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Papers of the Week

Papers: 28 Oct 2023 - 3 Nov 2023

2023 Oct 25



Loss of PKCδ/Prkcd prevents cartilage degeneration in joints but exacerbates hyperalgesia in an experimental osteoarthritis mouse model.


Singh G, O-Sullivan I, Natarajan Anbazhagan A, Ranjan KC, Farooqui Z, Ma K, Wang J, Mwale F, Votta-Velis G, Bruce B, Ronald Kahn C, van Wijnen AJ, Im HJ


Pain is the prime symptom of osteoarthritis (OA) that directly affects the quality of life. Protein kinase Cδ (PKCδ/Prkcd) plays a critical role in OA pathogenesis; however, its significance in OA-related pain is not entirely understood. The present study investigated the functional role of PKCδ in OA pain sensation. OA was surgically induced in control (Prkcd), global- (Prkcd; ROSA), and sensory neuron-specific conditional knockout (cKO) mice (Prkcd NaV1.8/Scn10a) followed by comprehensive analysis of longitudinal behavioral pain, histopathology and immunofluorescence studies. GlobalPrkcd cKO mice prevented cartilage deterioration by inhibiting matrix metalloproteinase-13 (MMP13) in joint tissues but significantly increased OA pain. Sensory neuron-specificdeletion of Prkcd in mice did not protect cartilage from degeneration but worsened OA-associated pain. Exacerbated pain sensitivity observed in global- and sensory neuron-specific cKO of Prkcd was corroborated with markedly increased specific pain mediators in knee synovium and dorsal root ganglia (DRG). These specific pain markers include nerve growth factor (NGF) and vascular endothelial growth factor (VEGF), and their cognate receptors, including tropomyosin receptor kinase A (TrkA) and vascular endothelial growth factor receptor-1 (VEGFR1). The increased levels of NGF/TrkA and VEGF/VEGFR1 were comparable in both global- and sensory neuron-specific cKO groups. These data suggest that the absence of Prkcd gene expression in the sensory neurons is strongly associated with OA hyperalgesia independent of cartilage protection. Thus, inhibition of PKCδ may be beneficial for cartilage homeostasis but could aggravate OA-related pain symptoms.