TY - JOUR
T1 - Thymidine phosphorylase exerts complex effects on bone resorption and formation in myeloma
AU - Liu, Huan
AU - Liu, Zhiqiang
AU - Du, Juan
AU - He, Jin
AU - Lin, Pei
AU - Amini, Behrang
AU - Starbuck, Michael W.
AU - Novane, Nora
AU - Shah, Jatin J.
AU - Davis, Richard E.
AU - Hou, Jian
AU - Gagel, Robert F.
AU - Yang, Jing
N1 - Funding Information:
This work was supported by the National Cancer Institute R01s (CA190863 and CA193362), the National Cancer Institute UTMDACC SPORE in Multiple Myeloma Career Development Award (CDP-060315) and Developmental Research Program (DRP-00013585), the American Cancer Society Research scholar grant (127337-RSG-15-069-01-TBG), the University of Texas MD Anderson Cancer Center Institutional Research Grants Basic Research, the Leukemia Research Foundation, the American Society of Hematology, and the National Natural Science Foundation of China (grant no. 81470356).
PY - 2016/8/24
Y1 - 2016/8/24
N2 - 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 αVβ3/α5β1 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.
AB - 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 αVβ3/α5β1 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.
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U2 - 10.1126/scitranslmed.aad8949
DO - 10.1126/scitranslmed.aad8949
M3 - Article
C2 - 27559096
AN - SCOPUS:84983439001
SN - 1946-6234
VL - 8
JO - Science translational medicine
JF - Science translational medicine
IS - 353
M1 - 353ra113
ER -