期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 8, 期 353, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aad8949
关键词
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资金
- National Cancer Institute [R01s (CA190863), CA193362]
- National Cancer Institute UTMDACC SPORE in Multiple Myeloma Career Development Award [CDP-060315]
- Developmental Research Program [DRP-00013585]
- American Cancer Society [127337-RSG-15-069-01-TBG]
- University of Texas MD Anderson Cancer Center Institutional Research Grants Basic Research
- Leukemia Research Foundation
- American Society of Hematology
- National Natural Science Foundation of China [81470356]
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 alpha(V)beta(3)/alpha(5)beta(1) 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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