Transgenic mice over-expressing carbonic anhydrase I showed aggravated joint inflammation and tissue destruction

Abstract

BackgroundStudies have demonstrated that carbonic anhydrase I (CA1) stimulates calcium salt precipitation and cell calcification, which is an essential step in new bone formation. Our study had reported that CA1 encoding gene has a strong association with rheumatoid arthritis (RA) and ankylosing spondylitis (AS), two rheumatic diseases with abnormal new bone formation and bone resorption in joints. This study investigated the effect of CA1 on joint inflammation and tissue destruction in transgenic mice that over-express CA1 (CA1-Tg).MethodsCA1-Tg was generated with C57BL/6J mice by conventional methods. CA1-Tg was treated with collagen-II to induce arthritis (CIA). Wild-type mice, CA1-Tg treated with bovine serum albumin (BSA) and transgenic mice over-expressing PADI4 (PADI4-Tg), a gene known to be involved in rheumatoid arthritis, were used as controls. Histochemistry and X-ray radiographic assay were used to examine joint destruction. Western blotting and real time-PCR were used to examine CA1 expression.ResultsCIA was observed in 60% of CA1-Tg, 20% of PADI4-Tg and 20% of wild-type mice after collagen injections. No CIA was found in CA1-Tg mice that received injections of BSA. The arthritic score was 5.5 ± 0.84 in the CA1-Tgs but the score was less than 2 in the injected wild-type mice and the PADI4-Tgs. The thickness of the hind paws in the CA1-Tgs was 3.46 ± 0.11 mm, which was thicker than that of PADI4-Tgs (2.23 ± 0.08 mm), wild-type mice (2.08 ± 0.06 mm) and BSA-treated CA1-Tgs (2.04 ± 0.07 mm). Histochemistry showed obvious inflammation, synovial hyperplasia and bone destruction in the joints of CA1-Tg that was not detected in PADI4-Tgs or wild-type mice. X-ray assays showed bone fusion in the paws and spines of CA1-Tg mice.ConclusionOver-expression of CA1 may aggravate joint inflammation and tissue destruction in the transgenic mice.

Progress in the development of human carbonic anhydrase inhibitors and their pharmacological applications: Where are we today?

“…108 Several studies observed abnormal expressions of the CAs I, III, and IV in a sample of RA patients, although only antibodies of these isoforms were detected. 109,110 CA III exhibits low carbon dioxide hydratase activity and its expression was observed to be high in the skeletal muscle, where free radical production is increased due to physical exercise. 111 It was hypothesized that this isoform may play a role to control free radicals and thereby shielding cells against oxidative damage.…”

Secondary osteoporosis in collagen-induced arthritis rats

“…Protein expression was visualized using a BeoECL Plus instrument (Beyotime, China). β-Actin antibody (SAB, USA) was used to normalize the sample loading [23,24]. The quantification was conducted with Image-Pro Plus 6.0.…”

Overexpression of the transmembrane carbonic anhydrase isoforms IX and XII in the inflamed synovium

“…Several forms of carbonic anhydrases (CAs, EC 4.2.1.1), metalloenzymes that reversibly catalyze the conversion of CO 2 to the bicarbonate ions and protons 4 , have been recognized in articular diseases, including CA I which is over-expressed in the synovium of the patients with ankylosing spondylitis 5 . Transgenic mice over-expressing CA I showed aggravated joint inflammation and destruction 6 . CA I has been identified as an oral biomarker in oral fluid of Sjogren's syndrome 7 , and antibodies to CA III and IV have been identified in rheumatoid arthritis 8 .…”