GSE200987
Osteocyte CIITA Aggravates Osteolytic Bone Lesions in Myeloma
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 mechanism underlying the differentiation and activity of osteoclasts and osteoblasts  within a myelomatous microenvironment remains 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. Overall design: Define a heretofore unrecognized role for osteocytes in genesis of myeloma-associated bone disease