PKCδ null mutations in a mouse model of osteoarthritis alter osteoarthritic pain independently of joint pathology by augmenting NGF/TrkA-induced axonal outgrowth

Ranjan Kc, Xin Li, Jeffrey S. Kroin, Zhiqiang Liu, Di Chen, Guozhi Xiao, Brett Levine, Jinyuan Li, John L. Hamilton, Andre J van Wijnen, Margaret Piel, Daniel A. Shelly, Dovrat Brass, Ela Kolb, Hee Jeong Im

Research output: Contribution to journalArticle

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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 PKCd 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.

Original languageEnglish (US)
JournalAnnals of the Rheumatic Diseases
DOIs
StateAccepted/In press - Jan 18 2016

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Nerve Growth Factor Receptor
Tropomyosin
Arthralgia
Cartilage
Nerve Growth Factor
Pathology
Osteoarthritis
Protein Kinase C
Phosphotransferases
Hyperalgesia
Mutation
Tibial Meniscus
Joints
Knee Osteoarthritis
Sensory Receptor Cells
Neurons
Tissue
Histology
Biopsy
Pain

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Allergy

Cite this

PKCδ null mutations in a mouse model of osteoarthritis alter osteoarthritic pain independently of joint pathology by augmenting NGF/TrkA-induced axonal outgrowth. / Kc, Ranjan; Li, Xin; Kroin, Jeffrey S.; Liu, Zhiqiang; Chen, Di; Xiao, Guozhi; Levine, Brett; Li, Jinyuan; Hamilton, John L.; van Wijnen, Andre J; Piel, Margaret; Shelly, Daniel A.; Brass, Dovrat; Kolb, Ela; Im, Hee Jeong.

In: Annals of the Rheumatic Diseases, 18.01.2016.

Research output: Contribution to journalArticle

Kc, Ranjan ; Li, Xin ; Kroin, Jeffrey S. ; Liu, Zhiqiang ; Chen, Di ; Xiao, Guozhi ; Levine, Brett ; Li, Jinyuan ; Hamilton, John L. ; van Wijnen, Andre J ; Piel, Margaret ; Shelly, Daniel A. ; Brass, Dovrat ; Kolb, Ela ; Im, Hee Jeong. / PKCδ null mutations in a mouse model of osteoarthritis alter osteoarthritic pain independently of joint pathology by augmenting NGF/TrkA-induced axonal outgrowth. In: Annals of the Rheumatic Diseases. 2016.
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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 PKCd 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.",
author = "Ranjan Kc and Xin Li and Kroin, {Jeffrey S.} and Zhiqiang Liu and Di Chen and Guozhi Xiao and Brett Levine and Jinyuan Li and Hamilton, {John L.} and {van Wijnen}, {Andre J} and Margaret Piel and Shelly, {Daniel A.} and Dovrat Brass and Ela Kolb and Im, {Hee Jeong}",
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T1 - PKCδ null mutations in a mouse model of osteoarthritis alter osteoarthritic pain independently of joint pathology by augmenting NGF/TrkA-induced axonal outgrowth

AU - Kc, Ranjan

AU - Li, Xin

AU - Kroin, Jeffrey S.

AU - Liu, Zhiqiang

AU - Chen, Di

AU - Xiao, Guozhi

AU - Levine, Brett

AU - Li, Jinyuan

AU - Hamilton, John L.

AU - van Wijnen, Andre J

AU - Piel, Margaret

AU - Shelly, Daniel A.

AU - Brass, Dovrat

AU - Kolb, Ela

AU - Im, Hee Jeong

PY - 2016/1/18

Y1 - 2016/1/18

N2 - 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 PKCd 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.

AB - 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 PKCd 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.

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U2 - 10.1136/annrheumdis-2015-208444

DO - 10.1136/annrheumdis-2015-208444

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JF - Annals of the Rheumatic Diseases

SN - 0003-4967

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