An osteoprotegerin-like peptidomimetic inhibits osteoclastic bone resorption and osteolytic bone disease in myeloma

Deborah J. Heath, Karin Vanderkerken, Xin Cheng, Orla Gallagher, Matthew Prideaux, Ramachandran Murali, Peter I. Croucher

Research output: Contribution to journalArticle

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Abstract

Multiple myeloma is a B-cell malignancy characterized by the uncontrolled growth of plasma cells in the bone marrow and the development of osteolytic bone disease. Myeloma cells express the receptor activator of nuclear factor κB ligand (RANKL), induce RANKL expression in the bone marrow, and down-regulate expression of the decoy receptor osteoprotegerin, thereby promoting bone resorption. Targeting this system in myeloma has clear therapeutic potential. However, osteoprotegerin also binds tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and prevents TRAIL-induced apoptosis of myeloma cells. Whether or not osteoprotegerin can bind TRAIL and prevent apoptosis in vivo and the relative importance of osteoprotegerin binding to TRAIL and RANKL are unclear. In the present study, we have investigated the ability of an osteoprotegerin-like peptidomimetic (OP3-4), designed to block the RANKL/RANK interaction, to inhibit osteoclastic bone resorption and TRAIL-induced apoptosis in vitro and myeloma bone disease in vivo. OP3-4 inhibited osteoclast formation (P < 0.01) and bone resorption (P < 0.01) in vitro. However, OP3-4 had no effect on TRAIL-induced apoptosis of RPMI 8226 myeloma cells. Treatment of 5T2MM myeloma-bearing mice with OP3-4 decreased osteoclast number and the proportion of bone surface covered by osteoclasts (P < 0.05). Treatment also prevented the tumor-induced decrease in cancellous bone area and the development of osteolytic lesions (P < 0.05). OP3-4 also reduced tumor burden when compared with the control (P < 0.05). These data suggest that OP3-4 and the selective inhibition of RANKL, but not TRAIL activity, are effective in preventing myeloma bone disease and offer a novel therapeutic approach to treating this aspect of myeloma.

Original languageEnglish (US)
Pages (from-to)202-208
Number of pages7
JournalCancer Research
Volume67
Issue number1
DOIs
StatePublished - Jan 1 2007
Externally publishedYes

Fingerprint

Peptidomimetics
Osteoprotegerin
Bone Diseases
Bone Resorption
Apoptosis
Osteoclasts
Bone Development
Bone Marrow
Ligands
Cytoplasmic and Nuclear Receptors
Plasma Cells
Tumor Burden
Multiple Myeloma
Neoplasms
B-Lymphocytes
Down-Regulation
Tumor Necrosis Factor-alpha
Bone and Bones
Therapeutics
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Heath, D. J., Vanderkerken, K., Cheng, X., Gallagher, O., Prideaux, M., Murali, R., & Croucher, P. I. (2007). An osteoprotegerin-like peptidomimetic inhibits osteoclastic bone resorption and osteolytic bone disease in myeloma. Cancer Research, 67(1), 202-208. https://doi.org/10.1158/0008-5472.CAN-06-1287

An osteoprotegerin-like peptidomimetic inhibits osteoclastic bone resorption and osteolytic bone disease in myeloma. / Heath, Deborah J.; Vanderkerken, Karin; Cheng, Xin; Gallagher, Orla; Prideaux, Matthew; Murali, Ramachandran; Croucher, Peter I.

In: Cancer Research, Vol. 67, No. 1, 01.01.2007, p. 202-208.

Research output: Contribution to journalArticle

Heath, DJ, Vanderkerken, K, Cheng, X, Gallagher, O, Prideaux, M, Murali, R & Croucher, PI 2007, 'An osteoprotegerin-like peptidomimetic inhibits osteoclastic bone resorption and osteolytic bone disease in myeloma', Cancer Research, vol. 67, no. 1, pp. 202-208. https://doi.org/10.1158/0008-5472.CAN-06-1287
Heath, Deborah J. ; Vanderkerken, Karin ; Cheng, Xin ; Gallagher, Orla ; Prideaux, Matthew ; Murali, Ramachandran ; Croucher, Peter I. / An osteoprotegerin-like peptidomimetic inhibits osteoclastic bone resorption and osteolytic bone disease in myeloma. In: Cancer Research. 2007 ; Vol. 67, No. 1. pp. 202-208.
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