Glucocorticoid therapy causes contradictory changes of serum Wnt signaling-related molecules in systemic autoimmune diseases
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The objective of this study was to investigate the clinical significance of the Wnt/β-catenin signaling pathway in glucocorticoid-induced osteoporosis. A total of 91 patients with systemic autoimmune diseases who received initial glucocorticoid therapy with prednisolone (30–60 mg daily) were prospectively enrolled. We measured serum levels of N-terminal peptide of type I procollagen (P1NP), bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), N-telopeptide cross-linked type I collagen (NTX), sclerostin, Dickkopf-1 (Dkk-1), and Wnt3a before starting glucocorticoid therapy and every week for 4 weeks after its initiation. The effects of dexamethasone on expression of mRNA and protein of sclerostin and Dkk-1 by cultured normal human osteoblasts (NHOst) were evaluated by RT-PCR and ELISA, respectively. Serum levels of sclerostin and Dkk-1 increased significantly by 1 week of glucocorticoid therapy and then decreased from the second week onward. Serum Wnt3a tended to decrease and serum P1NP showed a significant decrease. However, TRACP-5b was significantly elevated from the first week of treatment onwards. In vitro study, dexamethasone increased Dkk-1 mRNA expression in cultured NHOst, but sclerostin mRNA was not detected. Dexamethasone also increased Dkk-1 protein production by osteoblasts, whereas sclerostin protein was not detected. Bone formation might be impaired at least in the first week of the initiation of glucocorticoid therapy by increase of the serum Wnt signaling inhibitors; however, their reductions in the subsequent weeks were contradictory to the maintained suppression of the bone formation markers after glucocorticoid therapy for patients with systemic autoimmune diseases.
KeywordsDickkopf-1 Glucocorticoid Osteoporosis Sclerostin Wnt signaling
Acknowledgements and funding information
We thank Sonoko Sakurai for secretarial assistance. This study was partly supported by a grant from the Strategic Research Foundation Project for Private Schools in Heisei 23 (S1101016) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (2011–2015) to Toho University and a grant from the Japan Agency for Medical Research and Development on Regulatory Science of Pharmaceuticals and Medical Devices (2015–2016) to SK.
Compliance with ethical standards
This study was approved by the ethics committees of Toho University Omori Medical Center (approval number: 24-78, 25-215) 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 of the subjects gave written informed consent before enrollment.
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