Jaw bone marrow-derived osteoclast precursors internalize more bisphosphonate than long-bone marrow precursors

Jenny A. F. Vermeer, Ineke D. C. Jansen, Matangi Marthi, Fraser P. Coxon, Charles E. McKenna, Shuting Sun, Teun J. de Vries, Vincent Everts

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Bisphosphonates (BPs) are widely used in the treatment of several bone diseases, such as osteoporosis and cancers that have metastasized to bone, by virtue of their ability to inhibit osteoclastic bone resorption. Previously, it was shown that osteoclasts present at different bone sites have different characteristics. We hypothesized that BPs could have distinct effects on different populations of osteoclasts and their precursors, for example as a result of a different capacity to endocytose the drugs. To investigate this, bone marrow cells were isolated from jaw and long bone from mice and the cells were primed to differentiate into osteoclasts with the cytokines M-CSF and RANKL. Before fusion occurred, cells were incubated with fluorescein-risedronate (FAM-RIS) for 4 or 24h and uptake was determined by flow cytometry. We found that cultures obtained from the jaw internalized 1.7 to 2.5 times more FAM-RIS than long-bone cultures, both after 4 and 24h, and accordingly jaw osteoclasts were more susceptible to inhibition of prenylation of Rap1a after treatment with BPs for 24h. Surprisingly, differences in BP uptake did not differentially affect osteoclastogenesis. This suggests that jaw osteoclast precursors are less sensitive to bisphosphonates after internalization. This was supported by the finding that gene expression of the anti-apoptotic genes Bcl-2 and Bcl-xL was higher in jaw cells than long bone cells, suggesting that the jaw cells might be more resistant to BP-induced apoptosis. Our findings suggest that bisphosphonates have distinct effects on both populations of osteoclast precursors and support previous findings that osteoclasts and precursors are bone-site specific. This study may help to provide more insights into bone-site-specific responses to bisphosphonates.

Original languageEnglish
Pages (from-to)242-251
Number of pages10
JournalBone
Volume57
Issue number1
Early online date17 Aug 2013
DOIs
Publication statusPublished - Nov 2013

Fingerprint

Diphosphonates
Osteoclasts
Jaw
Bone Marrow
Bone and Bones
Prenylation
bcl-2 Genes
Macrophage Colony-Stimulating Factor
Cell Fusion
Bone Diseases
Bone Resorption
Endocytosis
Fluorescein
Osteogenesis
Bone Marrow Cells
Population
Osteoporosis
Flow Cytometry
Apoptosis
Cytokines

Keywords

  • Osteoclast heterogeneity
  • Jaw
  • Osteonecrosis
  • Bisphosphonates
  • Endocytosis

Cite this

Vermeer, J. A. F., Jansen, I. D. C., Marthi, M., Coxon, F. P., McKenna, C. E., Sun, S., ... Everts, V. (2013). Jaw bone marrow-derived osteoclast precursors internalize more bisphosphonate than long-bone marrow precursors. Bone, 57(1), 242-251. https://doi.org/10.1016/j.bone.2013.08.007

Jaw bone marrow-derived osteoclast precursors internalize more bisphosphonate than long-bone marrow precursors. / Vermeer, Jenny A. F.; Jansen, Ineke D. C.; Marthi, Matangi; Coxon, Fraser P.; McKenna, Charles E.; Sun, Shuting; de Vries, Teun J.; Everts, Vincent.

In: Bone, Vol. 57, No. 1, 11.2013, p. 242-251.

Research output: Contribution to journalArticle

Vermeer, JAF, Jansen, IDC, Marthi, M, Coxon, FP, McKenna, CE, Sun, S, de Vries, TJ & Everts, V 2013, 'Jaw bone marrow-derived osteoclast precursors internalize more bisphosphonate than long-bone marrow precursors', Bone, vol. 57, no. 1, pp. 242-251. https://doi.org/10.1016/j.bone.2013.08.007
Vermeer, Jenny A. F. ; Jansen, Ineke D. C. ; Marthi, Matangi ; Coxon, Fraser P. ; McKenna, Charles E. ; Sun, Shuting ; de Vries, Teun J. ; Everts, Vincent. / Jaw bone marrow-derived osteoclast precursors internalize more bisphosphonate than long-bone marrow precursors. In: Bone. 2013 ; Vol. 57, No. 1. pp. 242-251.
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abstract = "Bisphosphonates (BPs) are widely used in the treatment of several bone diseases, such as osteoporosis and cancers that have metastasized to bone, by virtue of their ability to inhibit osteoclastic bone resorption. Previously, it was shown that osteoclasts present at different bone sites have different characteristics. We hypothesized that BPs could have distinct effects on different populations of osteoclasts and their precursors, for example as a result of a different capacity to endocytose the drugs. To investigate this, bone marrow cells were isolated from jaw and long bone from mice and the cells were primed to differentiate into osteoclasts with the cytokines M-CSF and RANKL. Before fusion occurred, cells were incubated with fluorescein-risedronate (FAM-RIS) for 4 or 24h and uptake was determined by flow cytometry. We found that cultures obtained from the jaw internalized 1.7 to 2.5 times more FAM-RIS than long-bone cultures, both after 4 and 24h, and accordingly jaw osteoclasts were more susceptible to inhibition of prenylation of Rap1a after treatment with BPs for 24h. Surprisingly, differences in BP uptake did not differentially affect osteoclastogenesis. This suggests that jaw osteoclast precursors are less sensitive to bisphosphonates after internalization. This was supported by the finding that gene expression of the anti-apoptotic genes Bcl-2 and Bcl-xL was higher in jaw cells than long bone cells, suggesting that the jaw cells might be more resistant to BP-induced apoptosis. Our findings suggest that bisphosphonates have distinct effects on both populations of osteoclast precursors and support previous findings that osteoclasts and precursors are bone-site specific. This study may help to provide more insights into bone-site-specific responses to bisphosphonates.",
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AU - de Vries, Teun J.

AU - Everts, Vincent

N1 - The authors would like to thank Manon Ketting, Emine Özokcu, Sophie Kroon, Lieneke Bakker, Mei-Ling Tsui, and Jolanda Hogervorst for technical assistance. For support and advice regarding flow cytometry we thank Kamran Nazmi and Dr. Anke Roelofs, and for advice regarding Western blotting we thank Dr. Behrouz Zandieh Doulabi.

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N2 - Bisphosphonates (BPs) are widely used in the treatment of several bone diseases, such as osteoporosis and cancers that have metastasized to bone, by virtue of their ability to inhibit osteoclastic bone resorption. Previously, it was shown that osteoclasts present at different bone sites have different characteristics. We hypothesized that BPs could have distinct effects on different populations of osteoclasts and their precursors, for example as a result of a different capacity to endocytose the drugs. To investigate this, bone marrow cells were isolated from jaw and long bone from mice and the cells were primed to differentiate into osteoclasts with the cytokines M-CSF and RANKL. Before fusion occurred, cells were incubated with fluorescein-risedronate (FAM-RIS) for 4 or 24h and uptake was determined by flow cytometry. We found that cultures obtained from the jaw internalized 1.7 to 2.5 times more FAM-RIS than long-bone cultures, both after 4 and 24h, and accordingly jaw osteoclasts were more susceptible to inhibition of prenylation of Rap1a after treatment with BPs for 24h. Surprisingly, differences in BP uptake did not differentially affect osteoclastogenesis. This suggests that jaw osteoclast precursors are less sensitive to bisphosphonates after internalization. This was supported by the finding that gene expression of the anti-apoptotic genes Bcl-2 and Bcl-xL was higher in jaw cells than long bone cells, suggesting that the jaw cells might be more resistant to BP-induced apoptosis. Our findings suggest that bisphosphonates have distinct effects on both populations of osteoclast precursors and support previous findings that osteoclasts and precursors are bone-site specific. This study may help to provide more insights into bone-site-specific responses to bisphosphonates.

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KW - Endocytosis

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