Pain is the most troublesome symptom for people with arthritis, and yet the relationships between pathological change within the joint and symptoms are often weak. Key progress on understanding which specific pathological processes contribute to the generation of pain signals from the arthritic joint have pointed to new blood vessel growth (angiogenesis). Angiogenesis is a component of normal tissue growth and even pathological angiogenesis need not of itself cause pain, for example in diabetic retinopathy. However, angiogenesis is also characteristic of chronic inflammation, and the various growth factors and cytokines that stimulate blood vessel growth can also induce sensitisation of peripheral sensory nerves. Furthermore, vascular growth factors can also stimulate neuronal growth and, reciprocally, nerve growth factors might be angiogenic. This close interplay between vascular and neuronal growth is reflected in the normal sequence by which angiogenesis is followed by the extension of sensory nerve terminals, often into diseased tissues that would not normally receive innervation nor be a source of pain. Examples of tissues that might be sources of pain from arthritic, but not normal joints include the non-calcified articular cartilage and inner two thirds of knee menisci. Angiogenesis might also facilitate inflammation, permitting increased cellular recruitment, concomitant release of other neuronal sensitising factors and exacerbation of structural change. Furthermore, blood vessel growth is a prerequisite for endochondral ossification, contributing directly to structural change and altered biomechanics within the joint. Angiogenesis might be a marker for other pathological processes associated with pain. For example, vascular breaching of the osteochondral junction in OA is associated with subchondral marrow replacement by fibrovascular tissues that is characteristic of some bone marrow lesions observed by MRI scanning. Angiogenesis inhibitors have potential to prevent or relieve arthritis pain, but their application to human arthritis has been limited by potential toxicity that might result from inhibition of physiological angiogenesis (e.g. during the menstrual cycle or pregnancy) or tissue repair. Reduction of pain by angiogenesis inhibitors might result from indirect effects on inflammation that could be achieved by other strategies. However, more recent research into the plurality of effects of vascular endothelial growth factor and its isoforms suggests that inhibition of angiogenic factors might also directly influence pain transmission in the central nervous system, independent of effects on blood vessel growth. Continuing research into angiogenesis in arthritis is revealing previously unexpected insights into the relationship between joint structure and patient symptoms, particularly pain.
Disclosure of Interest None declared
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