N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation

Richard W J Groen, Martin F M de Rooij, Kinga A. Kocemba, Rogier M. Reijmers, Anneke de Haan-Kramer, Marije B. Overdijk, Linda Aalders, Henk Rozemuller, Anton C M Martens, Peter Leif Bergsagel, Marie José Kersten, Steven T. Pals, Marcel Spaargaren

Research output: Contribution to journalArticle

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Abstract

Background Multiple myeloma is a hematologic malignancy characterized by a clonal expansion of malignant plasma cells in the bone marrow, which is accompanied by the development of osteolytic lesions and/or diffuse osteopenia. The intricate bi-directional interaction with the bone marrow microenvironment plays a critical role in sustaining the growth and survival of myeloma cells during tumor progression. Identification and functional analysis of the (adhesion) molecules involved in this interaction will provide important insights into the pathogenesis of multiple myeloma. Design and Methods Multiple myeloma cell lines and patients' samples were analyzed for expression of the adhesion molecule N-cadherin by immunoblotting, flow cytometry, immunofluorescence microscopy, immunohistochemistry and expression microarray. In addition, by means of blocking antibodies and inducible RNA interference we studied the functional consequence of N-cadherin expression for the myeloma cells, by analysis of adhesion, migration and growth, and for the bone marrow microenvironment, by analysis of osteogenic differentiation. Results The malignant plasma cells in approximately half of the multiple myeloma patients, belonging to specific genetic subgroups, aberrantly expressed the homophilic adhesion molecule N-cadherin. N-cadherin-mediated cell-substrate or homotypic cell-cell adhesion did not contribute to myeloma cell growth in vitro. However, N-cadherin directly mediated the bone marrow localization/ retention of myeloma cells in vivo, and facilitated a close interaction between myeloma cells and N-cadherin-positive osteoblasts. Furthermore, this N-cadherin-mediated interaction contributed to the ability of myeloma cells to inhibit osteoblastogenesis. Conclusions Taken together, our data show that myeloma cells frequently display aberrant expression of Ncadherin and that N-cadherin mediates the interaction of myeloma cells with the bone marrow microenvironment, in particular the osteoblasts. This N-cadherin-mediated interaction inhibits osteoblast differentiation and may play an important role in the pathogenesis of myeloma bone disease.

Original languageEnglish (US)
Pages (from-to)1653-1661
Number of pages9
JournalHaematologica
Volume96
Issue number11
DOIs
StatePublished - Nov 1 2011

Fingerprint

Cadherins
Osteoblasts
Multiple Myeloma
Bone Marrow
Plasma Cells
Cell Adhesion
Growth
Blocking Antibodies
Metabolic Bone Diseases
Bone Diseases
Hematologic Neoplasms
RNA Interference
Fluorescence Microscopy
Immunoblotting
Bone Marrow Cells
Cell Survival
Flow Cytometry
Immunohistochemistry
Cell Line

Keywords

  • Multiple myeloma
  • N-cadherin
  • Osteoblast differentiation

ASJC Scopus subject areas

  • Hematology

Cite this

Groen, R. W. J., de Rooij, M. F. M., Kocemba, K. A., Reijmers, R. M., de Haan-Kramer, A., Overdijk, M. B., ... Spaargaren, M. (2011). N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation. Haematologica, 96(11), 1653-1661. https://doi.org/10.3324/haematol.2010.038133

N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation. / Groen, Richard W J; de Rooij, Martin F M; Kocemba, Kinga A.; Reijmers, Rogier M.; de Haan-Kramer, Anneke; Overdijk, Marije B.; Aalders, Linda; Rozemuller, Henk; Martens, Anton C M; Bergsagel, Peter Leif; Kersten, Marie José; Pals, Steven T.; Spaargaren, Marcel.

In: Haematologica, Vol. 96, No. 11, 01.11.2011, p. 1653-1661.

Research output: Contribution to journalArticle

Groen, RWJ, de Rooij, MFM, Kocemba, KA, Reijmers, RM, de Haan-Kramer, A, Overdijk, MB, Aalders, L, Rozemuller, H, Martens, ACM, Bergsagel, PL, Kersten, MJ, Pals, ST & Spaargaren, M 2011, 'N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation', Haematologica, vol. 96, no. 11, pp. 1653-1661. https://doi.org/10.3324/haematol.2010.038133
Groen RWJ, de Rooij MFM, Kocemba KA, Reijmers RM, de Haan-Kramer A, Overdijk MB et al. N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation. Haematologica. 2011 Nov 1;96(11):1653-1661. https://doi.org/10.3324/haematol.2010.038133
Groen, Richard W J ; de Rooij, Martin F M ; Kocemba, Kinga A. ; Reijmers, Rogier M. ; de Haan-Kramer, Anneke ; Overdijk, Marije B. ; Aalders, Linda ; Rozemuller, Henk ; Martens, Anton C M ; Bergsagel, Peter Leif ; Kersten, Marie José ; Pals, Steven T. ; Spaargaren, Marcel. / N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation. In: Haematologica. 2011 ; Vol. 96, No. 11. pp. 1653-1661.
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AU - de Haan-Kramer, Anneke

AU - Overdijk, Marije B.

AU - Aalders, Linda

AU - Rozemuller, Henk

AU - Martens, Anton C M

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N2 - Background Multiple myeloma is a hematologic malignancy characterized by a clonal expansion of malignant plasma cells in the bone marrow, which is accompanied by the development of osteolytic lesions and/or diffuse osteopenia. The intricate bi-directional interaction with the bone marrow microenvironment plays a critical role in sustaining the growth and survival of myeloma cells during tumor progression. Identification and functional analysis of the (adhesion) molecules involved in this interaction will provide important insights into the pathogenesis of multiple myeloma. Design and Methods Multiple myeloma cell lines and patients' samples were analyzed for expression of the adhesion molecule N-cadherin by immunoblotting, flow cytometry, immunofluorescence microscopy, immunohistochemistry and expression microarray. In addition, by means of blocking antibodies and inducible RNA interference we studied the functional consequence of N-cadherin expression for the myeloma cells, by analysis of adhesion, migration and growth, and for the bone marrow microenvironment, by analysis of osteogenic differentiation. Results The malignant plasma cells in approximately half of the multiple myeloma patients, belonging to specific genetic subgroups, aberrantly expressed the homophilic adhesion molecule N-cadherin. N-cadherin-mediated cell-substrate or homotypic cell-cell adhesion did not contribute to myeloma cell growth in vitro. However, N-cadherin directly mediated the bone marrow localization/ retention of myeloma cells in vivo, and facilitated a close interaction between myeloma cells and N-cadherin-positive osteoblasts. Furthermore, this N-cadherin-mediated interaction contributed to the ability of myeloma cells to inhibit osteoblastogenesis. Conclusions Taken together, our data show that myeloma cells frequently display aberrant expression of Ncadherin and that N-cadherin mediates the interaction of myeloma cells with the bone marrow microenvironment, in particular the osteoblasts. This N-cadherin-mediated interaction inhibits osteoblast differentiation and may play an important role in the pathogenesis of myeloma bone disease.

AB - Background Multiple myeloma is a hematologic malignancy characterized by a clonal expansion of malignant plasma cells in the bone marrow, which is accompanied by the development of osteolytic lesions and/or diffuse osteopenia. The intricate bi-directional interaction with the bone marrow microenvironment plays a critical role in sustaining the growth and survival of myeloma cells during tumor progression. Identification and functional analysis of the (adhesion) molecules involved in this interaction will provide important insights into the pathogenesis of multiple myeloma. Design and Methods Multiple myeloma cell lines and patients' samples were analyzed for expression of the adhesion molecule N-cadherin by immunoblotting, flow cytometry, immunofluorescence microscopy, immunohistochemistry and expression microarray. In addition, by means of blocking antibodies and inducible RNA interference we studied the functional consequence of N-cadherin expression for the myeloma cells, by analysis of adhesion, migration and growth, and for the bone marrow microenvironment, by analysis of osteogenic differentiation. Results The malignant plasma cells in approximately half of the multiple myeloma patients, belonging to specific genetic subgroups, aberrantly expressed the homophilic adhesion molecule N-cadherin. N-cadherin-mediated cell-substrate or homotypic cell-cell adhesion did not contribute to myeloma cell growth in vitro. However, N-cadherin directly mediated the bone marrow localization/ retention of myeloma cells in vivo, and facilitated a close interaction between myeloma cells and N-cadherin-positive osteoblasts. Furthermore, this N-cadherin-mediated interaction contributed to the ability of myeloma cells to inhibit osteoblastogenesis. Conclusions Taken together, our data show that myeloma cells frequently display aberrant expression of Ncadherin and that N-cadherin mediates the interaction of myeloma cells with the bone marrow microenvironment, in particular the osteoblasts. This N-cadherin-mediated interaction inhibits osteoblast differentiation and may play an important role in the pathogenesis of myeloma bone disease.

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