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Abstract
Objective The persistent, systemic inflammation in rheumatic disease results in chronic tissue damage. Fibrosis – promoted by transforming growth factor (TGF-β) - forms part of the repair process, but in rheumatic disease, is excessive. This leads to progressive architectural changes and dysfunction in organs, to the point of organ failure. The heart is commonly affected, with cardiovascular disease a leading cause of death in rheumatology patients. In the context of fibrosis, bone morphogenetic protein-7 (BMP-7) counters the effects of TGF-β. Based on the ability of BMP-7 to regulate inflammation and fibrosis, therapeutic modulation of the TGF-β:BMP-7 ratio may benefit rheumatic disease management. This study aimed to determine the extent to which different (traditional and experimental) treatments may alter the TGF-β:BMP-7 ratio, using a preclinical model of myocarditis.
Method Following ethical approval, a sclerosing agent was injected into the pericardial space of larval zebrafish (2 days post fertilization). Larvae were subsequently maintained in media containing either a placebo, or one of 25 µg/ml prednisolone, 28.57 µg/ml HCQ or 750 ng/ml BMP-7, for a period of 60 hours. Thereafter larvae were euthanised, fixed and fluorescently labelled for TGF-β, BMP-7 and the fibroblast marker vimentin.
Results Following injection with a sclerosing agent, larval hearts exhibited increased TGF-β expression (p<0.01), which was partially rescued by all treatments. BMP-7 expression was increased in the cardiac region following treatment with HCQ (vs control and prednisolone, both p<0.05) and BMP-7 (vs control, p=0.05). Prednisolone did not affect BMP-7 expression.
Conclusion Injection with a sclerosing agent into the pericardial space of zebrafish larvae increased TGF-β, a pro-fibrotic agent. Preliminary data indicates that treatment with HCQ and BMP-7 increased BMP-7 and altered the TGF-β/BMP-7 ratio, demonstrating potential in the treatment of myocarditis. Given the known long-term side-effects of HCQ, BMP-7 should be evaluated as alternative anti-fibrotic treatment in rheumatology patients.
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