Transcriptional regulation of Rankl by Txnip-Ecd in aging and diabetic related osteoporosis

Abstract

Introduction: Bone homeostasis between osteoclast bone resorption and osteoblastic bone formation is tightly regulated by a series of factors such as the receptor activator of nuclear factor-κB ligand (RANKL). Denosumab that neutralizes RANKL is effective and widely applied in the treatment of postmenopausal osteoporosis. However, factors that participated in the RANKL-related bone remodeling process in primary and secondary osteoporosis are less known.

Objectives: Revealing the novel transcriptional regulatory mechanism of RANKL is of great significance for the treatment of osteoporosis.

Methods: After differential expression genes (DEGs) intersection and screening, we generated Thioredoxin-interacting protein (Txnip) bone marrow-derived mesenchymal stromal cells (BMSCs) genetic knockout mice and performed bone histomorphometry and histological analysis. RNA-Sequencing, Western blotting and immunofluorescence staining verified Rankl downregulation. Co-immunoprecipitation and immunofluorescence staining were used for Rankl regulation mechanism exploration. A specific inhibitor was selected for treatment effect verification.

Results: Txnip knockout in BMSCs impaired its osteogenic differentiation, suppressed Rankl expression and subsequent osteoclast formation and thus led to increased bone mass. The regulatory function of Txnip on Rankl expression was revealed for the first time through the novel transcription-related Ecdysoneless (Ecd)-P300 axis. Pharmacological inhibition of Txnip can effectively prevent bilateral ovariectomy (OVX)-induced osteoporosis.

Conclusions: Inhibition of Txnip is an alternative way to suppress Rankl-mediated osteoblast and osteoclast crosstalk. This interesting finding rendered Txnip an ideal therapeutic target for the treatment of both ovariectomy-induced and diabetes-induced osteoporosis.

Keywords: Bone remodeling; Osteoblast; Osteoporosis; Receptor activator of nuclear factor-κB ligand (Rankl); Thioredoxin-interacting protein (Txnip).