Peripheral neuronal sensitization and neurovascular remodelling in osteoarthritis pain

Abstract

Pain is the primary complaint in individuals with osteoarthritis (OA) and changes as the disease progresses. Anatomical changes in several joint structures potentially contribute to pain, including the increased innervation of the periosteum, synovium and subchondral bone, and the pathological innervation of articular cartilage, which is aneural under physiological conditions. Research has focused on molecules that sensitize afferent neurons, such as neuropeptides, neurotrophins, pro-inflammatory cytokines and ion channels. The neurotrophin nerve growth factor (NGF) is the best validated target in OA pain, with proven analgesic effects in preclinical and clinical studies, although the development of NGF-targeted therapeutics has been hampered by serious side effects. One relatively neglected area of research is the contribution to OA pain of the molecular pathways that mediate remodelling of nerves in disease. Remodelling requires coordination between the nerve and the associated vasculature, along with signals that are received from the surrounding parenchyma. Key cell guidance molecules, including angiogenic factors, ephrins, semaphorins and SLIT proteins are involved in nerve growth during development, and their expression is increased in osteoarthritic joints. Peripheral mechanisms of pain in osteoarthritis include nociceptor sensitization via the function of ion channels and pro-inflammatory molecules, and, potentially, pathways supporting neuronal growth and differentiation within the diseased joint. This Review discusses how neuronal trophism and neurovascular remodelling could be targeted in combination with neuronal de-sensitization or joint re-structuring approaches to reduce osteoarthritic pain.