Tau is a receptor with low affinity for glucocorticoids and is required for glucocorticoid-induced bone loss PMID: 39743632

ADC Targets in Oncology

2026-04-10

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

Cell Res. 2025 Jan;35(1):23-44. doi: 10.1038/s41422-024-01016-0.

Wenyu Fu ^# ¹ ² , Meng Chen ^# ² , Kaidi Wang ^# ² , Yujianan Chen ² ³ , Yazhou Cui ² ⁴ , Yangli Xie ⁵ , Zi-Ning Lei ⁶ , Wenhuo Hu ⁷ , Guodong Sun ² , Guiwu Huang ¹ , Chaopeng He ¹ , Jackie Fretz ¹ , Aubryanna Hettinghouse ² , Ronghan Liu ² , Xianyi Cai ² , Mingshuang Zhang ² , Yuehong Chen ² , Nan Jiang ² , Minchun He ² , Daniel H Wiznia ¹ , Huiyun Xu ⁸ , Zhe-Sheng Chen ⁶ , Lin Chen ⁵ , Kanglai Tang ³ , Hong Zhou ⁹ , Chuan-Ju Liu ¹⁰ ¹¹ ¹²

Affiliations

1. Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA.
2. Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA.
3. Department of Orthopedics/Sports Medicine Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
4. Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China.
5. Laboratory of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China.
6. Department of Pharmaceutical Science, College of Pharmacy and Health Sciences, St. John's University, New York, NY, USA.
7. Human 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.
8. School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China.
9. Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, NSW, Australia.
10. Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA. [email protected].
11. Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA. [email protected].
12. Department of Cell Biology, New York University Grossman School of Medicine, New York, NY, USA. [email protected].
# Contributed equally.

Abstract

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.