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Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease.

ABSTRACT: Osteolytic lesions in multiple myeloma are caused by osteoclast-mediated bone resorption and reduced bone formation. A unique feature of myeloma is a failure of bone healing after successful treatment. We observed adipocytes on trabecular bone near the resorbed area in successfully treated patients. Normal marrow adipocytes, when cocultured with myeloma cells, were reprogrammed and produced adipokines that activate osteoclastogenesis and suppress osteoblastogenesis. These adipocytes have reduced expression of peroxisome proliferator-activated receptor ? (PPAR?) mediated by recruitment of polycomb repressive complex 2 (PRC2), which modifies PPAR? promoter methylation at trimethyl lysine-27 histone H3. We confirmed the importance of methylation in the PPAR? promoter by demonstrating that adipocyte-specific knockout of EZH2, a member of the PRC2, prevents adipocyte reprogramming and reverses bone changes in a mouse model. We validated the strong correlation between the frequency of bone lesions and the expression of EZH2 in marrow adipocytes from patients in remission. These results define a role for adipocytes in genesis of myeloma-associated bone disease and that reversal of adipocyte reprogramming has therapeutic implications.

SUBMITTER: Liu H

PROVIDER: S-EPMC6999853 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease.

Liu Huan H He Jin J Koh Su Pin SP Zhong Yuping Y Liu Zhiqiang Z Wang Zhiqiang Z Zhang Yujin Y Li Zongwei Z Tam Bjorn T BT Lin Pei P Xiao Min M Young Ken H KH Amini Behrang B Starbuck Michael W MW Lee Hans C HC Navone Nora M NM Davis Richard E RE Tong Qiang Q Bergsagel P Leif PL Hou Jian J Yi Qing Q Orlowski Robert Z RZ Gagel Robert F RF Yang Jing J

Science translational medicine 20190501 494

Osteolytic lesions in multiple myeloma are caused by osteoclast-mediated bone resorption and reduced bone formation. A unique feature of myeloma is a failure of bone healing after successful treatment. We observed adipocytes on trabecular bone near the resorbed area in successfully treated patients. Normal marrow adipocytes, when cocultured with myeloma cells, were reprogrammed and produced adipokines that activate osteoclastogenesis and suppress osteoblastogenesis. These adipocytes have reduced ...[more]

PMID: 31142679

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Project description:Multiple myeloma (MM) is a lethal B cell neoplasm characterized by clonal expansion of malignant plasma cells in the bone marrow and remains incurable due to disease relapse and drug resistance. Bone marrow adipocytes (BMAs) are emerging as playing active functions that can support myeloma cell growth and survival. The aim of this study is to investigate myeloma-mesenchymal stem cells (MSCs) interaction and the impact of such interactions on the pathogenesis of MM using in vitro co-culture assay. Here we provide evidence that MM cell up-regulated MSCs to express PPAR-γ and pushes MSCs differentiation toward adipocytes at the expense of osteoblasts in co-culture manner. The increased BMAs can effectively enhance MM cell to proliferation, migration, and chemoresistance via cell-cell contact and/or cytokines release regulated by PPAR-γ signal pathway. This effect was partially reversed in medium containing PPAR-γ antagonist G3335 and indicated that G3335 distorts the maturation of MSC-derived adipocytes and cytokines release by adipocytes through inhibition of PPAR-γ, a key transcriptional factor for the activation of adipogenesis, or cell to cell contact, or both. In meantime, we observed higher expression of adipocyte differentiation associated genes DLK1, DGAT1, FABP4, and FASN both in MSCs and MSC derived adipocytes, but the osteoblast differentiation-associated gene ALP was down regulated in MSCs. These finding mean that direct consequence of MM/MSC interaction that play a role in MM pathogenesis. Consistent with those in vitro results, our primary clinical observation also showed that bone marrow samples from MM patients had significantly higher bone adiposity in comparison with controls and the number of adipocytes decreased in those who were response to anti-MM therapy. Our finding suggested that BMAs may have an important contribution to MM progression, particularly in drugs resistant of MM cells, and plays an important contribution in MM bone disease and treatment failure, but more clinical studies are needed to confirm its role.

Dataset Information

Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease.

Publications

Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease.

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