EGF-like ligands stimulate osteoclastogenesis by regulating expression of osteoclast regulatory factors by osteoblasts: Implications for osteolytic bone metastases

Ji Zhu, Xun Jia, Guozhi Xiao, Yibin Kang, Nicola Partridge, Ling Qin

Research output: Contribution to journalArticle

Abstract

Epidermal growth factor (EGF)-like ligands and their receptors constitute one of the most important signaling networks functioning in normal tissue development and cancer biology. Recent in vivo mouse models suggest this signaling network plays an essential role in bone metabolism. Using a coculture system containing bone marrow macrophage and osteoblastic cells, here we report that EGF-like ligands stimulate osteoclastogenesis by acting on osteoblastic cells. This stimulation is not a direct effect because osteoclasts do not express functional EGF receptors (EGFRs). Further studies reveal that EGF-like ligands strongly regulate the expression of two secreted osteoclast regulatory factors in osteoblasts by decreasing osteoprotegerin (OPG) expression and increasing monocyte chemoattractant protein 1 (MCP1) expression in an EGFR-dependent manner and consequently stimulate TRAP-positive osteoclast formation. Addition of exogenous OPG completely inhibited osteoclast formation stimulated by EGF-like ligands, while addition of a neutralizing antibody against MCP-1 exhibited partial inhibition. Coculture with bone metastatic breast cancer MDA-MB-231 cells had similar effects on the expression of OPG and MCP1 in the osteoblastic cells, and those effects could be partially abolished by the EGFR inhibitor PD153035. Because a high percentage of human carcinomas express EGF-like ligands, our findings suggest a novel mechanism for osteolytic lesions caused by cancer cells metastasizing to bone.

Original languageEnglish (US)
Pages (from-to)26656-26664
Number of pages9
JournalJournal of Biological Chemistry
Volume282
Issue number37
DOIs
StatePublished - Sep 14 2007

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Osteoblasts
Osteoclasts
Epidermal Growth Factor
Osteogenesis
Bone
Osteoprotegerin
Neoplasm Metastasis
Ligands
Bone and Bones
Chemokine CCL2
Coculture Techniques
Macrophages
Neutralizing Antibodies
Metabolism
Neoplasms
Bone Marrow
Cells
Tissue
Breast Neoplasms
Carcinoma

ASJC Scopus subject areas

  • Biochemistry

Cite this

EGF-like ligands stimulate osteoclastogenesis by regulating expression of osteoclast regulatory factors by osteoblasts : Implications for osteolytic bone metastases. / Zhu, Ji; Jia, Xun; Xiao, Guozhi; Kang, Yibin; Partridge, Nicola; Qin, Ling.

In: Journal of Biological Chemistry, Vol. 282, No. 37, 14.09.2007, p. 26656-26664.

Research output: Contribution to journalArticle

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