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
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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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