title: Role of the C-C chemokine receptor-2 in a murine model of injury-induced osteoarthritis.
abstract: We previously found in our embryonic studies that proper regulation of the chemokine CCL12 through its sole receptor CCR2, is critical for joint and growth plate development. In the present study, we examined the role of CCR2 in injury-induced-osteoarthritis (OA).
  
  
  
  We used a murine model of injury-induced-OA (destabilization of medial meniscus, DMM), and systemically blocked CCR2 using a specific antagonist (RS504393) at different times during disease progression. We examined joint degeneration by assessing cartilage (cartilage loss, chondrocyte hypertrophy, MMP-13 expression) and bone lesions (bone sclerosis, osteophytes formation) with or without the CCR2 antagonist. We also performed pain behavioral studies by assessing the weight distribution between the normal and arthritic hind paws using the IITS incapacitance meter.
  
  
  
  Testing early vs delayed administration of the CCR2 antagonist demonstrated differential effects on joint damage. We found that OA changes in articular cartilage and bone were ameliorated by pharmacological CCR2 blockade, if given early in OA development: specifically, pharmacological targeting of CCR2 during the first 4 weeks (wks) following injury, reduced OA cartilage and bone damage, with less effectiveness with later treatments. Importantly, our pain-related behavioral studies showed that blockade of CCR2 signaling during early, 1-4 wks post-surgery or moderate, 4-8 wks post-surgery, OA was sufficient to decrease pain measures, with sustained improvement at later stages, after treatment was stopped.
  
  
  
  Our data highlight the potential efficacy of antagonizing CCR2 at early stages to slow the progression of post-injury OA and, in addition, improve pain symptoms.
authors.affiliation: Division of Rheumatology, Allergy and Immunology and the Thurston Arthritis Research Center, University of North Carolina-Chapel Hill, NC, USA. Electronic address: lara_longobardi@med.unc.edu.
authors.forename: L
authors.initials: L
authors.lastname: Longobardi
authors.affiliation: Department of Biomedical Engineering, UNC-Chapel Hill, NC, USA; Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA. Electronic address: Joseph_Temple@rush.edu.
authors.forename: J D
authors.initials: JD
authors.lastname: Temple
authors.affiliation: Department of Neurology, Duke University, Durham, NC, USA. Electronic address: lidiatag@hotmail.it.
authors.forename: L
authors.initials: L
authors.lastname: Tagliafierro
authors.affiliation: Department of Cell Biology and Physiology, UNC-Chapel Hill, NC, USA. Electronic address: helen_willcockson@med.unc.edu.
authors.forename: H
authors.initials: H
authors.lastname: Willcockson
authors.affiliation: Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA. Electronic address: Alessandra_Esposito@rush.edu.
authors.forename: A
authors.initials: A
authors.lastname: Esposito
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy. Electronic address: nunzia.donofrio@unina2.it.
authors.forename: N
authors.initials: N
authors.lastname: D'Onofrio
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA. Electronic address: emstein90@gmail.com.
authors.forename: E
authors.initials: E
authors.lastname: Stein
authors.affiliation: Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA. Electronic address: Tieshi_Li@rush.edu.
authors.forename: T
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Pediatrics, UNC-Chapel Hill, NC, USA. Electronic address: timothymyers59@gmail.com.
authors.forename: T J
authors.initials: TJ
authors.lastname: Myers
authors.affiliation: Department of Orthopaedics, Gulhane Military Medical Academy, Etlik, Ankara, Turkey. Electronic address: heorto@yahoo.com.
authors.forename: H
authors.initials: H
authors.lastname: Ozkan
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy. Electronic address: marialuisa.balestrieri@unina2.it.
authors.forename: M L
authors.initials: ML
authors.lastname: Balestrieri
authors.affiliation: Division of Rheumatology, Allergy and Immunology and the Thurston Arthritis Research Center, University of North Carolina-Chapel Hill, NC, USA. Electronic address: verau79@yahoo.com.
authors.forename: V
authors.initials: V
authors.lastname: Ulici
authors.affiliation: Division of Rheumatology, Allergy and Immunology and the Thurston Arthritis Research Center, University of North Carolina-Chapel Hill, NC, USA. Electronic address: richard_loeser@med.unc.edu.
authors.forename: R F
authors.initials: RF
authors.lastname: Loeser
authors.affiliation: Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA. Electronic address: Anna_Spagnoli@rush.edu.
authors.forename: A
authors.initials: A
authors.lastname: Spagnoli
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology*; D001842:Bone and Bones / Q000187:drug effects* / Q000473:pathology; D002358:Cartilage, Articular / Q000187:drug effects*; D019902:Chondrocytes / Q000187:drug effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D006984:Hypertrophy; D053509:Matrix Metalloproteinase 13 / Q000187:drug effects / Q000378:metabolism; D008592:Menisci, Tibial / Q000187:drug effects* / Q000601:surgery; D051379:Mice; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology*; D054850:Osteophyte; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D012598:Sclerosis; D013141:Spiro Compounds / Q000494:pharmacology*; D000070600:Tibial Meniscus Injuries
chemical_list: D048588:Benzoxazines; C515335:Ccr2 protein, mouse; C579117:RS 504393; D054390:Receptors, CCR2; D013141:Spiro Compounds; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse
keywords: Animal model; Bone; Cartilage; Chemokines; Joint disease; Osteoarthritis