Osteocyte CIITA aggravates osteolytic bone lesions in myeloma

Huan Liu, Jin He, Rozita Bagheri-Yarmand, Zongwei Li, Rui Liu, Zhiming Wang, Duc-hiep Bach, Yung-hsing Huang, Pei Lin, Theresa A. Guise, Robert F. Gagel () and Jing Yang ()
Additional contact information
Huan Liu: Houston Methodist Hospital
Jin He: Houston Methodist Hospital
Rozita Bagheri-Yarmand: The University of Texas MD Anderson Cancer Center
Zongwei Li: Houston Methodist Hospital
Rui Liu: Xiamen University
Zhiming Wang: Houston Methodist Hospital
Duc-hiep Bach: Houston Methodist Hospital
Yung-hsing Huang: Houston Methodist Hospital
Pei Lin: The University of Texas MD Anderson Cancer Center
Theresa A. Guise: The University of Texas MD Anderson Cancer Center
Robert F. Gagel: The University of Texas MD Anderson Cancer Center
Jing Yang: Houston Methodist Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-31356-7

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