Emerging Targets for the Management of Osteoarthritis Pain

Abstract

Worldwide, osteoarthritis (OA) is one of the leading causes of chronic pain, for which adequate relief is not available. Ongoing peripheral input from the affected joint is a major factor in OA-associated pain. Therefore, this review focuses predominantly on peripheral targets emerging in the preclinical and clinical arena. Nerve growth factor is the most advanced of these targets, and its blockade has shown tremendous promise in clinical trials in knee OA. A number of different types of ion channels, including voltage-gated sodium channels and calcium channels, transient receptor potential channels and acid-sensing ion channels, are important for neuronal excitability and play a role in pain genesis. Few channel blockers have been tested in preclinical models of OA, with varying results. Finally, we discuss some examples of G-protein coupled receptors, which may offer attractive therapeutic strategies for OA pain, including receptors for bradykinin, calcitonin gene-related peptide, and chemokines. Since many of the pathways described above can be selectively and potently targeted, they offer an exciting opportunity for pain management in OA, either systemically or locally.

Understanding the Molecular Mechanisms Underlying the Pathogenesis of Arthritis Pain Using Animal Models

“…In a recent study that used CRISPR/Cas9 technology to ablate OA-associated genes, although ablation of matrix metalloproteinase 13 (MMP-13) or interleukin 1beta (IL-1β) markedly attenuated structural deterioration, the extent of pain relief was modest compared to the ablation of NGF, which significantly increased joint damage, despite its profound analgesic effect [92]. In MNX-and MIA-induced OA of rats, it was shown that pain responses to NGF locally administered into the knee cavity were increased in OA compared to non-OA joints, indicating that local production of NGF may be crucial for the generation of pain [62,93]. In a DMM model, the loss of protein kinase C delta (PKCδ) expression prevented cartilage degeneration but exacerbated OA-associated hyperalgesia [94].…”

Mechanosensitive ion channels in articular nociceptors drive mechanical allodynia in osteoarthritis

“…Osteoarthritis (OA) is a chronic and progressive debilitating disease that affects 10e15% of the world's adult population and a leading cause of pain, disability, and reduction in quality of life 1,2 . Pain is the most prominent symptom of OA and can be caused by innocuous stimuli (termed mechanical allodynia) such as joint movement during walking 1 .…”

Nerve growth factor blockade for the management of osteoarthritis pain: what can we learn from clinical trials and preclinical models?

“…As understanding of the pathophysiology of OA pain has progressed, it has become apparent that much of the refractory pain associated with OA may be of neurogenic origin or may be responsive to neutralizing specific neurotransmitters (5, 6). Of the potential novel strategies for pain control in OA (7), clinical development is most advanced for strategies that target the neurotrophin, nerve growth factor (NGF). This narrative review provides a brief summary of the current status of NGF-blockade for the treatment of OA pain.…”