Role of the sensory nervous system in subchondral bone remodeling and synovial inflammation in OA pathology

点击翻译按钮获取中文摘要

The joints are innervated by calcitonin gene-related peptide (alpha-CGRP)- and substance P (SP) positive sensory nerve fibers and there is evidence that sensory neurotransmitters have crucial trophic effects which are essential for proper bone metabolism and bone remodeling. Alteration of sensory joint innervation might be partly responsible for degenerative changes, which contribute to development of osteoarthritis (OA). Underlying molecular mechanisms which add to abnormal subchondral bone remodeling during the pathogenesis of OA due to changes in sensory joint innervation and their respective neurotransmitter milieu are mostly unknown. In the first funding period we observed that cartilage matrix degradation was accelerated in both neuropeptide-deficient mouse strains) which was accompanied by altered biomechanical properties (increased stiffness) of the AC assessed by indentation-type AFM (IT-AFM) compared to WT mice. Applying µCT and high-resolution nanoCT, we found clear evidence that both neuropeptides protect from DMM-induced subchondral bone degeneration/sclerosis and ectopic bone formation in the meniscus affecting bone microarchitecture already in an early OA stage. Both sensory neuropeptides and their receptors are involved in murine macrophage mechanotransduction affecting neuropeptide impact on adhesion and ROS activity. Taken together, our results imply that both SP and αCGRP have preserving functions for bone and cartilage in the context of structural and mechanical properties.We hypothesize that sensory neuropeptides are modulators of osteocyte metabolism and phenotype in response to aberrant mechanical loading during OA pathogenesis and that they are involved in modulating inflammatory processes in the joint during OA. For that we want to characterize the contribution of sensory neuropeptides to cellular changes in osteocytes during pathogenesis of DMM induced OA plus forced exercise (mice) and during spontaneous OA (WP1). Secondly, we want to characterize the influence of sensory neuropeptides on infiltration, activity and maturation of mononuclear cells, i.e. macrophages, and pro-inflammatory mediators into synovial tissue after DMM induced OA plus forced exercise and spontaneous OA (WP2). Finally, we will test if intra-articular application of rAAV5 virus expressing alpha-CGRP and SP impacts on joint tissues pathophysiological changes after OA induction.