Myeloma Cells Shift Osteoblastogenesis to Adipogenesis by Inhibiting the Ubiquitin Ligase MURF1 in Mesenchymal Stem Cells

Authors

Zhiqiang Liu
Huan Liu
Jin He
Pei Lin
Qiang Tong
Jing Yang

Publication Date

5-26-2020

Journal

Science Signaling

DOI

10.1126/scisignal.aay8203

PMID

32457115

PMCID

PMC7376968

PubMedCentral® Posted Date

11-26-2020

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Adipogenesis, Animals, Cell Communication, Cell Differentiation, Cell Line, Tumor, Humans, Mesenchymal Stem Cells, Mice, Mice, SCID, Multiple Myeloma, Muscle Proteins, Osteoblasts, Tripartite Motif Proteins, Ubiquitin-Protein Ligases

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 co-culture, and subcutaneous injection of MSCs and myeloma cells into mice. Our results revealed that the α4 subunit of integrin on myeloma cells stimulated vascular cell adhesion molecule 1 (VCAM1) on MSCs, leading to the activation of protein kinase C β1 (PKCβ1) signaling and repression of the muscle ring-finger protein-1 (MURF1)–mediated ubiquitylation of peroxisome proliferator-activated receptor γ2 (PPARγ2). Stabilized PPARγ2 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 myeloma patients by counteracting tumor-MSC interactions.

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