CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis

Abstract

Osteoarthritis is one of the leading causes of chronic pain, but almost nothing is known about the mechanisms and molecules that mediate osteoarthritis-associated joint pain. Consequently, treatment options remain inadequate and joint replacement is often inevitable. Here, we use a surgical mouse model that captures the long-term progression of knee osteoarthritis to longitudinally assess pain-related behaviors and concomitant changes in the innervating dorsal root ganglia (DRG). We demonstrate that monocyte chemoattractant protein (MCP)-1 (CCL2) and its high-affinity receptor, chemokine (C-C motif) receptor 2 (CCR2), are central to the development of pain associated with knee osteoarthritis. After destabilization of the medial meniscus, mice developed early-onset secondary mechanical allodynia that was maintained for 16 wk. MCP-1 and CCR2 mRNA, protein, and signaling activity were temporarily up-regulated in the innervating DRG at 8 wk after surgery. This result correlated with the presentation of movement-provoked pain behaviors, which were maintained up to 16 wk. Mice that lack Ccr2 also developed mechanical allodynia, but this started to resolve from 8 wk onwards. Despite severe allodynia and structural knee joint damage equal to wild-type mice, Ccr2-null mice did not develop movement-provoked pain behaviors at 8 wk. In wild-type mice, macrophages infiltrated the DRG by 8 wk and this was maintained through 16 wk after surgery. In contrast, macrophage infiltration was not observed in Ccr2-null mice. These observations suggest a key role for the MCP-1/CCR2 pathway in establishing osteoarthritis pain.O steoarthritis is the most common joint disorder and is one of the leading causes of chronic pain (1, 2). Osteoarthritis commonly affects knees, hips, and hands and is characterized by radiographic changes (primarily joint space narrowing, subchondral bone sclerosis, and osteophytes) accompanied by clinical symptoms, most prominently pain. Treatments that alter the progression of the structural damage in the joint are not yet available. Options for treating the pain include nonsteroidal anti-inflammatory drugs, steroids, and viscosupplementation, but analgesia is often inadequate, and uncontrolled pain is the number one reason why people with osteoarthritis undergo joint-replacement surgery (3). Despite the enormous health and economic burden of osteoarthritis and associated pain (4), very few studies have examined the molecular pathways that mediate osteoarthritis pain. As in all types of chronic pain, osteoarthritis pain is the dynamic result of a complex interaction between local tissue damage and inflammation, peripheral and central sensitization, and the brain (5-7). Joint pain associated with osteoarthritis, however, has unique clinical features that provide insight into the mechanisms that cause it. First, joint pain has a strong mechanical component: it is typically triggered by specific activities (for example, climbing stairs elicits knee pain) and is relieved by rest. As structural joint disease advance...

Reduction in Disease Progression by Inhibition of Transforming Growth Factor α–CCL2 Signaling in Experimental Posttraumatic Osteoarthritis

“…A very recent study demonstrated up-regulation of CCL2 and CCR2 in dorsal root ganglia in the DMM mouse model of posttraumatic OA (41). Genetic knockout of Ccr2 in these mice reduced the pain response to DMM surgery, providing support for targeting this chemokine pathway in OA.…”

Platelet-rich Plasma Modulates the Secretion of Inflammatory/Angiogenic Proteins by Inflamed Tenocytes

“…Actually, MCP-1/CCL2 attracts CCR2-expressing monocytes. In an experimental model for OA, Miller et al [29] demonstrated that CCR2 signaling mediates pain in this pathology. Moreover, in a recent metaanalysis involving microarray studies, MCP-1/CCL2 was identified as one of the important pronociceptive factors in many pain models [20].…”

Chemokine ligand 2 in the trigeminal ganglion regulates pain induced by experimental tooth movement

“…16,34 In addition, in the present study, peripheral application of recombinant CCL2 protein led to a pain response in a dosedependent manner. Thus, the development of nocifensive behaviors due to ETM could be dependent on the CCL2/CCR2 signaling pathway.…”

“…[12][13][14] A growing amount of evidence has demonstrated that the CCL2/CCR2 axis might play an essential role in neuropathic pain. 15,16 However, the importance of CCL2/CCR2 signaling remains to be explored in a special animal model of orofacial pain associated with experimental tooth movement (ETM).…”

“…These models included unilateral application of glycoprotein 120 into the sciatic nerve, 27 chronic constriction injury, 28 partial ligation of the sciatic nerve, 29 focal nerve demyelination, 30 and experimental osteoarthritis. 16 However, the change rhythms in CCL2 expression were different in some cases. ETMinduced pain has been identified as noninfection inflammatory pain, which is different from previous bacterial inflammatory and neuropathic pain models.…”