TY - JOUR
T1 - Osteocyte CIITA aggravates osteolytic bone lesions in myeloma
AU - Liu, Huan
AU - He, Jin
AU - Bagheri-Yarmand, Rozita
AU - Li, Zongwei
AU - Liu, Rui
AU - Wang, Zhiming
AU - Bach, Duc hiep
AU - Huang, Yung hsing
AU - Lin, Pei
AU - Guise, Theresa A.
AU - Gagel, Robert F.
AU - Yang, Jing
N1 - Funding Information:
We thank The University of Texas MD Anderson Myeloma Tissue Bank. This research was supported by the National Institutes of Health/National Cancer Institute (R01 awards CA190863 and CA193362, J.Y.), the American Cancer Society (Research Scholar Grant 127337-RSG-15-069-01-TBG, J.Y.), and the Cancer Prevention Research Institute of Texas (Scholar of CPRIT Established Investigator Award RR190108, T.A.G.). Supported also by the NIH/NCI under award number P30CA016672 (Core Labs) and used the Small Animal Imaging Facility, Bone Histomorphometry, and Research Histology Core Laboratory. We would like to thank Sarah Bronson, ELS, Research Medical Library, The University of Texas MD Anderson Cancer Center, who edited the manuscript.
Funding Information:
We thank The University of Texas MD Anderson Myeloma Tissue Bank. This research was supported by the National Institutes of Health/National Cancer Institute (R01 awards CA190863 and CA193362, J.Y.), the American Cancer Society (Research Scholar Grant 127337-RSG-15-069-01-TBG, J.Y.), and the Cancer Prevention Research Institute of Texas (Scholar of CPRIT Established Investigator Award RR190108, T.A.G.). Supported also by the NIH/NCI under award number P30CA016672 (Core Labs) and used the Small Animal Imaging Facility, Bone Histomorphometry, and Research Histology Core Laboratory. We would like to thank Sarah Bronson, ELS, Research Medical Library, The University of Texas MD Anderson Cancer Center, who edited the manuscript.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/6/27
Y1 - 2022/6/27
N2 - Osteolytic destruction is a hallmark of multiple myeloma, resulting from activation of osteoclast-mediated bone resorption and reduction of osteoblast-mediated bone formation. However, the molecular mechanisms underlying the differentiation and activity of osteoclasts and osteoblasts within a myelomatous microenvironment remain unclear. Here, we demonstrate that the osteocyte-expressed major histocompatibility complex class II transactivator (CIITA) contributes to myeloma-induced bone lesions. CIITA upregulates the secretion of osteolytic cytokines from osteocytes through acetylation at histone 3 lysine 14 in the promoter of TNFSF11 (encoding RANKL) and SOST (encoding sclerostin), leading to enhanced osteoclastogenesis and decreased osteoblastogenesis. In turn, myeloma cell–secreted 2-deoxy-D-ribose, the product of thymidine catalyzed by the function of thymidine phosphorylase, upregulates CIITA expression in osteocytes through the STAT1/IRF1 signaling pathway. Our work thus broadens the understanding of myeloma-induced osteolysis and indicates a potential strategy for disrupting tumor-osteocyte interaction to prevent or treat patients with myeloma bone disease.
AB - Osteolytic destruction is a hallmark of multiple myeloma, resulting from activation of osteoclast-mediated bone resorption and reduction of osteoblast-mediated bone formation. However, the molecular mechanisms underlying the differentiation and activity of osteoclasts and osteoblasts within a myelomatous microenvironment remain unclear. Here, we demonstrate that the osteocyte-expressed major histocompatibility complex class II transactivator (CIITA) contributes to myeloma-induced bone lesions. CIITA upregulates the secretion of osteolytic cytokines from osteocytes through acetylation at histone 3 lysine 14 in the promoter of TNFSF11 (encoding RANKL) and SOST (encoding sclerostin), leading to enhanced osteoclastogenesis and decreased osteoblastogenesis. In turn, myeloma cell–secreted 2-deoxy-D-ribose, the product of thymidine catalyzed by the function of thymidine phosphorylase, upregulates CIITA expression in osteocytes through the STAT1/IRF1 signaling pathway. Our work thus broadens the understanding of myeloma-induced osteolysis and indicates a potential strategy for disrupting tumor-osteocyte interaction to prevent or treat patients with myeloma bone disease.
KW - Humans
KW - Multiple Myeloma/complications
KW - Nuclear Proteins
KW - Osteoblasts/metabolism
KW - Osteoclasts/metabolism
KW - Osteocytes/metabolism
KW - Osteolysis/metabolism
KW - RANK Ligand/metabolism
KW - Trans-Activators
KW - Tumor Microenvironment
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UR - http://www.scopus.com/inward/citedby.url?scp=85132960957&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-31356-7
DO - 10.1038/s41467-022-31356-7
M3 - Article
C2 - 35760800
AN - SCOPUS:85132960957
SN - 2041-1723
VL - 13
SP - 3684
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3684
ER -