Targeting VEGF and Its Receptors for the Treatment of Osteoarthritis and Associated Pain

Abstract

Increased vascular endothelial growth factor (VEGF) levels are associated with osteoarthritis (OA) progression. Indeed, VEGF appears to be involved in OA-specific pathologies including cartilage degeneration, osteophyte formation, subchondral bone cysts and sclerosis, synovitis, and pain. Moreover, a wide range of studies suggest that inhibition of VEGF signaling reduces OA progression. This review highlights both the potential significance of VEGF in OA pathology and pain, as well as potential benefits of inhibition of VEGF and its receptors as an OA treatment. With the emergence of the clinical use of anti-VEGF therapy outside of OA, both as high-dose systemic treatments and low-dose local treatments, these particular therapies are now more widely understood. Currently, there is no established disease-modifying drug available for patients with OA, which warrants continued study of the inhibition of VEGF signaling in OA, as stand-alone or adjuvant therapy. © 2016 American Society for Bone and Mineral Research.

Keywords: ANGIOGENESIS; OSTEOARTHRITIS; VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF); VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR (VEGFR).

Figure 1

Potential pathways of VEGF-mediated OA progression and pain. Suggested mediators of increased VEGF expression at the joint tissue include mechanical overload, hypoxia, inflammatory cytokines, NO, ROS, growth factors, chondrocyte hypertrophy, and aging. Cartilage degeneration: Chondrocyte mediated pathways of cartilage degeneration include VEGF-mediated chondrocyte upregulation of MMP-1, MMP-3, MMP-9, MMP-13, and ADAMTS-5. VEGF can also decrease chondrocyte production of TIMP-1, TIMP-2, type II collagen, and aggrecan. VEGF can increase expression of NO in both chondrocytes and endothelial cells, leading to chondrocyte apoptosis. Increased levels of VEGF lead to a minor increase in expression of inflammatory cytokines from chondrocytes, including IL-1β, IL-6, TNF-α. Bone and neurovascular invasion of articular cartilage and osteophyte formation: VEGF stimulates vascular invasion of articular cartilage, and sensory nerve ingrowth can occur upon the tracks of vascular invasion. Increased sensory nerve ingrowth is a potential source of increased pain sensitivity in the joint. VEGF stimulates the recruitment and activity of osteo(chondro)clasts, which can resorb cartilage. Chondroclasts can express MMP-9, leading to matrix degradation of cartilage. Additionally, osteochondral angiogenesis is associated with increased fibrovascular tissue in the bone marrow expressing VEGF. Vascular invasion facilitates the migration of osteoblastic precursor cells towards the articular surface, which are further stimulated by VEGF to produce new bone. Synovitis: VEGF production is increased in synovial macrophages and fibroblasts. VEGF increases migration and/or activity of macrophages, fibroblasts, and neutrophils. Neutrophils may be an additional source of increased VEGF. VEGF stimulates macrophages to secrete MCP-1, TNF-α, and IL-6, and VEGF stimulates fibroblasts to express TNF-α and IL-6. VEGF stimulates endothelial cells to increase expression of IL-8 and MCP-1. IL-8 stimulates neutrophil recruitment, and MCP-1 stimulates macrophage recruitment. VEGF mediated angiogenesis facilitates inflammatory cell infiltration at the synovium. Subchondral bone sclerosis and resorption: VEGF stimulates osteoclast and osteoblast differentiation, migration, and ultimately activity, leading to areas of increased bone resorption and bone formation. Additionally, VEGF can potentially stimulate RANKL expression at chondrocytes, synovial fibroblasts, and osteoblasts, further stimulating osteoclastogenesis. Direct pain sensitization: VEGF can directly stimulate nociceptive sensory neurons to increase pain sensitivity and potentially nerve ingrowth; this may occur in the synovium, osteochondral junction, and meniscus (not shown).

Figure 2

Specific signaling pathways mediated by VEGFR-1 and VEGFR-2 activation that may lead to OA progression and pain. VEGF binds to both VEGFR-1 and VEGFR-2, inducing RTK signaling. NRP-1 and NRP-2 serve as co-receptors for specific VEGF isoforms to interact with VEGFR-1 and/or VEGFR-2. sVEGFR-1 serves as a soluble decoy receptor for VEGF. VEGFRs are expressed in a wide variety of cell types, mediating different cellular responses. Not shown, VEGFR-1 and VEGFR-2 are suggested to mediate osteoblast differentiation through intracrine signaling.