Research ArticleStem Cells

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

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Science Signaling  26 May 2020:
Vol. 13, Issue 633, eaay8203
DOI: 10.1126/scisignal.aay8203

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How myeloma promotes bone loss

Multiple myeloma can lead to bone loss by reducing the differentiation of mesenchymal stem cells (MSCs) into osteoblasts. Using a combination of single-cell RNA sequencing, in vitro coculture, and experiments with human myeloma cells and MSCs in mice, Liu et al. demonstrated how direct contact between myeloma cells and MSCs shifted the balance of MSC differentiation to favor adipogenesis over osteoblastogenesis. Integrin α4 on the surface of myeloma cells activated the adhesion molecule VCAM1 on MSCs, leading to protein kinase C β1 (PKCβ1)–dependent repression of the E3 ubiquitin ligase MURF1 and subsequent stabilization of the adipocyte transcription factor PPARγ2. These findings suggest a possible avenue for preventing or treating myeloma-induced bone loss in patients.

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 α4 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.

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