title: PKCδ null mutations in a mouse model of osteoarthritis alter osteoarthritic pain independently of joint pathology by augmenting NGF/TrkA-induced axonal outgrowth.
abstract: OBJECTIVE
  A key clinical paradox in osteoarthritis (OA), a prevalent age-related joint disorder characterised by cartilage degeneration and debilitating pain, is that the severity of joint pain does not strictly correlate with radiographic and histological defects in joint tissues. Here, we determined whether protein kinase Cδ (PKCδ), a key mediator of cartilage degeneration, is critical to the mechanism by which OA develops from an asymptomatic joint-degenerative condition to a painful disease.
  
  
  METHODS
  OA was induced in 10-week-old PKCδ null (PKCδ-/-) and wild-type mice by destabilisation of the medial meniscus (DMM) followed by comprehensive examination of the histology, molecular pathways and knee-pain-related-behaviours in mice, and comparisons with human biopsies.
  
  
  RESULTS
  In the DMM model, the loss of PKCδ expression prevented cartilage degeneration but exacerbated OA-associated hyperalgesia. Cartilage preservation corresponded with reduced levels of inflammatory cytokines and of cartilage-degrading enzymes in the joints of PKCδ-deficient DMM mice. Hyperalgesia was associated with stimulation of nerve growth factor (NGF) by fibroblast-like synovial cells and with increased synovial angiogenesis. Results from tissue specimens of patients with symptomatic OA strikingly resembled our findings from the OA animal model. In PKCδ null mice, increases in sensory neuron distribution in knee OA synovium and activation of the NGF-tropomyosin receptor kinase (TrkA) axis in innervating dorsal root ganglia were highly correlated with knee OA hyperalgesia.
  
  
  CONCLUSIONS
  Increased distribution of synovial sensory neurons in the joints, and augmentation of NGF/TrkA signalling, causes OA hyperalgesia independently of cartilage preservation.
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Ranjan
authors.initials: R
authors.lastname: Kc
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Kroin
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois, USA.|Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment, South University of Science and Technology of China, Shenzhen, China.
authors.forename: Guozhi
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Brett
authors.initials: B
authors.lastname: Levine
authors.affiliation: Department of Anesthesiology, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Jinyuan
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Hamilton
authors.affiliation: Departments of Orthopedic Surgery & Biochemistry & Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Piel
authors.affiliation: Novozymes Biopharma US, Franklinton, North Carolina, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Shelly
authors.affiliation: Alomone Labs Ltd, Jerusalem, Israel.
authors.forename: Dovrat
authors.initials: D
authors.lastname: Brass
authors.affiliation: Alomone Labs Ltd, Jerusalem, Israel.
authors.forename: Ela
authors.initials: E
authors.lastname: Kolb
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois, USA.|Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois, USA.|Department of Internal Medicine (Section of Rheumatology), Rush University Medical Center, Chicago, Illinois, USA.|Department of Bioengineering, University of Illinois at Chicago, Illinois, USA.|Jesse Brown Veterans Affairs Medical Center at Chicago, Illinois, USA.
authors.forename: Hee-Jeong
authors.initials: HJ
authors.lastname: Im
mesh_terms: D000818:Animals; D018771:Arthralgia / Q000235:genetics* / Q000473:pathology; D001369:Axons / Q000378:metabolism*; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000378:metabolism; D007719:Knee Joint / Q000473:pathology; D051379:Mice; D009154:Mutation; D020932:Nerve Growth Factor / Q000378:metabolism; D020370:Osteoarthritis, Knee / Q000150:complications / Q000235:genetics* / Q000473:pathology; D051745:Protein Kinase C-delta / Q000235:genetics*; D020917:Receptor, trkA / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D013583:Synovial Membrane / Q000378:metabolism
chemical_list: D020932:Nerve Growth Factor; D020917:Receptor, trkA; D051745:Protein Kinase C-delta
keywords: Chondrocytes; Fibroblasts; Knee Osteoarthritis; Synovitis