Mechanisms of nerve growth factor signaling in bone nociceptors and in an animal model of inflammatory bone pain

Abstract

Sequestration of nerve growth factor has been used successfully in the management of pain in animal models of bone disease and in human osteoarthritis. However, the mechanisms of nerve growth factor-induced bone pain and its role in modulating inflammatory bone pain remain to be determined. In this study, we show that nerve growth factor receptors (TrkA and p75) and some other nerve growth factor-signaling molecules (TRPV1 and Nav1.8, but not Nav1.9) are expressed in substantial proportions of rat bone nociceptors. We demonstrate that nerve growth factor injected directly into rat tibia rapidly activates and sensitizes bone nociceptors and produces acute behavioral responses with a similar time course. The nerve growth factor-induced changes in the activity and sensitivity of bone nociceptors we report are dependent on signaling through the TrkA receptor, but are not affected by mast cell stabilization. We failed to show evidence for longer term changes in expression of TrkA, TRPV1, Nav1.8 or Nav1.9 in the soma of bone nociceptors in a rat model of inflammatory bone pain. Thus, retrograde transport of NGF/TrkA and increased expression of some of the common nerve growth factor signaling molecules do not appear to be important for the maintenance of inflammatory bone pain. The findings are relevant to understand the basis of nerve growth factor sequestration and other therapies directed at nerve growth factor signaling, in managing pain in bone disease.

New Insights in Understanding and Treating Bone Fracture Pain

“…Many of these mechanosensitive nerve fibers that detect and signal the initial fracture pain are located in the periosteum which is tightly opposed to the outer cortical wall of mineralized bone [36]. Previous studies have shown that many of the sensory nerve fibers that innervate the periosteum are mechanosensitive C and A-delta nociceptors [34, 37, 38, 39•] that rapidly respond to mechanical distortion of the adjacent bone or increased intraosseous pressure [37, 40, 41]. Following bone fracture, any movement or loading of the fractured bone would be expected to result in mechanical stimulation of mechanosensitive sensory nerve fibers that innervate the periosteum, mineralized bone, and marrow [27••, 28, 37, 42, 43].…”

“…Previous studies have shown that many of the sensory nerve fibers that innervate the periosteum are mechanosensitive C and A-delta nociceptors [34, 37, 38, 39•] that rapidly respond to mechanical distortion of the adjacent bone or increased intraosseous pressure [37, 40, 41]. Following bone fracture, any movement or loading of the fractured bone would be expected to result in mechanical stimulation of mechanosensitive sensory nerve fibers that innervate the periosteum, mineralized bone, and marrow [27••, 28, 37, 42, 43]. Thus, normally, non-noxious loading of the bone will distort the mechanosensitive nerve fibers so that even normally innocuous movement or loading of the fractured bone will now be perceived as a highly noxious event.…”

“…Interestingly, therapies targeting these mediators have been shown to relieve a variety of human skeletal pains in animals and humans including osteoarthritis, low back pain, and bone cancer pain [47, 48••]. One molecule that appears to be particularly effective in sensitizing bone nociceptors is nerve growth factor (NGF) [32••, 37]. When NGF binds to its cognate receptor tropomyosin receptor kinase A (TrkA), a variety of mechanotransducers, ion channels, receptors, and neurotransmitters expressed by nociceptors appear to be sensitized and/or upregulated [32••, 49] so that normally innocuous stimulation of a bone nociceptor is now per-ceived as a noxious event (Fig.…”

“…Following bone fracture, several neurotrophic factors, including NGF, are released by stromal and inflammatory cells, which can induce an exuberant and highly ectopic sprouting resulting in hyper-innervation of the marrow, mineralized bone, and periosteum [33•]. Importantly, NGF can not only induce ectopic nerve sprouting into areas of bone that are normally poorly innervated, but can also sensitize these newly sprouted nerve fibers so normal loading or movement of the fractured bone is perceived as a highly noxious event [6••, 37]. While ectopic sprouting of sensory/sympathetic nerve fibers probably occurs in the callus at most fracture sites [50], with rapid and effective bone healing, NGF levels decline and these newly sprouted nerve fibers are “pruned” back resulting in a normal innervation of the bone and non-sensitized nociceptors [51].…”

“…However, in the last decade, significant progress has been made. Thus, in terms of bone fracture pain, we now know that the bone is innervated by a limited repertoire of sensory nerve fibers [37, 49, 56] (Fig. 5) and that many forms of skeletal pain have both a nociceptive and a neuropathic component [6••].…”