Volume 35, No 1, Jan 2025

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 35 Issue 1, January 2025: 23-44   |  Open Access

ORIGINAL ARTICLES

Tau is a receptor with low affinity for glucocorticoids and is required for glucocorticoid-induced bone loss

Wenyu Fu^1,2,† , Meng Chen^2,† , Kaidi Wang^2,† , Yujianan Chen^2,3 , Yazhou Cui^2,4 , Yangli Xie⁵ , Zi-Ning Lei⁶ , Wenhuo Hu⁷ , Guodong Sun² , Guiwu Huang¹ , Chaopeng He¹ , Jackie Fretz¹ , Aubryanna Hettinghouse² , Ronghan Liu² , Xianyi Cai² , Mingshuang Zhang² , Yuehong Chen² , Nan Jiang² , Minchun He² , Daniel H. Wiznia¹ , Huiyun Xu⁸ , Zhe-Sheng Chen⁶ , Lin Chen⁵ , Kanglai Tang³ , Hong Zhou⁹ , Chuan-Ju Liu^1,2,10,*

¹Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA
²Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA
³Department of Orthopedics/Sports Medicine Center, Southwest Hospital, Third Military Medical University, Chongqing, China
⁴Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
⁵Laboratory of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
⁶Department of Pharmaceutical Science, College of Pharmacy and Health Sciences, St. John’s University, New York, NY, USA
⁷Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
⁸School of Life Sciences, Northwestern Polytechnical University, Xi’an, Shaanxi, China
⁹Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, NSW, Australia
¹⁰Department of Cell Biology, New York University Grossman School of Medicine, New York, NY, USA
^†These authors contributed equally: Wenyu Fu, Meng Chen, Kaidi Wang
Correspondence: Chuan-Ju Liu(chuan-ju.liu@yale.edu)

Glucocorticoids (GCs) are the most prescribed anti-inflammatory and immunosuppressive drugs. However, their use is often limited by substantial side effects, such as GC-induced osteoporosis (GIO) with the underlying mechanisms still not fully understood. In this study, we identify Tau as a low-affinity binding receptor for GCs that plays a crucial role in GIO. Tau deficiency largely abolished bone loss induced by high-dose dexamethasone, a synthetic GC, in both inflammatory arthritis and GIO models. Furthermore, TRx0237, a Tau inhibitor identified from an FDA-approved drug library, effectively prevented GIO. Notably, combinatorial administration of TRx0237 and dexamethasone completely overcame the osteoporosis adverse effect of dexamethasone in treating inflammatory arthritis. These findings present Tau as a previously unrecognized GC receptor with low affinity, and provide potential strategies to mitigate a spectrum of GC-related adverse effects, particularly osteoporosis.

https://doi.org/10.1038/s41422-024-01016-0

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