Vascular Endothelial Growth Factor in Cartilage Development and Osteoarthritis

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.

Absence of VEGFR‐1/Flt‐1 signaling pathway in mice results in insensitivity to discogenic low back pain in an established disc injury mouse model

“…Inflammatory and angiogenic molecules, such as TNF‐α and VEGF (Nagao et al, ), are well‐known catabolic meditators. They can stimulate matrix degrading enzymes (e.g., MMPs and ADAMTS), which in turn leads to acceleration of IVD degeneration.…”

“…VEGFR‐2 activation could mediate the effects of VEGF on endothelial cell proliferation, differentiation, survival, migration, and permeability, thus contributing to vasculature development and maintenance in embryonic, fetal, postnatal, and adult period (Ferrara et al, ; Maharaj & D'Amore, ; Takahashi & Shibuya, ), as well as being essential in some pathological process such as tumor angiogenesis, tissue repair and remodeling, and so forth. Furthermore, accumulating evidence suggests that VEGF can induce and accelerate the development of knee OA through activation of VEGFR‐2 (Hamilton et al, ; Nagao et al, ). In our DDD mouse model, it was noted that both WT and vegfr‐1 TK−/− mice show similar presentations of disc degeneration.…”

Low‐intensity pulsed ultrasound inhibits VEGFA expression in chondrocytes and protects against cartilage degeneration in experimental osteoarthritis

“…In addition, injecting VEGFA into both keen and temporomandibular joint induced OA phenotype in mice . Correspondingly, another study reported that either deleting VEGFA in Col Π‐Cre lineage cells or intra‐articular injecting anti‐VEGFA antibody attenuated progression of surgically induced OA in mice . These findings suggest that controlling VEGFA secretion may help prevent OA escalation and OA‐associated joint deterioration.…”

Phenotypic instability of chondrocytes in osteoarthritis: on a path to hypertrophy

“…Hif‐2α gene (Epas1) expression is higher in OA cartilage than normal cartilage and it promotes cartilage degradation in part by modulating the expression of Col10a1 , Mmp13 , or Vegfa . Abnormal expression of these factors can in turn drive cartilage destruction or mediate catabolic processes in OA chondrocytes . HIF‐2α can also mediate cartilage destruction by controlling MMP3 and MMP13 levels via IL‐6 expression and by inducing FAS‐mediated chondrocyte apoptosis, as shown in mice subjected to the destabilization of the medial meniscus (DMM) surgical OA model and in mice with intra‐articular injection of AdEpas1, which can induce OA.…”