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Fludarabine inhibits STAT1-mediated up-regulation of caspase-3 expression in dexamethasone-induced osteoblasts apoptosis and slows the progression of steroid-induced avascular necrosis of the femoral head in rats

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Abstract

Steroid-induced avascular necrosis of the femoral head (SANFH) is a major limitation of long-term or excessive clinical administration of glucocorticoids. Fludarabine, which is a compound used to treat various hematological malignancies, such as chronic lymphocytic leukemia, acts by down-regulating signal transducer and activator of transcription 1 (STAT1) by inhibiting STAT1 phosphorylation in both normal and cancer cells. This study assessed the effects of fludarabine in vitro (primary murine osteoblasts) and in vivo (rat SANFH model). In vitro, pretreatment with fludarabine significantly inhibited Dexamethasone (Dex)-induced apoptosis in osteoblasts, which was examined by TUNEL staining. Treatment with Dex caused a remarkable decrease in the expression of Bcl-2; an increase in cytochrome c release; activation of BAX, caspase-9, and caspase-3; and an obvious enhancement in STAT1 phosphorylation. However, treatment resulted in the up-regulation of caspase-3 expression. Enhanced P-STAT1 activity and up-regulation of caspase-3 expression were also observed in osteoblasts. In vivo, the subchondral trabeculae in fludarabine-treated rats exhibited less bone loss and a lower ratio of empty lacunae. Taken together, our results suggest that STAT1-mediated up-regulation of caspase-3 is involved in osteoblast apoptosis induced by Dex and indicates that fludarabine may serve as a potential agent for the treatment of SANFH.

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Acknowledgements

The authors thank the staff of the Laboratory of the Orthopaedic Research Institute and the Scientific Research Center of the Second Affiliated Hospital of Wenzhou Medical University. This work was generously supported by grants from the Zhejiang Province Public Welfare Technology Application Research Project, China (2015C33209) and Wenzhou Public Welfare Science and Technology Project, Zhejiang Province, China (Y20150243).

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Authors and Affiliations

  1. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, 109 xueyuan xi Road, Wenzhou, 325000, China

    Zhenhua Feng, Wenhao Zheng, Qian Tang, Liang Cheng, Hang Li, Wenfei Ni & Xiaoyun Pan

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  1. Zhenhua Feng
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  2. Wenhao Zheng
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  3. Qian Tang
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Correspondence to Xiaoyun Pan.

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Feng, Z., Zheng, W., Tang, Q. et al. Fludarabine inhibits STAT1-mediated up-regulation of caspase-3 expression in dexamethasone-induced osteoblasts apoptosis and slows the progression of steroid-induced avascular necrosis of the femoral head in rats. Apoptosis 22, 1001–1012 (2017). https://doi.org/10.1007/s10495-017-1383-1

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