Background & Aims
Joint pain stands out as one of the most frequently reported types of pain in the United States. For individuals grappling with inflammatory conditions like osteoarthritis (OA) and gout, prolonged inflammation resulting from the excessive expression of key cytokines has been associated with heightened sensitivity and damage to nerve cells within the joints. (1,2) Consequently, a subset of patients experiences the onset of chronic pain. The conventional pharmacological approach to managing joint pain encompasses the utilization of analgesic medications such as acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, antidepressants, as well as corticosteroid and hyaluronic acid injections directly into the affected joint.(3,4) Here we explored the potential therapeutic and analgesic benefits of inhibiting TAK1 in models of joint pain induced by monoiodoacetate (MIA) and monosodium urate (MSU).
Methods
To assess outcomes, separate groups of rats were subjected to the selective TAK1 inhibitor HS-276, gabapentin, or a control vehicle, with measurements of mechanical allodynia (Von Frey), weight-bearing, and histological changes in both the MSU and MIA models.
Results
Our findings affirm that TAK1 inhibition effectively forestalled the development of mechanical allodynia and differential weight-bearing in the MIA model. In the MSU model of gouty arthritis, the administration of HS-276 significantly alleviated mechanical allodynia and knee edema in female rats, though no such effect was observed in male rats. Histological examinations of affected joints in both models demonstrated a notable reduction in disease-induced joint degradation with HS-276 treatment.
Conclusions
This collective evidence supports the assertion that TAK1 plays a pivotal role as a signaling node in inflammatory joint diseases such as OA and gouty arthritis. Consequently, TAK1 emerges as a promising and novel therapeutic target for the effective treatment of painful joint diseases.
References
1.Sommer, C. & Kress, M. Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci Lett 361, 184-187 (2004).
2.Vanderwall, A.G. & Milligan, E.D. Cytokines in Pain: Harnessing Endogenous Anti-Inflammatory Signaling for Improved Pain Management. Front Immunol 10, 3009 (2019).
3. Holden, M.A., et al. Recommendations for the delivery of therapeutic exercise for people with knee and/or hip osteoarthritis. An international consensus study from the OARSI Rehabilitation Discussion Group. Osteoarthritis Cartilage 31, 386-396 (2023).
4.Bennell, K.L., et al. Comparing Video-Based, Telehealth-Delivered Exercise and Weight Loss Programs With Online Education on Outcomes of Knee Osteoarthritis : A Randomized Trial. Ann Intern Med 175, 198-209 (2022).