한빛사논문
- 조회343
University of Illinois at Chicago and Jesse Brown Veterans Affairs Medical Center (JBVAMC)
Ranjan Kc,1 Xin Li,1 Jeffrey S Kroin,2 Zhiqiang Liu,1 Di Chen,1 Guozhi Xiao,1,3 Brett Levine,4 Jinyuan Li,2 John L Hamilton,1 Andre J van Wijnen,5 Margaret Piel,1 Daniel A Shelly,6 Dovrat Brass,7 Ela Kolb,7 Hee-Jeong Im1,4,8,9,10
1Department of Biochemistry, Rush University Medical Center, Chicago, Illinois, USA
2Department of Anesthesiology, Rush University Medical Center, Chicago, Illinois, USA
3Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment, South University of Science and Technology of China, Shenzhen, China
4Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois, USA
5Departments of Orthopedic Surgery & Biochemistry & Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA
6Novozymes Biopharma US, Franklinton, North Carolina, USA
7Alomone Labs Ltd, Jerusalem, Israel
8Department of Internal Medicine (Section of Rheumatology), Rush University Medical Center, Chicago, Illinois, USA
9Department of Bioengineering, University of Illinois at Chicago, Illinois, USA
10Jesse Brown Veterans Affairs Medical Center at Chicago, Illinois, USA
Correspondence to Dr Hee-Jeong Im
Abstract
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.
논문정보
- Research article
- 2016년 12월 (BRIC 등록일 2023-03-30)
- 국외 연구진
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