Inflammation, angiogenesis and sensory nerve sprouting in the synovium of bony ankylosed and not bony ankylosed knees with end‐stage haemophilic arthropathy

Abstract

Introduction Clinical practice showed that patients with haemophilia (PwH) with bony ankylosed end‐stage haemophilic arthropathy knees reported milder pain than those with not bony ankylosed knees. Aim To compare the differences in pain sensation and the histopathological differences in synovial samples of affected knee joints between PwH with bony ankylosed end‐stage haemophilic arthropathy knees and those with not bony ankylosed knees. Methods From January 2011 to December 2019, the synovial samples of knee joints were collected during total knee arthroplasty (TKA) surgery for end‐stage haemophilic arthropathy. The visual analogue scale (VAS, 0–10) pain score was reviewed from the chart data of the patients. The thickness of the inner layer of the synovium in haematoxylin and eosin (H&E) staining sections was measured. The expression levels of Ki67, IL‐1β, TNF‐α, CD31, VEGF, NGF and PGP9.5 in the synovium were detected by immunohistochemistry (IHC) method. Results Fifty‐two end‐stage haemophilic arthropathy knee synovial samples from 36 male PwH (34 type A and 2 type B) were collected. Fifteen knees had bony ankylosed (BA‐group), and 37 were not bony ankylosed (Not‐BA‐group). The mean age of patients at TKA surgery of BA‐group and Not‐BA‐group was 32 years (15) and 32 years (10), respectively (p = 0.824). Before TKA surgery, the mean VAS pain scores of patients in the Not‐BA‐group were significantly higher than those in the BA‐group (p < 0.001). The mean thickness of the inner layer of the synovium, the mean rate of Ki67+ cells, the mean density of CD31+ vascular endothelial cells and the expression levels of IL‐1β, TNF‐α, VEGF and NGF in samples in the Not‐BA‐group was significantly higher than those in samples in the BA‐group (p < 0.001, p = 0.02, p = 0.001, p = 0.117, p < 0.001, p = 0.003 and p = 0.008), respectively. The mean density of PGP9.5+ sensory neural fibres in the Not‐BA‐group was slightly higher than in the BA‐group (p = 0.131). Linear regression analysis showed a significant positive correlation between the VAS pain score and indicators including the synovial thickness, the rate of Ki67+ cells, the expression level of IL‐1β, TNF‐α, VEGF, NGF and the densities of CD31+ vascular endothelial cells and PGP9.5+ nerve fibres (p < 0.05). Conclusions Worsened hypertrophic synovitis, angiogenesis and sensory nerve sprouting in the synovium may play a critical role in causing worse pain sensation in PwH with not bony ankylosed haemophilic arthropathy knees than in those with bony ankylosed knees.

Neuroinflammatory markers in patients with haemophilia and healthy controls: Where are the differences?

“…NGF has also a pro‐algesic effect and can enhance muscoskeletal pain. In synovial fluid of haemophilic patients at the end stadium of haemophilic arthropathy enhanced levels of NGF were detected 31 . We, however, detected lower NGF levels in PwH compared to healthy controls.…”

“…In synovial fluid of haemophilic patients at the end stadium of haemophilic arthropathy enhanced levels of NGF were detected. 31 We, however, detected lower NGF levels in PwH compared to healthy controls. As we had not analyzed synovial fluid it is not known if the blood levels of ß-NGF do reflect the levels in synovial fluid of arthropathic joints.…”

NGF Signaling Exacerbates KOA Peripheral Hyperalgesia via the Increased TRPV1-Labeled Synovial Sensory Innervation in KOA Rats

“…As a potential target for pain treatments [ 1 ], it regulates neuronal growth and development and is important for sensory nerve innervation [ 2 , 3 ]. NGF initiates signal transduction through its primary functional receptor tropomyosin receptor kinase A (TrKA) [ 4 , 5 ]. The activation of NGF/TrkA recruits many signaling molecules that bind to the intracellular-phosphorylated tyrosine residues within TrkA by means of Src homology domains.…”