Vascular Endothelial Growth Factor in Cartilage Development and Osteoarthritis

Masashi Nagao,Xuchen Duan,Agnes D Berendsen,Ranjan Kc,John L Hamilton,Bjorn R Olsen,Chan Wook Cheong,Xin Li,Hee-Jeong Im

doi:10.1038/s41598-017-13417-w

Abstract

Genome wide studies indicate that vascular endothelial growth factor A (VEGF) is associated with osteoarthritis (OA), and increased VEGF expression correlates with increased disease severity. VEGF is also a chondrocyte survival factor during development and essential for bone formation, skeletal growth and postnatal homeostasis. This raises questions of how the important embryonic and postnatal functions of VEGF can be reconciled with an apparently destructive role in OA. Addressing these questions, we find that VEGF acts as a survival factor in growth plate chondrocytes during development but only up until a few weeks after birth in mice. It is also required for postnatal differentiation of articular chondrocytes and the timely ossification of bones in joint regions. In surgically induced knee OA in mice, a model of post-traumatic OA in humans, increased expression of VEGF is associated with catabolic processes in chondrocytes and synovial cells. Conditional knock-down of Vegf attenuates induced OA. Intra-articular anti-VEGF antibodies suppress OA progression, reduce levels of phosphorylated VEGFR2 in articular chondrocytes and synovial cells and reduce levels of phosphorylated VEGFR1 in dorsal root ganglia. Finally, oral administration of the VEGFR2 kinase inhibitor Vandetanib attenuates OA progression.

Highlights

Osteoarthritis (OA), the most common form of arthritis, is a leading cause of pain and disability
vascular endothelial growth factor A (VEGF) functions as survival factor for growth plate chondrocytes during embryonic development[9,10]
VEGF functions as survival factor for chondrocytes in hypoxic regions during development and early postnatal life, and its expression by hypertrophic chondrocytes is crucial for timely ossification of both primary and secondary centers in endochondral bones

Summary

Introduction

Osteoarthritis (OA), the most common form of arthritis, is a leading cause of pain and disability. VEGF functions as survival factor for growth plate chondrocytes during embryonic development[9,10]. These findings raise questions regarding distinct VEGF mechanisms in chondrocytes during development, postnatal growth and progression of pathological conditions such as OA. To address these questions, we targeted Vegf expression in Col2-expressing and endothelial lineage cells in mice. We surgically induced knee OA in a mouse model of traumatic knee OA in humans, and compared the effects of treatments that targeted VEGF and the VEGF receptor 2 (VEGFR2) kinase activity. The data provide novel insights into roles of VEGF in cartilage development and OA progression

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Results

Conclusion