Thymidine phosphorylase exerts complex effects on bone resorption and formation in myeloma

Huan Liu, Zhiqiang Liu, Juan Du, Jin He, Pei Lin, Behrang Amini, Michael W. Starbuck, Nora Novane, Jatin J. Shah, Richard E. Davis, Jian Hou, Robert F. Gagel, Jing Yang

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Myelomatous bone disease is characterized by the development of lytic bone lesions and a concomitant reduction in bone formation, leading to chronic bone pain and fractures. To understand the underlying mechanism, we investigated the contribution of myeloma-expressed thymidine phosphorylase (TP) to bone lesions. In osteoblast progenitors, TP up-regulated the methylation of RUNX2 and osterix, leading to decreased bone formation. In osteoclast progenitors, TP up-regulated the methylation of IRF8 and thereby enhanced expression of NFATc1 (nuclear factor of activated T cells, cytoplasmic 1 protein), leading to increased bone resorption. TP reversibly catalyzes thymidine into thymine and 2-deoxy-D-ribose (2DDR). Myeloma-secreted 2DDR bound to integrin αVβ35β1 in the progenitors, activated PI3K (phosphoinositide 3-kinase)/Akt signaling, and increased DNMT3A (DNA methyltransferase 3A) expression, resulting in hypermethylation of RUNX2, osterix, and IRF8. This study elucidates an important mechanism for myeloma-induced bone lesions, suggesting that targeting TP may be a viable approach to healing resorbed bone in patients. Because TP overexpression is common in bone-metastatic tumors, our findings could have additional mechanistic implications.

Original languageEnglish (US)
Article number353ra113
JournalScience translational medicine
Volume8
Issue number353
DOIs
StatePublished - Aug 24 2016

ASJC Scopus subject areas

  • Medicine(all)

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