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

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Abstract

Objective

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.

Methods

A 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.

Results

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.

Conclusion

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.

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Funding

This study was partly supported by a Project Research Grant (No. 17-12, 18-26) from Toho University School of Medicine to MK; the Nukada scholarship for Medical Research from Toho University School of Medicine to MK; a Research Promotion Grant from Toho University Graduate School of Medicine (No. 17-01) to TN; the Program for the Strategic Research Foundation for Private Universities (S1411015) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan to TN; and the Private University Research Branding Project from the Ministry of Education, Culture, Sports, Science, and Technology, Japan to TN.

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Authors and Affiliations

  1. Division of Rheumatology, Department of Internal Medicine, School of Medicine, Faculty of Medicine, Toho University, 6-11-1 Omori-Nishi, Ota-ku, Tokyo, 143-8541, Japan

    Mai Kawazoe, Kaichi Kaneko & Toshihiro Nanki

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  1. Mai Kawazoe
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  2. Kaichi Kaneko
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  3. Toshihiro Nanki
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Correspondence to Toshihiro Nanki.

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Ethical standards

This study was approved by the ethics committee of Toho University Omori Medical Center (approval number 24-78, 25-215, M20010) and complied with the 1964 Declaration of Helsinki and its later amendments and Ethical Guidelines for Medical and Health Research Involving Human Subjects by Ministries of Education, Culture, Sports, Science and Technology and Health, Labour and Welfare of the Japanese Government. All subjects provided written informed consent before enrollment.

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Kawazoe, M., Kaneko, K. & Nanki, T. Glucocorticoid therapy suppresses Wnt signaling by reducing the ratio of serum Wnt3a to Wnt inhibitors, sFRP-1 and Wif-1. Clin Rheumatol 40, 2947–2954 (2021). https://doi.org/10.1007/s10067-020-05554-x

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