CCR2 Chemokine Receptor Signaling Mediates Pain in Experimental Osteoarthritis

Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20602-7. doi: 10.1073/pnas.1209294110. Epub 2012 Nov 26.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / genetics
  • Arthritis, Experimental / immunology*
  • Arthritis, Experimental / pathology
  • Arthritis, Experimental / physiopathology*
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / immunology
  • Chemokine CCL2 / physiology
  • Disease Models, Animal
  • Ganglia, Spinal / immunology
  • Ganglia, Spinal / pathology
  • Ganglia, Spinal / physiopathology
  • Humans
  • Hyperalgesia / genetics
  • Hyperalgesia / immunology
  • Hyperalgesia / physiopathology
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Osteoarthritis / genetics
  • Osteoarthritis / immunology*
  • Osteoarthritis / pathology
  • Osteoarthritis / physiopathology*
  • Pain / genetics
  • Pain / immunology
  • Pain / physiopathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, CCR2 / deficiency
  • Receptors, CCR2 / genetics
  • Receptors, CCR2 / physiology*
  • Signal Transduction

Substances

  • Ccl2 protein, mouse
  • Ccr2 protein, mouse
  • Chemokine CCL2
  • RNA, Messenger
  • Receptors, CCR2