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Extended report
PKCδ null mutations in a mouse model of osteoarthritis alter osteoarthritic pain independently of joint pathology by augmenting NGF/TrkA-induced axonal outgrowth
  1. Ranjan Kc1,
  2. Xin Li1,
  3. Jeffrey S Kroin2,
  4. Zhiqiang Liu1,
  5. Di Chen1,
  6. Guozhi Xiao1,3,
  7. Brett Levine4,
  8. Jinyuan Li2,
  9. John L Hamilton1,
  10. Andre J van Wijnen5,
  11. Margaret Piel1,
  12. Daniel A Shelly6,
  13. Dovrat Brass7,
  14. Ela Kolb7,
  15. Hee-Jeong Im1,4,8,9,10
  1. 1Department of Biochemistry, Rush University Medical Center, Chicago, Illinois, USA
  2. 2Department of Anesthesiology, Rush University Medical Center, Chicago, Illinois, USA
  3. 3Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment, South University of Science and Technology of China, Shenzhen, China
  4. 4Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois, USA
  5. 5Departments of Orthopedic Surgery & Biochemistry & Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA
  6. 6Novozymes Biopharma US, Franklinton, North Carolina, USA
  7. 7Alomone Labs Ltd, Jerusalem, Israel
  8. 8Department of Internal Medicine (Section of Rheumatology), Rush University Medical Center, Chicago, Illinois, USA
  9. 9Department of Bioengineering, University of Illinois at Chicago, Illinois, USA
  10. 10Jesse Brown Veterans Affairs Medical Center at Chicago, Illinois, USA
  1. Correspondence to Dr Hee-Jeong Im, Rush University Medical Center, Cohn Research BD 516, 1735 W. Harrison, Chicago, IL 60612, USA; Hee-Jeong_Sampen{at}


Objectives 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.

  • Knee Osteoarthritis
  • Chondrocytes
  • Fibroblasts
  • Synovitis

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  • Handling editor Tore K Kvien

  • RKc and XL contributed equally and are joint first authors.

  • Contributors RK and XL contributed equally. RK performed experiments, analysed data and wrote the manuscript. XL, JSK, ZL, JL and JLH performed experiments and analysed data. DC, GX, BL, AJvW, MP, DAS, DB and EK analysed data. H-JI designed experiments, analysed data and wrote the manuscript. All authors reviewed the manuscript.

  • Funding This work was supported by an NIH NIAMS R01 grant (AR053220) to HJI; an NIH NIAMS R01 grant (AR062136) to HJI; an R21 grant (AR067935) to HJI; a VA BLD&R Merit Review Award to HJI and an Arthritis Foundation to HJI.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Human Investigation Committee of Rush University Medical Center.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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