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. 2000 Feb;59(2):125–131. doi: 10.1136/ard.59.2.125

Angiotensin converting enzyme in human synovium: increased stromal [125I]351A binding in rheumatoid arthritis

D A Walsh 1, J Catravas 1, J Wharton 1
PMCID: PMC1753069  PMID: 10666168

Abstract

OBJECTIVE—To determine whether tissue angiotensin converting enzyme (ACE) is increased in synovia from patients with rheumatoid arthritis, osteoarthritis or chondromalacia patellae.
METHODS—Sections of synovia from patients with rheumatoid arthritis (n = 7), osteoarthritis (n = 7) or chondromalacia patellae (n = 6) were tested for immunoreactivity for ACE, and for binding of the ACE inhibitor [125I]351A. The amount of ACE was measured with computer assisted image analysis as the proportion of synovial section area occupied by ACE-immunoreactive cells, and the density of [125I]351A binding.
RESULTS—[125I]351A binding sites had characteristics of ACE and colocalised with ACE-like immunoreactivity to microvascular endothelium and fibroblast-like stromal cells in inflamed and non-inflamed human synovium. Stromal [125I]351A binding densities (Beq) and the fraction of synovial section area occupied by ACE-immunoreactivity (fractional area) were higher in synovia from patients with rheumatoid arthritis (Beq 28 amol/mm2, fractional area 0.21) than from those with osteoarthritis (Beq 9 amol/mm2, fractional area 0.10) or chondromalacia patellae (Beq 9 amol/mm2, fractional area 0.09)(p < 0.05). Density of [125I]351A binding to stroma was similar to that to blood vessels in rheumatoid arthritis, but less dense than vascular binding in chondromalacia patellae and osteoarthritis. Increases in [125I]351A binding densities were attributable to increases in the numbers of binding sites, and were consistent with an increase in the density of ACE bearing stromal cells.
CONCLUSION—ACE is upregulated in synovial stroma in rheumatoid arthritis. Increased tissue ACE may result in increased local generation of the vasoconstrictor and mitogenic peptide angiotensin II and thereby potentiate synovial hypoxia and proliferation in rheumatoid arthritis.



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Figure 1  .

Figure 1  

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Localisation of [125I]351A binding sites and angiotensin converting enzyme-like immunoreactivity (ACE-LI) in human synovium. (A) [125I]351A binding to synovium from a patient with chondromalacia patellae showing punctate binding to blood vessels (small arrows), with less dense binding to stromal tissue between vessels. (B) ACE-LI in the field of a consecutive tissue section that corresponds to the box shown in (A). Small arrows indicate ACE-LI localised to vascular endothelium corresponding to the punctate [125I]351A binding in (A). Less intense ACE-LI is localised to spindle shaped cells within the synovial stroma. (C) [125I]351A binding to synovium from a patient with rheumatoid arthritis showing diffuse stromal binding of a similar density to punctate binding (small arrow). (D) ACE-LI in the field of a consecutive tissue section that corresponds to the box shown in (C). Intense ACE-LI is localised to stromal cells, particularly those immediately beneath the lining cells and around blood vessels. The small arrow indicates ACE-LI localised to vascular endothelium corresponding to punctate binding in (C). (A) and (C) Reversal prints of film autoradiograms. (B) and (D) Immunohistochemistry with rabbit polyclonal antihuman ACE, developed with DAB using glucose oxidase/nickel enhancement. Open arrows indicate synovial lining region. Bars = 500 µm.

Figure 2  .

Figure 2  

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Characteristics of [125I]351A binding to human synovium. (A) Association (filled circles) and dissociation (empty circles) at 22°C of 0.03 nM [125I]351A binding to blood vessels in synovia from patients with rheumatoid arthritis. For dissociation time course, sections were transferred to an excess of buffer without [125I]351A at 180 minutes (arrow). (B) Inhibition of 0.03 nM [125I]351A binding to blood vessels in synovia from patients with rheumatoid arthritis by unlabelled lisinopril (circles) or captopril (triangles). (C) Saturation of [125I]351A binding to blood vessels in synovia from patients with rheumatoid arthritis. (D) Saturation of [125I]351A binding to synovial stroma from patients with rheumatoid arthritis (filled circles) or osteoarthritis (empty circles). Points represent means (SEM) for synovia from six to eight patients.

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