Open AccessMyeloma cells shift osteoblastogenesis to adipogenesis by inhibiting the ubiquitin ligase MURF1 in mesenchymal stem cells
Author(s) -
Zhiqiang Liu,
Huan Liu,
Jin He,
Pei Lin,
Qiang Tong,
Jing Yang
Publication year - 2020
Publication title -
science signaling
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.659
H-Index - 154
eISSN - 1937-9145
pISSN - 1945-0877
DOI - 10.1126/scisignal.aay8203
Subject(s) - adipogenesis , mesenchymal stem cell , microbiology and biotechnology , chemistry , bone resorption , cancer research , biology , endocrinology
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 α 4 integrin subunit 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 patients with myeloma by counteracting tumor-MSC interactions.