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. 2018 Jun 26;19(1):204.
doi: 10.1186/s12891-018-2127-2.

Vascular endothelial growth factor expression and their action in the synovial membranes of patients with painful knee osteoarthritis

Shotaro Takano  1 , Kentaro Uchida  2 , Gen Inoue  1 , Toshihide Matsumoto  3 , Jun Aikawa  1 , Dai Iwase  1 , Manabu Mukai  1 , Masayuki Miyagi  1 , Masashi Takaso  1
Affiliations

Vascular endothelial growth factor expression and their action in the synovial membranes of patients with painful knee osteoarthritis

Shotaro Takano et al. BMC Musculoskelet Disord. .

Abstract

Background: Research suggests that vascular endothelial growth factor (VEGF) levels in the synovial fluid of knee osteoarthritis (KOA) patients are positively correlated with KOA severity. The relationship between synovial VEGF levels and pain in human KOA patients is not fully understood, and the role of VEGF in the pain pathway remains unclear.

Methods: We harvested synovial membrane (SM) from 102 patients with radiographic evidence of KOA (unilateral Kellgren/Lawrence [K/L] grade 2-4) during total knee arthroplasty. Patients scored their pain on a 0 to 10 cm visual analog scale (VAS). VEGF levels in the SM of KOA patients with strong/severe (VAS ≥ 6) and mild/moderate pain (VAS < 6) were compared. Correlations between VAS and VEGF mRNA expression were investigated. To investigate a possible mechanism for VEGF-induced pain, the distribution of VEGF and the neuropeptide apelin was determined by immunohistochemical analyses. To investigate the role of VEGF in regulating apelin expression, SM cells were exposed to VEGF.

Results: VEGF expression in the VAS ≥ 6 group was significantly greater than expression in the VAS < 6 group. Expression levels of VEGF were also positively correlated with VAS. VEGF-positive cells were identified in the lining of the SM. Expression of apelin mRNA and protein were significantly elevated in SM cells treated with exogenous VEGF compared to those treated with vehicle.

Conclusion: Synovial VEGF may be involved in pain pathways in KOA and its action may be mediated by apelin.

Keywords: Neuropeptides; Osteoarthritis; Pain; Synovial membrane; Vascular endothelial growth factor.

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Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the Ethics Review Board of Kitasato University (reference number: KMEO B13-113). Written consent to participate was obtained from the all participants for the harvesting of their synovial tissue for use in this study.

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
qPCR analysis of VEGF expression in the synovial membranes (SMs) of knee osteoarthritis (KOA) patients according to their VAS score. a “Box and whisker” plot of VEGF expression in the SMs of KOA patients with mild/moderate (VAS < 6) (n = 44) and strong/severe pain (VAS ≥ 6) (n = 58). The plot shows the median values (bold horizontal line), interquartile range (IQR) (box), and range. Outliers beyond 1.5-fold of the IQR from the box are plotted. * P = 0.008. VAS, visual analog scale. b Scatter plot showing the correlation between VAS scores and VEGF levels. Relative expression was calculated based on the mean of all samples of the VAS < 6 group
Fig. 2
Fig. 2
Relationship between VEGF mRNA expression level and Kellgren/Lawrence (K/L) grade. To investigate the relationship between VEGF and K/L grades, 102 knee OA patients were divided into three groups according to their K/L grade (2, 3, or 4). The three groups did not differ by patient age, male/female ratio, body mass index, or pain score based on the visual analog scale. Relative expression was calculated based on the mean of all samples of the KL2 group. The plot indicates median (bold horizontal line), interquartile range (IQR) (box), and range. Outliers beyond 1.5-fold of the IQR from the box are plotted
Fig. 3
Fig. 3
Immunostaining of VEGF and apelin in the synovial membranes of knee OA patients. Synovial membranes stained with a DAPI (nuclei), b VEGF, or c apelin. d The merged images. Region enclosed by dotted lines indicates the lining layer (LL), which is above the sublining layer (SLL) in the synovial membrane. Scale bar = 100 μm
Fig. 4
Fig. 4
Effect of VEGF on apelin mRNA expression. qPCR analysis for apelin. Synovial membrane cells were stimulated with 10 or 100 ng/mL human recombinant VGEF or vehicle for 24 h preceding the extraction and analysis of apelin mRNA. All data are shown as the mean ± standard error (n = 6). *P < 0.05
Fig. 5
Fig. 5
Effect of VEGF on apelin protein expression. Western blotting analysis for apelin. Synovial membrane cells were stimulated with 10 or 100 ng/mL human recombinant VGEF or vehicle for 24 h preceding protein extraction and analysis of apelin protein. a Western blot of apelin and β-actin. b Densitometric analysis of apelin bands. All data are shown as the mean ± standard error (n = 6). *P < 0.05 compared with the vehicle control
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