Osteocyte CIITA aggravates osteolytic bone lesions in myeloma

• Published in: Nature communications Vol. 13; no. 1; p. 3684
• Main Authors: Liu, Huan, He, Jin, Bagheri-Yarmand, Rozita, Li, Zongwei, Liu, Rui, Wang, Zhiming, Bach, Duc-hiep, Huang, Yung-hsing, Lin, Pei, Guise, Theresa A., Gagel, Robert F., Yang, Jing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.06.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/31; 38/91; 45/70; 45/88; 631/67/1990/804; 631/67/327; 64; 64/60; 692/698/1671/63; 96; Acetylation; Biomedical materials; Bone diseases; Bone growth; Bone resorption; Bone tumors; CIITA protein; Cytokines; D-Ribose; Histones; Humanities and Social Sciences; Interferon regulatory factor 1; Lesions; Lysine; Major histocompatibility complex; Microenvironments; Molecular modelling; multidisciplinary; Multiple myeloma; Osteoblastogenesis; Osteoblasts; Osteoclastogenesis; Osteoclasts; Osteocytes; Osteogenesis; Osteolysis; Phosphorylase; Plasma cells; Ribose; Science; Science (multidisciplinary); Signal transduction; Thymidine; TRANCE protein; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31356-7

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. Osteocytes play an important role in the development and progression of tumour-associated bone disease. Here the authors report an interaction between malignant plasma cells and osteocytes in multiple myeloma and show that the osteocyte-expressed major histocompatibility complex class II transactivator (CIITA) contributes to myeloma-induced bone lesions.