Multiple frontlines in osteoarthritis pain: Neuroimmune mechanisms and emerging therapeutic pathways

Osteoarthritis (OA) is a highly prevalent joint disease and a leading cause of disability, in which pain is the main symptom driving patients to seek medical care. However, current treatments are often insufficient, and pain can persist even after joint replacement, indicating that mechanisms beyond structural joint damage are involved. Increasing evidence suggests that interactions between the immune system and the nervous system play a key role in the development and persistence of OA pain. This thesis investigates these neuroimmune mechanisms, with a particular focus on the role of macrophages in dorsal root ganglia (DRG) and the identification of molecular markers and therapeutic targets in both experimental models and human patients.

This thesis demonstrates that macrophages accumulate in the DRG during OA progression and adopt a pro-inflammatory, M1-like phenotype that is essential for the maintenance of persistent pain. Sensory neurons were shown to drive this pain-promoting macrophage phenotype. Importantly, targeting these macrophages, either by promoting anti-inflammatory M2 macrophages or using an IL4-10 fusion protein, reduced persistent OA pain. These findings establish DRG macrophages as key regulators of chronic OA pain.

To further understand the mechanisms driving macrophage accumulation and activation, this thesis identifies myostatin and CXCL11 as critical mediators. CXCL11, produced by satellite glial cells, promotes macrophage recruitment to the DRG, while myostatin, derived from sensory neurons, programs macrophages toward a pro-inflammatory, pain-sustaining phenotype. Although macrophages accumulate early in OA, they are not required for pain initiation but are essential for pain maintenance. Inhibition of these factors prevented or reduced chronic pain, and notably, myostatin inhibition emerged as a promising therapeutic strategy.

To translate these findings to humans, this thesis analyzes cerebrospinal fluid (CSF) and synovial tissue from OA patients. Proteomic analysis of CSF identified distinct patient subgroups based on protein expression profiles and revealed associations between specific proteins and pain severity, pain at rest, and neuropathic-like symptoms. These findings highlight the heterogeneity of OA pain and suggest that CSF protein profiles may help classify patients and provide insight into underlying mechanisms.

In addition, this thesis identifies the complement system as a key contributor to OA pain. Complement factors were found to be elevated in synovial tissue of patients with more severe pain. Functional studies in mouse models demonstrated that complement components, including C2 and C5aR1, contribute to persistent pain. Importantly, targeting complement factor C2 reduced established OA pain, identifying it as a novel therapeutic target.

Overall, this thesis reveals that OA pain is driven by complex neuroimmune interactions, in which macrophages in the DRG and complement activation play central roles in maintaining chronic pain. By integrating mechanistic insights from preclinical models with molecular findings in patients, this work provides a comprehensive framework for understanding OA pain and identifies new opportunities for more targeted and personalized treatments.