Pain Pathways


Our long-term goal is to define origins and mechanisms of pain in osteoarthritis and other rheumatic diseases, thus allowing identification of new targets, and development of new therapies and biomarkers for musculoskeletal pain. 

We address the novel concept that the pain pathway constitutes an integral part of the failing joint as an organ.  


We validated a sophisticated murine model of pain associated with slowly progressive knee osteoarthritis (OA). We demonstrated a specific temporal pattern of pain-related behaviors associated with progressive joint damage after destabilization of the medial meniscus (DMM). This temporal pattern of pain behaviors is associated with concomitant molecular and cellular changes in the innervating dorsal root ganglia (DRG). Specifically, we have shown that signaling by the chemokine MCP-1 through its receptor CCR2 is a key event for persistence of pain in this model (Miller RE et al, PNAS 2012 PMID: 23185004). We are using this robust experimental model, in combination with state-of-the-art approaches and novel pharmacological agents, to systematically address the central hypothesis that “pathological matrix turnover in the OA joint chronically activates joint nociceptors and causes plasticity changes in the nervous system, resulting in the initiation and the persistence of pain”. To this end we are

(1) Documenting longitudinal plasticity changes in the peripheral and central nervous system after DMM surgery; 

(2) Evaluating the contribution of Pattern Recognition Receptors and their ligands (Damage Associated Molecular Patterns, DAMPs) to joint nociceptor activation; 

(3) Exploring the relationship between joint damage and pain pathways.


The experimental approach combines basic, molecular, and translational methods in order to elucidate the relationship between joint tissue damage and fundamental changes in the properties of pain-sensing neurons. 



We study OA-related pain in several knock-out lines, including Adamts-4/Adamts-5 null mice, Pcsk6 null mice, and Ccr2 null mice. We employ reporter mice to study the neurobiology of pain. 


In collaboration with Dr. Ana Valdes, King’s College London, we are studying genetic variation in OA pain, in order to understand why in the presence of similar structural damage to the joint, some patients develop chronic pain and others are spared.