treated with endostatin had significantly decreased vessel length and vessel branches compared to untreated cells, while cells treated with endostatin and Bgn at a 1:1 molar ratio had vessel length and vessel branches comparable to untreated cells. This indicated that Bgn was able to mitigate the inhibitory effect of endostatin on endothelial cell growth. In summary, these results suggest that Bgn is needed for proper blood vessel formation during fracture healing, and one mechanism by which Bgn impacts angiogenesis is through inhibition of endostatin.

A current view of perlecan in physiology and pathology: A mosaic of functions

“…It is also worthy to mention a recent study which demonstrates that biglycan, an extracellular matrix SLRP and close relative to decorin, can counteract the anti-angiogenic effects of endostatin [159]. As endostatin is pro-autophagic, it is conceivable that future studies may show that biglycan is yet another matrix component that follows the aforementioned model where it could potentially inhibit autophagy to promote angiogenesis.…”

Proteoglycan neofunctions: regulation of inflammation and autophagy in cancer biology

“…Furthermore, in order to connect the processes of tumor progression and autophagy, a worthy hypothesis may be that, in the absence of decorin, lower levels of autophagy promote a protumorigenic microenvironment. In contrast, biglycan, another class I SLRP that shares the most structural homology with decorin [29,30], possesses proangiogenic properties through its ability to bind VEGFA and activate VEGFR2 signaling [31]. Additionally, when overexpressed in colon cancer cells, biglycan upregulates VEGFA leading to increased angiogenesis and tumor growth through activation of the extracellular signal-regulated kinase (ERK) pathway [32].…”

Extracellular Matrix, a Hard Player in Angiogenesis

“…Through the binding to VEGFA and activation of VEGFR2 biglycan exerts a pro-angiogenic stimulus in fracture healing processes [176]. The pro-angiogenic function is also the result of its interaction with and inactivation of endostatin [177]. In colon cancer, the over-expression of biglycan induces VEGF up-regulation and angiogenesis and thus the molecule may be a promising target for the development of anti-angiogenic strategies [178].…”