Role of the sensory nervous system in osteoarthritis pathology

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Osteoarthritis (OA), a degenerative, slowly progressive synovial joint disease represents the leading cause of disability and chronic pain in the elderly. OA is a failure of all joint tissues, including the articular cartilage and the subchondral bone, and is initiated by multiple risk factors. To date pharmacological interventions can only relieve pain, whilst cell- and compound based therapies have limited success in the regeneration of damaged tissues. Thus, there is a need for identification of novel targets for diagnostic and therapeutic approaches to improve the treatment and life quality of OA patients. The joints are innervated by calcitonin gene-related peptide (alpha CGRP)- and substance P (SP) positive sensory nerve fibers which are a potential source of tibial-femoral pain during pathological changes in osteoarthritis. Alteration of sensory joint innervation might be partly responsible for degenerative changes which contribute to development of osteoarthritis. We pose following questions: 1. How do alpha CGRP- and SP-positive sensory nerves and neurotransmitters modulate OA pathology? 2. How do alpha CGRP- and SP affect articular chondrocyte metabolism and function? We assume that alpha CGRP neuropeptides are primarily anabolic whereas SP effects may be concentration dependent both: anabolic and catabolic. 3. How do nerve repellent factors contribute to changes in alpha CGRP- and SP-positive sensory nervous innervation density of the joint in OA pathology and how does inhibition of their effects modulate chondrocyte differentiation? We propose that expression of sensory nerve repellent factors is altered during OA pathology. 4. How do SP and alpha CGRP modulate metabolic activity and differentiation capacity of osteo-chondroprogenitor cells? We suggest that SP and alpha CGRP sensory neuronal pathways affect chondrogenic and osteogenic differentiation of BMSC oppositely. 5. How will a biomaterial-based therapy approach with both sensory neurotransmitters affect joint pathology? We assume that alpha CGRP will primarily be OA protective whereas SP will -concentration dependent- promote or alleviate OA pathogenesis when applied to the joint in early OA-pathology.