NGF Expression and Elevation in Hip Osteoarthritis Patients with Pain and Central Sensitization

Abstract

Osteoarthritis (OA) is a chronic degenerative musculoskeletal disease that causes articular cartilage degeneration and chronic pain. Research into OA animal models suggests that elevated NGF levels in the synovium contribute to pain and central sensitization (CS). However, it is unclear whether synovial NGF contributes to CS in patients with OA. We investigated the association between synovial NGF expression and clinical assessments of pain and CS in hip OA (hOA) patients. We also aimed to identify which cells in the synovium of hOA patients express NGF. Sixty-six patients who received total hip replacement and a diagnosis of hOA were enrolled. We measured NGF mRNA expression in synovial samples obtained from 50 patients using qPCR and analyzed the correlation of NGF expression with the CS inventory (CSI) score and Japanese Orthopaedic Association (JOA) score, a clinical scoring system for OA. To identify the synovial cells expressing NGF, we analyzed NGF mRNA expression in CD14+ and CD14- cells, which represent macrophage-rich and fibroblast-rich fractions, respectively, extracted from 8 patients. To further identify which macrophage subtypes express NGF, we examined NGF mRNA expression in CD14high and CD14low cells sorted from 8 patients. Synovial NGF mRNA expression was negatively correlated with JOA score but positively correlated with CSI score (JOA pain, r = − 0.337 , P = 0.017 ; CSI score, r = 0.358 , P = 0.011 ). Significantly greater levels of NGF were observed in CD14- cells compared to CD14+ cells ( P = 0.036 ) and in CD14high cells compared to CD14low cells ( P = 0.008 ). In conclusion, synovial NGF expression is correlated with the degree of pain and CS in hOA patients. NGF is predominantly expressed in synovial fibroblasts. Further, CD14high synovial macrophages expressed higher levels of NGF. Our results may provide a novel NGF-targeted therapeutic strategy for hOA pain.

Differences in outcomes after total hip arthroplasty for osteoarthritis between patients with and without central sensitivity syndromes other than fibromyalgia

“…CS in osteoarthritis is triggered by an increased expression of various cytokines, including nerve growth factor (NGF), in synovial inflammation 25 . Furthermore, NGF gene expression in the synovium was reported as correlated with pre-operative CSI and pain scores in 50 patients with HOA 26 . Taken together, the present results and those of previous studies suggest that comorbidities of the pathophysiology of HOA and CSS may be a cause of persistent post-operative pain.…”

Increased Synovial CD14 mRNA Expression and Proportion of CD14high Subsets in Early-Stage Hip Osteoarthritis: Propensity Matched Score Analysis

“…The data were analyzed using FlowJo, version 10.8.0 (FlowJo, Ashland, OR, USA). We previously found CD14 high and CD14 low subsets in synovium from advanced and end-stage hip OA [ 40 ]. Therefore, we compared the percentage of CD14 high and CD14 low subsets in early and late hip osteoarthritis patients.…”

Mechanisms of Peripheral and Central Sensitization in Osteoarthritis Pain

“…Synovial fibroblast had higher NGF production ability compared to macrophages following TNF-α stimulation [ 35 , 40 ]. CD14high positive cells had higher NGF expression compared to CD14low cells in HOA [ 41 ]. It binds tropomyosin-related kinase A (TrkA), which is expressed in a range of sensory and sympathetic fibers and regulates their survival [ 42 ].…”

“…Results in models are illustrative: in one rat model, systemic administration of NGF caused mechanical and thermal hyperalgesia [ 53 ], while in rat models of OA, intra-articular injection of NGF produced a decrease in the hind paw mechanical withdrawal threshold in one [ 54 ] and contributed to spinal nociceptive sensitization in another [ 55 ]. Our previous study described a positive correlation between expression levels of NGF mRNA in the synovial membrane and scores for the central sensitization inventory (CSI) and pain in patients with HOA [ 41 ]. These findings support previous evidence that monoclonal antibodies against NGF reduce pain symptoms from OA [ 56 - 58 ].…”