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

Sci Transl Med. 2016 Aug 24;8(353):353ra113. doi: 10.1126/scitranslmed.aad8949.

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 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.

MeSH terms

  • Bone Neoplasms / enzymology*
  • Bone Neoplasms / pathology*
  • Bone Neoplasms / physiopathology
  • Bone Resorption / enzymology*
  • Bone Resorption / pathology*
  • Bone Resorption / physiopathology
  • Cell Line, Tumor
  • Core Binding Factor Alpha 1 Subunit / genetics
  • CpG Islands
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA Methylation
  • DNA Methyltransferase 3A
  • Down-Regulation
  • Humans
  • Interferon Regulatory Factors / genetics
  • Multiple Myeloma / enzymology*
  • Multiple Myeloma / pathology*
  • Multiple Myeloma / physiopathology
  • Osteoblasts / pathology
  • Osteoblasts / physiology
  • Osteoclasts / pathology
  • Osteoclasts / physiology
  • Osteogenesis / physiology*
  • Osteolysis / enzymology
  • Osteolysis / pathology
  • Osteolysis / prevention & control
  • RANK Ligand / metabolism
  • Sp7 Transcription Factor / genetics
  • Thymidine Phosphorylase / antagonists & inhibitors
  • Thymidine Phosphorylase / metabolism*
  • Up-Regulation

Substances

  • Core Binding Factor Alpha 1 Subunit
  • DNMT3A protein, human
  • Interferon Regulatory Factors
  • RANK Ligand
  • RUNX2 protein, human
  • Sp7 Transcription Factor
  • Sp7 protein, human
  • TNFSF11 protein, human
  • interferon regulatory factor-8
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methyltransferase 3A
  • TYMP protein, human
  • Thymidine Phosphorylase