GDNF, Neurturin, and Artemin Activate and Sensitize Bone Afferent Neurons and Contribute to Inflammatory Bone Pain

Abstract

Pain associated with skeletal pathology or disease is a significant clinical problem, but the mechanisms that generate and/or maintain it remain poorly understood. In this study, we explored roles for GDNF, neurturin, and artemin signaling in bone pain using male Sprague Dawley rats. We have shown that inflammatory bone pain involves activation and sensitization of peptidergic, NGF-sensitive neurons via artemin/GDNF family receptor α-3 (GFRα3) signaling pathways, and that sequestering artemin might be useful to prevent inflammatory bone pain derived from activation of NGF-sensitive bone afferent neurons. In addition, we have shown that inflammatory bone pain also involves activation and sensitization of nonpeptidergic neurons via GDNF/GFRα1 and neurturin/GFRα2 signaling pathways, and that sequestration of neurturin, but not GDNF, might be useful to treat inflammatory bone pain derived from activation of nonpeptidergic bone afferent neurons. Our findings suggest that GDNF family ligand signaling pathways are involved in the pathogenesis of bone pain and could be targets for pharmacological manipulations to treat it. Pain associated with skeletal pathology, including bone cancer, bone marrow edema syndromes, osteomyelitis, osteoarthritis, and fractures causes a major burden (both in terms of quality of life and cost) on individuals and health care systems worldwide. We have shown the first evidence of a role for GDNF, neurturin, and artemin in the activation and sensitization of bone afferent neurons, and that sequestering these ligands reduces pain behavior in a model of inflammatory bone pain. Thus, GDNF family ligand signaling pathways are involved in the pathogenesis of bone pain and could be targets for pharmacological manipulations to treat it.

Nerves in Bone: Evolving Concepts in Pain and Anabolism

“…Beyond de novo sprouting, chronic, particularly inflammatory, processes can cause peripheral and/or central sensitization of skeletal nociceptors. Specifically, sensory nerves that innervate both periosteum and the bone marrow can be sensitized by a number of different inflammatory mediators, including NGF, artemin, neurturin, GDNF, histamine, serotonin, bradykinin, and PGE2 . Thus, even in the absence of a change in innervation, inflammation can elicit pain in response to normally innocuous stimuli (allodynia) or increase sensitivity to noxious stimuli (hyperalgesia).…”

“…However, preclinical studies that that use cutaneous sensitivity as a surrogate for bone pain may overestimate analgesic efficacy, impacting potential for clinical translational success. It is noteworthy that many preclinical studies are now incorporating alternative, more clinically relevant assays (eg, changes in weight distribution and activity levels) that better reflect the patient experience of bone pain and provide information about functional status …”

“…(161,162) Small-diameter mechanosensitive sensory afferents covering the periosteal surface can be selectively activated by high-threshold mechanical stimuli, (163,164) and Aδ nociceptors in bone marrow respond to high-threshold intraosseous pressure, (22) providing the physiological foundation for perceived pain in response to mechanical distortions. In addition, peripheral sensory endings in bone can be activated by growth factors NGF and the GDNF family of ligands, as well as mixture of inflammatory mediators including histamine, serotonin, bradykinin, and PGE2, (46,164,165) and can directly contribute to pain associated with inflammation and bone metastases.…”

“…Specifically, sensory nerves that innervate both periosteum and the bone marrow can be sensitized by a number of different inflammatory mediators, including NGF, artemin, neurturin, GDNF, histamine, serotonin, bradykinin, and PGE2. (46,(164)(165)(166) Thus, even in the absence of a change in innervation, inflammation can elicit pain in response to normally innocuous stimuli (allodynia) or increase sensitivity to noxious stimuli (hyperalgesia). In many cases bone pain also presents as cutaneous sensitivity at sites surrounding or distant to the injury (referred pain).…”

“…It is noteworthy that many preclinical studies are now incorporating alternative, more clinically relevant assays (eg, changes in weight distribution and activity levels) that better reflect the patient experience of bone pain and provide information about functional status. (46,165,166,(172)(173)(174)(175)(176)(177) Relationships between the nervous system, bone pain, and anabolism It is interesting that the nerves that innervate skeletal tissues appear to function in both skeletal pain and anabolism, and influence a variety of different skeletal cell types. This implies that manipulating sensory or sympathetic neurons with drug therapies targeted to bone pain could have effects on anabolism and vice versa.…”