Peripheral Nerve Fibers and Their Neurotransmitters in Osteoarthritis Pathology

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.

A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases

“…Few studies have focused on the presence of VIP and its receptors in chondrocytes [37]. As previously described in SF, articular cartilage from OA patients also has lower VIP levels compared to controls.…”

“…Thus, VIP treatment in rat OA knees promotes synovial hyperemia, as well as sensitization of joint afferent fibers via AC/cAMP/PKA, also increasing firing rate and decreasing mechanical threshold during movement. Therefore, VIP might promote mechanosensitivity and pain in rat OA models [37,225,232,237,238]. Moreover, Rahman et al reported that VIP stimulates PGE2 production in human articular chondrocytes, human osteoblast-like cells, and human SF, as well as cAMP production in human osteoblast-like cells, suggesting a pro-inflammatory role for this peptide [239].…”

“…Thus, VIP treatment in rat OA knees promotes synovial hyperemia, as well as sensitization of joint afferent fibers via AC/cAMP/PKA, also increasing firing rate and decreasing mechanical threshold during movement. Therefore, VIP might promote mechanosensitivity and pain in rat OA models [37,225,232,237,238]. Moreover, Rahman et al…”

“…In this sense, nerve fibers of the sympathetic nervous system in the joints have been reported in rheumatic diseases. Moreover, a decrease in the number of these nerve endings has been described in osteoarthritis (OA) and RA [37]. Regarding cellular origin, synovial fibroblasts (SF) from OA and RA patients have been found to express and release VIP [38].…”

“…Concerning subchondral bone, VIP receptors have been described on osteoclasts and osteoblasts of several species, including human, mouse, and rat [37,244]. VIP inhibits osteoclast-mediated bone resorption and induces the production of IL-6 from osteoblasts, regulates the expression of osteoclastogenic factors like RANKL and OPG in osteoblasts, and seems to be involved in osteoblastogenesis [37,242,245,246]. In addition, VIP promotes osteoblast activity and proliferation and stimulates bone remodeling [244,247].…”