Glucocorticoid therapy suppresses Wnt signaling by reducing the ratio of serum Wnt3a to Wnt inhibitors, sFRP-1 and Wif-1.

Abstract

Our previous study suggested that suppression of Wnt/β-catenin signaling by increasing serum Wnt co-receptor inhibitors, sclerostin and Dickkopf-1, impairs bone formation in the first week after starting glucocorticoid therapy. The objective of this study was to investigate the involvement of the Wnt/β-catenin signaling pathway and its clinical significance in the subsequent suppression of bone formation. A total of 53 patients with systemic autoimmune diseases who received initial glucocorticoid therapy with prednisolone (30-60mg daily) were prospectively enrolled. We measured serum levels of Wnt3a and Wnt inhibitors, secreted Frizzled-related protein 1 (sFRP-1) and Wnt inhibitory factor 1 (Wif-1), before starting glucocorticoid therapy and every week for 4 weeks after its initiation. Serum levels of sFRP-1 and Wif-1 slightly decreased compared with before glucocorticoid therapy from the second week. The serum Wnt3a level decreased from the first week. The ratios of Wnt3a to sFRP-1 and that of Wnt3a to Wif-1 both decreased from the first week onward. The reduction of the ratio of Wnt3a to Wnt inhibitors, sFRP-1 and Wif-1, suppresses Wnt signaling, which may result in impaired bone formation. Taken together with our previous studies, glucocorticoids may suppress Wnt signaling by inhibiting co-receptors of the Wnt/β-catenin signaling pathway in the early phase of glucocorticoid therapy and inhibiting its ligand in the subsequent weeks, which together impair bone formation. Key Points • The decrease in Wnt pathway-related molecules by glucocorticoids impairs bone formation. • Glucocorticoids inhibit co-receptors of Wnt signaling in the early phase of therapy. • Glucocorticoids inhibit ligands of Wnt signaling in the subsequent phase of therapy.