Abstract
The importance of the nociceptive nervous system for maintaining tissue homeostasis has been known for some time, and it has also been suggested that organogenesis and tissue repair are under neuronal control. Changes in peripheral joint innervation are supposed to be partly responsible for degenerative alterations in joint tissues which contribute to development of osteoarthritis. Various resident cell types of the musculoskeletal system express receptors for sensory and sympathetic neurotransmitters, allowing response to peripheral neuronal stimuli. Among them are mesenchymal stem cells, synovial fibroblasts, bone cells and chondrocytes of different origin, which express distinct subtypes of adrenoceptors (AR), receptors for vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP). Some of these cell types synthesize and secrete neuropeptides such as SP, and they are positive for tyrosine-hydroxylase (TH), the rate limiting enzyme for biosynthesis of catecholamines. Sensory and sympathetic neurotransmitters are involved in the pathology of inflammatory diseases such as rheumatoid arthritis (RA) which manifests mainly in the joints. In addition, they seem to play a role in pathogenesis of priori degenerative joint disorders such as osteoarthritis (OA). Altogether it is evident that sensory and sympathetic neurotransmitters have crucial trophic effects which are critical for joint tissue and bone homeostasis. They modulate articular cartilage, subchondral bone and synovial tissue properties in physiological and pathophysiological conditions, in addition to their classical neurological features.
Highlights
Osteoarthritis (OA) is an age-related and/or trauma-induced multi-factorial, slowly progressing and primarily non-inflammatory degenerative disorder of the synovial joints, culminating in the irreversible destruction of the articular cartilage
Increased nerve growth factor (NGF) production may contribute to OA pain, both structurally and through peripheral sensitization. This was confirmed in studies in human OA material, showing that increased vascular penetration and density of perivascular calcitonin gene-related peptide (CGRP)—positive sensory nerve profiles in the meniscus are a potential source of pain in knee OA and lead in addition to propagation of further inflammation and tissue damage [36,40]
In a similar OA model, Murakami et al reported that the densities of protein gene product (PGP) 9.5- and CGRP-positive nerve fibers in the synovium were drastically decreased just one week after the collagenase injection [42]. This aggressive and painful method of OA induction leads to various degenerative alterations in synovial joint tissues after a few weeks. In contrast to these reports, some studies on human knee OA revealed an increase in substance P (SP)- and CGRP-positive nerve fiber density in the synovial tissue [38,39,43], whereas others have described a decrease of these nerve fibers in the synovium [44]
Summary
Osteoarthritis (OA) is an age-related and/or trauma-induced multi-factorial, slowly progressing and primarily non-inflammatory degenerative disorder of the synovial joints, culminating in the irreversible destruction of the articular cartilage. A recent survey in 15 European countries revealed that on average 19% of the population suffers from chronic pain, most frequently caused by disorders of the musculoskeletal system, OA, herniated and/or deteriorating discs, traumatic injury and rheumatoid arthritis [6]. Sympathetic and sensory nerve fibers innervate synovium, trabecular and subchondral bone, bone marrow, periosteum and fracture callus [7,8]. Despite lack of nervous innervation, cartilage metabolism is modulated and influenced by neurotransmitters released either from nerve fibers located in neighboring tissue or directly from chondrocytes (for review see [11,12]). This review focusses on recent literature describing effects of sensory and sympathetic nerve fibers and their neurotransmitters on joint tissue pathophysiology in OA affecting cartilage and bone turnover
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