Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease

Huan Liu, Jin He, Su Pin Koh, Yuping Zhong, Zhiqiang Liu, Zhiqiang Wang, Yujin Zhang, Zongwei Li, Bjorn T. Tam, Pei Lin, Min Xiao, Ken H. Young, Behrang Amini, Michael W. Starbuck, Hans C. Lee, Nora M. Navone, Richard E. Davis, Qiang Tong, Peter Leif Bergsagel, Jian Hou & 4 others Qing Yi, Robert Z. Orlowski, Robert F. Gagel, Jing Yang

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbereaau9087
JournalScience translational medicine
Volume11
Issue number494
DOIs
StatePublished - Jan 1 2019

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Bone Diseases
Adipocytes
Bone Marrow
Peroxisomes
Polycomb Repressive Complex 2
Osteogenesis
Bone and Bones
Methylation
Adipokines
Osteoclasts
Bone Resorption
Multiple Myeloma
Histones
Lysine
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Liu, H., He, J., Koh, S. P., Zhong, Y., Liu, Z., Wang, Z., ... Yang, J. (2019). Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease. Science translational medicine, 11(494), [eaau9087]. https://doi.org/10.1126/scitranslmed.aau9087

Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease. / Liu, Huan; He, Jin; Koh, Su Pin; Zhong, Yuping; Liu, Zhiqiang; Wang, Zhiqiang; Zhang, Yujin; Li, Zongwei; Tam, Bjorn T.; Lin, Pei; Xiao, Min; Young, Ken H.; Amini, Behrang; Starbuck, Michael W.; Lee, Hans C.; Navone, Nora M.; Davis, Richard E.; Tong, Qiang; Bergsagel, Peter Leif; Hou, Jian; Yi, Qing; Orlowski, Robert Z.; Gagel, Robert F.; Yang, Jing.

In: Science translational medicine, Vol. 11, No. 494, eaau9087, 01.01.2019.

Research output: Contribution to journalArticle

Liu, H, He, J, Koh, SP, Zhong, Y, Liu, Z, Wang, Z, Zhang, Y, Li, Z, Tam, BT, Lin, P, Xiao, M, Young, KH, Amini, B, Starbuck, MW, Lee, HC, Navone, NM, Davis, RE, Tong, Q, Bergsagel, PL, Hou, J, Yi, Q, Orlowski, RZ, Gagel, RF & Yang, J 2019, 'Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease', Science translational medicine, vol. 11, no. 494, eaau9087. https://doi.org/10.1126/scitranslmed.aau9087
Liu, Huan ; He, Jin ; Koh, Su Pin ; Zhong, Yuping ; Liu, Zhiqiang ; Wang, Zhiqiang ; Zhang, Yujin ; Li, Zongwei ; Tam, Bjorn T. ; Lin, Pei ; Xiao, Min ; Young, Ken H. ; Amini, Behrang ; Starbuck, Michael W. ; Lee, Hans C. ; Navone, Nora M. ; Davis, Richard E. ; Tong, Qiang ; Bergsagel, Peter Leif ; Hou, Jian ; Yi, Qing ; Orlowski, Robert Z. ; Gagel, Robert F. ; Yang, Jing. / Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease. In: Science translational medicine. 2019 ; Vol. 11, No. 494.
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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.",
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AU - Koh, Su Pin

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AU - Zhang, Yujin

AU - Li, Zongwei

AU - Tam, Bjorn T.

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AU - Davis, Richard E.

AU - Tong, Qiang

AU - Bergsagel, Peter Leif

AU - Hou, Jian

AU - Yi, Qing

AU - Orlowski, Robert Z.

AU - Gagel, Robert F.

AU - Yang, Jing

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N2 - 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.

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