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

objectiveOur 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.

methodsA total of 53 patients with systemic autoimmune diseases who received initial glucocorticoid therapy with prednisolone (30-60 mg 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.

resultsSerum 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.

conclusionThe 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.