Myeloma cells shift osteoblastogenesis to adipogenesis by inhibiting the ubiquitin ligase MURF1 in mesenchymal stem cells

Authors: LIU, ZHIQIANG - Md Anderson Cancer Center; LIU, HUAN - Md Anderson Cancer Center; HE, JIN - Md Anderson Cancer Center; LIN, PEI - Md Anderson Cancer Center; TONG, QIANG - Children'S Nutrition Research Center (CNRC); YANG, JIAN - Children'S Nutrition Research Center (CNRC)

Submitted to: Science Signaling
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/29/2020
Publication Date: 5/26/2020
Citation: Liu, Z., Liu, H., He, J., Lin, P., Tong, Q., Yang, J. 2020. Myeloma cells shift osteoblastogenesis to adipogenesis by inhibiting the ubiquitin ligase MURF1 in mesenchymal stem cells. Science Signaling. 13(633):eaay8203. https://doi.org/10.1126/scisignal.aay8203.
DOI: https://doi.org/10.1126/scisignal.aay8203

Interpretive Summary: Multiple myeloma, a type of cancer in bone marrow, blocks bone formation from bone progenitor cells, which can also convert into fat cells. We investigated myeloma-bone progenitor cell interactions. Our results revealed that the a protein called a4 integrin subunit on myeloma cells stimulated the cell surface protein VCAM1 on the bone progenitor cells, leading to the activation of the signaling protein PKCß1 and repression of the MURF1 protein-mediated degradation of the PPARy2 protein. Stabilized PPARy2 proteins enhanced fat cell formation and consequently reduced bone formation from the progenitor cells. These findings reveal that suppressed bone formation is a direct consequence of myeloma-bone progenitor cell contact that promotes the conversion of progenitor cells into fat cells at the expense of bone cells. Thus, this study provides a potential strategy for treating bone loss in patients with myeloma by counteracting tumor-bone progenitor cell interactions.

Technical Abstract: The suppression of bone formation is a hallmark of multiple myeloma. Myeloma cells inhibit osteoblastogenesis from mesenchymal stem cells (MSCs), which can also differentiate into adipocytes. We investigated myeloma-MSC interactions and the effects of such interactions on the differentiation of MSCs into adipocytes or osteoblasts using single-cell RNA sequencing, in vitro coculture, and subcutaneous injection of MSCs and myeloma cells into mice. Our results revealed that the a4 integrin subunit on myeloma cells stimulated vascular cell adhesion molecule-1 (VCAM1) on MSCs, leading to the activation of protein kinase C B1 (PKCB1) signaling and repression of the muscle ring-finger protein-1 (MURF1)-mediated ubiquitylation of peroxisome proliferator-activated receptor y2 (PPARy2). Stabilized PPARy2 proteins enhanced adipogenesis and consequently reduced osteoblastogenesis from MSCs, thus suppressing bone formation in vitro and in vivo. These findings reveal that suppressed bone formation is a direct consequence of myeloma-MSC contact that promotes the differentiation of MSCs into adipocytes at the expense of osteoblasts. Thus, this study provides a potential strategy for treating bone resorption in patients with myeloma by counteracting tumor-MSC interactions.