FRI0368 GLUCOCORTICOID THERAPY MIGHT SUPPRESS WNT SIGNALING BY REDUCING THE RATIO OF SERUM WNT3A TO WNT INHIBITORS, SFRP-1 AND WIF-1, AND IMPAIR BONE FORMATION
Authors: M. Kawazoe, K. Kaneko, T. Nanki
Journal: Annals of the Rheumatic Diseases (2020)

Background: Glucocorticoids decrease bone density by multiple mechanisms, including suppression of bone formation via Wnt/β-catenin signaling. Binding of Wnt ligands to a specific receptor and its co-receptors is required for activation of the Wnt pathway, whereas this pathway is inactivated by some negative regulators of Wnt signaling. Sclerostin (Scl) and Dickkopf-1 (Dkk-1) bind to Wnt co-receptors, and secreted Frizzled-related protein 1 (sFRP-1) and Wnt inhibitory factor 1 (Wif-1) bind to Wnt ligand, thereby inactivating the Wnt pathway [1-4]. However, the detailed changes of Wnt signaling in patients with glucocorticoid-induced osteoporosis have not been clarified. Objectives: We measured serum levels of Scl, Dkk-1 and Wnt3a before and after starting glucocorticoid therapy in our previous study, and the results suggested that suppression of Wnt/β-catenin signaling by increasing serum Scl and Dkk-1 might impaired bone formation at least in the first week of the initiation of glucocorticoid therapy [5]. However, the involvement of Wnt signaling in subsequent suppression of bone formation was unclear. The objective of this study was to investigate the involvement of the Wnt/β-catenin signaling pathway and its clinical significance after the early phase of glucocorticoid therapy in glucocorticoid-induced osteoporosis. 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 sFRP-1, Wif-1 and Wnt3a before starting glucocorticoid therapy and every week for four weeks after its initiation. Patients underwent measurement of bone mineral density (BMD) of the lumbar spine (L2-4) by dual-energy X-ray absorptiometry before starting therapy and after 16.3 ± 1.4 months (the mean ± SEM). Results: Serum sFRP-1 and Wif-1 level tended to decrease compared to before therapy from the first week. Serum level of Wnt3a also decreased from the first week. Both the ratio of Wnt3a to sFRP-1 and the ratio of Wnt3a to Wif-1 decreased from the first week onward. Moreover, we stratified the subjects into two groups according to the baseline serum sFRP-1 level at median and found that the decrease of BMD after initiation of glucocorticoid therapy in the High sFRP-1 group was larger than that in the Low sFRP-1 group. There was no difference in BMD changes between High Wif-1 and Low Wif-1 group, when stratified into two groups according to the median baseline serum Wif-1 level. Conclusion: Our previous study indicated that increase of Scl and Dkk-1 could inhibit Wnt signaling pathway in the early phase of glucocorticoid therapy. Current study suggested that the reduction in the ratio of Wnt3a to Wnt inhibitors, sFRP-1 and Wif-1, would suppress Wnt signaling, which might result in impairment of bone formation subsequent. Taken together, bone formation was impaired via suppressing Wnt signaling in patients treated with glucocorticoid. Furthermore, higher serum sFRP-1 level before glucocorticoid administration might be a predictor of future severity of glucocorticoid-induced osteoporosis. References: [1]Canalis E, et al. Osteoporos Int 2007; 18: 1319-1328. [2]Ke HZ, et al. Endocr Rev 2012; 33: 747-783. [3]Bodine PV, et al. J Cell Biochem 2005; 96: 1212-30. [4]Surmann-Schmitt C, et al. J Cell Sci 2009; 122: 3627-37. [5]Kawazoe M, et al. Clin Rheumatol 2018; 37: 2169-2178. [6]Wang FS, et al. Endocrinology 2005; 146: 2415-23. Disclosure of Interests: Mai Kawazoe: None declared, Kaichi Kaneko: None declared, Toshihiro Nanki Grant/research support from: Chugai Pharmaceutical Co., Eisai Co., Ltd., Teijin Pharma Ltd., Eli Lilly Japan K.K., Bristol-Myers K.K., Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., Asahikasei Pharma Corp., Mitsubishi-Tanabe Pharma Co., Astellas Pharma Inc., Ayumi Pharmaceutical Co., Pfizer Japan Inc., Daiichi Sankyo Co., Ltd., Shionogi &amp; Co., Ltd., Sanofi K.K., Nippon Kayaku Co., Ltd., Yutoku Pharmaceutical Ind. Co., Ltd., UCB Japan Co. Ltd., Nihon Pharmaceutical Co., Ltd., and Bayer Yakuhin, Ltd., Consultant of: UCB Japan Co., Ltd., Eisai Co., Ltd., and Chugai Pharmaceutical Co., Speakers bureau: Mitsubishi-Tanabe Pharma Co., Chugai Pharmaceutical Co., Eisai Co., Ltd., Astellas Pharma Inc., Janssen Pharmaceutical K.K., Ayumi Pharmaceutical Co., Pfizer Japan Inc., Asahikasei Pharma Corp., Sanofi K.K., Novartis Pharma K.K., Eli Lilly Japan K.K., Nippon Kayaku Co., Ltd., Teijin Pharma Ltd., Takeda Pharmaceutical Co., Nippon Boehringer Ingelheim Co., Ltd., and AbbVie GK.