title: Thymidine phosphorylase exerts complex effects on bone resorption and formation in myeloma.
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.
authors: Department of Lymphoma and Myeloma, Division of Cancer Medicine, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Huan
authors: H
authors: Liu
authors: Department of Lymphoma and Myeloma, Division of Cancer Medicine, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Zhiqiang
authors: Z
authors: Liu
authors: Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.
authors: Juan
authors: J
authors: Du
authors: Department of Lymphoma and Myeloma, Division of Cancer Medicine, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Jin
authors: J
authors: He
authors: Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Pei
authors: P
authors: Lin
authors: Department of Diagnostic Radiology, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Behrang
authors: B
authors: Amini
authors: Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Michael W
authors: MW
authors: Starbuck
authors: Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Nora
authors: N
authors: Novane
authors: Department of Lymphoma and Myeloma, Division of Cancer Medicine, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Jatin J
authors: JJ
authors: Shah
authors: Department of Lymphoma and Myeloma, Division of Cancer Medicine, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Richard E
authors: RE
authors: Davis
authors: Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.
authors: Jian
authors: J
authors: Hou
authors: Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Robert F
authors: RF
authors: Gagel
authors: Department of Lymphoma and Myeloma, Division of Cancer Medicine, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. jiyang@mdanderson.org.
authors: Jing
authors: J
authors: Yang
mesh_terms: D001859:Bone Neoplasms / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D001862:Bone Resorption / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D045744:Cell Line, Tumor; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D015536:Down-Regulation; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics; D009101:Multiple Myeloma / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D010006:Osteoblasts / Q000473:pathology / Q000502:physiology; D010010:Osteoclasts / Q000473:pathology / Q000502:physiology; D010012:Osteogenesis / Q000502:physiology*; D010014:Osteolysis / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D053245:RANK Ligand / Q000378:metabolism; D000076182:Sp7 Transcription Factor / Q000235:genetics; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation; D000099185:Interferon Regulatory Factor-8
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D050835:Interferon Regulatory Factors; D053245:RANK Ligand; D000076182:Sp7 Transcription Factor; D013939:Thymidine Phosphorylase; D000099185:Interferon Regulatory Factor-8; C000717967:DNMT3A protein, human; C493709:RUNX2 protein, human; C478163:SP7 protein, human; C505688:TNFSF11 protein, human; C543750:TYMP protein, human