title: 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.
authors.affiliation: Department of Internal Medicine, Section of Rheumatology, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Miller
authors.forename: Phuong B
authors.initials: PB
authors.lastname: Tran
authors.forename: Rosalina
authors.initials: R
authors.lastname: Das
authors.forename: Nayereh
authors.initials: N
authors.lastname: Ghoreishi-Haack
authors.forename: Dongjun
authors.initials: D
authors.lastname: Ren
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Miller
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Malfait
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology / Q000502:physiology; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006930:Hyperalgesia / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D010146:Pain / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D012333:RNA, Messenger; D054390:Receptors, CCR2