Melphalan modifies the bone microenvironment by enhancing osteoclast formation

Ryan C. Chai, Michelle M. McDonald, Rachael L. Terry, Nataša Kovačić, Jenny M. Down, Sindhu T. Mohanty, Gholamreza Haffari, Jiake Xu, Matthew T. Gillespie, Michael J. Rogers, John T. Price, Peter I. Croucher, Julian M W Quinn

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Melphalan is a cytotoxic chemotherapy used to treat patients with multiple myeloma (MM). Bone resorption by osteoclasts, by remodeling the bone surface, can reactivate dormant MM cells held in the endosteal niche to promote tumor development. Dormant MM cells can be reactivated after melphalan treatment; however, it is unclear whether melphalan treatment increases osteoclast formation to modify the endosteal niche.
Melphalan treatment of mice for 14 days decreased bone volume and the endosteal bone surface, and this was associated with increases in osteoclast numbers. Bone marrow cells (BMC) from melphalan-treated mice formed more osteoclasts than BMCs from vehicle-treated mice, suggesting that osteoclast progenitors were increased. Melphalan also increased osteoclast formation in BMCs and RAW264.7 cells in vitro, which was prevented with the cell stress response (CSR) inhibitor KNK437. Melphalan also increased expression of the osteoclast regulator the microphthalmia-associated transcription factor (MITF), but not nuclear factor of activated T cells 1 (NFATc1). Melphalan increased expression of MITF-dependent cell fusion factors, dendritic cell-specific transmembrane protein (Dc-stamp) and osteoclast-stimulatory transmembrane protein (Oc-stamp) and increased cell fusion. Expression of osteoclast stimulator receptor activator of NFκB ligand (RANKL) was unaffected by melphalan treatment.
These data suggest that melphalan stimulates osteoclast formation by increasing osteoclast progenitor recruitment and differentiation in a CSR-dependent manner. Melphalan-induced osteoclast formation is associated with bone loss and reduced endosteal bone surface. As well as affecting bone structure this may contribute to dormant tumor cell activation, which has implications for how melphalan is used to treat patients with MM.
Original languageEnglish
Pages (from-to)68047-68058
Number of pages12
JournalOncotarget
Volume8
Issue number40
DOIs
Publication statusPublished - 2017

Keywords

  • osteoclast
  • chemotherapy
  • bone loss
  • cell stress
  • bone microenvironment

Cite this

Chai, R. C., McDonald, M. M., Terry, R. L., Kovačić, N., Down, J. M., Mohanty, S. T., ... Quinn, J. M. W. (2017). Melphalan modifies the bone microenvironment by enhancing osteoclast formation. Oncotarget, 8(40), 68047-68058. https://doi.org/10.18632/oncotarget.19152
Chai, Ryan C. ; McDonald, Michelle M. ; Terry, Rachael L. ; Kovačić, Nataša ; Down, Jenny M. ; Mohanty, Sindhu T. ; Haffari, Gholamreza ; Xu, Jiake ; Gillespie, Matthew T. ; Rogers, Michael J. ; Price, John T. ; Croucher, Peter I. ; Quinn, Julian M W. / Melphalan modifies the bone microenvironment by enhancing osteoclast formation. In: Oncotarget. 2017 ; Vol. 8, No. 40. pp. 68047-68058.
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abstract = "Melphalan is a cytotoxic chemotherapy used to treat patients with multiple myeloma (MM). Bone resorption by osteoclasts, by remodeling the bone surface, can reactivate dormant MM cells held in the endosteal niche to promote tumor development. Dormant MM cells can be reactivated after melphalan treatment; however, it is unclear whether melphalan treatment increases osteoclast formation to modify the endosteal niche.Melphalan treatment of mice for 14 days decreased bone volume and the endosteal bone surface, and this was associated with increases in osteoclast numbers. Bone marrow cells (BMC) from melphalan-treated mice formed more osteoclasts than BMCs from vehicle-treated mice, suggesting that osteoclast progenitors were increased. Melphalan also increased osteoclast formation in BMCs and RAW264.7 cells in vitro, which was prevented with the cell stress response (CSR) inhibitor KNK437. Melphalan also increased expression of the osteoclast regulator the microphthalmia-associated transcription factor (MITF), but not nuclear factor of activated T cells 1 (NFATc1). Melphalan increased expression of MITF-dependent cell fusion factors, dendritic cell-specific transmembrane protein (Dc-stamp) and osteoclast-stimulatory transmembrane protein (Oc-stamp) and increased cell fusion. Expression of osteoclast stimulator receptor activator of NFκB ligand (RANKL) was unaffected by melphalan treatment.These data suggest that melphalan stimulates osteoclast formation by increasing osteoclast progenitor recruitment and differentiation in a CSR-dependent manner. Melphalan-induced osteoclast formation is associated with bone loss and reduced endosteal bone surface. As well as affecting bone structure this may contribute to dormant tumor cell activation, which has implications for how melphalan is used to treat patients with MM.",
keywords = "osteoclast, chemotherapy, bone loss, cell stress, bone microenvironment",
author = "Chai, {Ryan C.} and McDonald, {Michelle M.} and Terry, {Rachael L.} and Nataša Kovačić and Down, {Jenny M.} and Mohanty, {Sindhu T.} and Gholamreza Haffari and Jiake Xu and Gillespie, {Matthew T.} and Rogers, {Michael J.} and Price, {John T.} and Croucher, {Peter I.} and Quinn, {Julian M W}",
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Chai, RC, McDonald, MM, Terry, RL, Kovačić, N, Down, JM, Mohanty, ST, Haffari, G, Xu, J, Gillespie, MT, Rogers, MJ, Price, JT, Croucher, PI & Quinn, JMW 2017, 'Melphalan modifies the bone microenvironment by enhancing osteoclast formation', Oncotarget, vol. 8, no. 40, pp. 68047-68058. https://doi.org/10.18632/oncotarget.19152

Melphalan modifies the bone microenvironment by enhancing osteoclast formation. / Chai, Ryan C.; McDonald, Michelle M. ; Terry, Rachael L.; Kovačić, Nataša ; Down, Jenny M.; Mohanty, Sindhu T.; Haffari, Gholamreza; Xu, Jiake; Gillespie, Matthew T.; Rogers, Michael J. ; Price, John T.; Croucher, Peter I. ; Quinn, Julian M W.

In: Oncotarget, Vol. 8, No. 40, 2017, p. 68047-68058.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Chai, Ryan C.

AU - McDonald, Michelle M.

AU - Terry, Rachael L.

AU - Kovačić, Nataša

AU - Down, Jenny M.

AU - Mohanty, Sindhu T.

AU - Haffari, Gholamreza

AU - Xu, Jiake

AU - Gillespie, Matthew T.

AU - Rogers, Michael J.

AU - Price, John T.

AU - Croucher, Peter I.

AU - Quinn, Julian M W

PY - 2017

Y1 - 2017

N2 - Melphalan is a cytotoxic chemotherapy used to treat patients with multiple myeloma (MM). Bone resorption by osteoclasts, by remodeling the bone surface, can reactivate dormant MM cells held in the endosteal niche to promote tumor development. Dormant MM cells can be reactivated after melphalan treatment; however, it is unclear whether melphalan treatment increases osteoclast formation to modify the endosteal niche.Melphalan treatment of mice for 14 days decreased bone volume and the endosteal bone surface, and this was associated with increases in osteoclast numbers. Bone marrow cells (BMC) from melphalan-treated mice formed more osteoclasts than BMCs from vehicle-treated mice, suggesting that osteoclast progenitors were increased. Melphalan also increased osteoclast formation in BMCs and RAW264.7 cells in vitro, which was prevented with the cell stress response (CSR) inhibitor KNK437. Melphalan also increased expression of the osteoclast regulator the microphthalmia-associated transcription factor (MITF), but not nuclear factor of activated T cells 1 (NFATc1). Melphalan increased expression of MITF-dependent cell fusion factors, dendritic cell-specific transmembrane protein (Dc-stamp) and osteoclast-stimulatory transmembrane protein (Oc-stamp) and increased cell fusion. Expression of osteoclast stimulator receptor activator of NFκB ligand (RANKL) was unaffected by melphalan treatment.These data suggest that melphalan stimulates osteoclast formation by increasing osteoclast progenitor recruitment and differentiation in a CSR-dependent manner. Melphalan-induced osteoclast formation is associated with bone loss and reduced endosteal bone surface. As well as affecting bone structure this may contribute to dormant tumor cell activation, which has implications for how melphalan is used to treat patients with MM.

AB - Melphalan is a cytotoxic chemotherapy used to treat patients with multiple myeloma (MM). Bone resorption by osteoclasts, by remodeling the bone surface, can reactivate dormant MM cells held in the endosteal niche to promote tumor development. Dormant MM cells can be reactivated after melphalan treatment; however, it is unclear whether melphalan treatment increases osteoclast formation to modify the endosteal niche.Melphalan treatment of mice for 14 days decreased bone volume and the endosteal bone surface, and this was associated with increases in osteoclast numbers. Bone marrow cells (BMC) from melphalan-treated mice formed more osteoclasts than BMCs from vehicle-treated mice, suggesting that osteoclast progenitors were increased. Melphalan also increased osteoclast formation in BMCs and RAW264.7 cells in vitro, which was prevented with the cell stress response (CSR) inhibitor KNK437. Melphalan also increased expression of the osteoclast regulator the microphthalmia-associated transcription factor (MITF), but not nuclear factor of activated T cells 1 (NFATc1). Melphalan increased expression of MITF-dependent cell fusion factors, dendritic cell-specific transmembrane protein (Dc-stamp) and osteoclast-stimulatory transmembrane protein (Oc-stamp) and increased cell fusion. Expression of osteoclast stimulator receptor activator of NFκB ligand (RANKL) was unaffected by melphalan treatment.These data suggest that melphalan stimulates osteoclast formation by increasing osteoclast progenitor recruitment and differentiation in a CSR-dependent manner. Melphalan-induced osteoclast formation is associated with bone loss and reduced endosteal bone surface. As well as affecting bone structure this may contribute to dormant tumor cell activation, which has implications for how melphalan is used to treat patients with MM.

KW - osteoclast

KW - chemotherapy

KW - bone loss

KW - cell stress

KW - bone microenvironment

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Chai RC, McDonald MM, Terry RL, Kovačić N, Down JM, Mohanty ST et al. Melphalan modifies the bone microenvironment by enhancing osteoclast formation. Oncotarget. 2017;8(40):68047-68058. https://doi.org/10.18632/oncotarget.19152