Lack of noggin expression by cancer cells is a determinant of the osteoblast response in bone metastases

Am J Pathol. 2007 Jan;170(1):160-75. doi: 10.2353/ajpath.2007.051276.


Prostate and mammary cancer bone metastases can be osteoblastic or osteolytic, but the mechanisms determining these features are unclear. Bone morphogenetic and Wnt proteins are osteoinductive molecules. Their activity is modulated by antagonists such as noggin and dickkopf-1. Differential expression analysis of bone morphogenetic and Wnt protein antagonists in human prostate and mammary cancer cell lines showed that osteolytic cell lines constitutively express in vitro noggin and dickkopf-1 and at least one of the osteolytic cytokines parathyroid hormone-related protein, colony-stimulating factor-1, and interleukin-8. In contrast, osteoinductive cell lines express neither noggin nor dickkopf-1 nor osteolytic cytokines in vitro. The noggin differential expression profile observed in vitro was confirmed in vivo in prostate cancer cell lines xenografted into bone and in clinical samples of bone metastasis. Forced noggin expression in an osteoinductive prostate cancer cell line abolished the osteoblast response induced in vivo by its intraosseous xenografts. Basal bone resorption and tumor growth kinetics were marginally affected. Lack of noggin and possibly dickkopf-1 expression by cancer cells may be a relevant mechanism contributing to the osteoblast response in bone metastases. Concomitant lack of osteolytic cytokines may be permissive of this effect. Noggin is a candidate drug for the adjuvant therapy of bone metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / antagonists & inhibitors
  • Bone Neoplasms* / metabolism
  • Bone Neoplasms* / secondary
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carrier Proteins / biosynthesis*
  • Carrier Proteins / genetics
  • Cell Differentiation / genetics
  • Cell Proliferation
  • Cytokines / biosynthesis
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Intercellular Signaling Peptides and Proteins / biosynthesis
  • Intercellular Signaling Peptides and Proteins / genetics
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Neoplasm Transplantation
  • Osteoblasts* / metabolism
  • Osteoblasts* / pathology
  • Osteoclasts / metabolism
  • Osteoclasts / pathology
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology


  • Bone Morphogenetic Proteins
  • Carrier Proteins
  • Cytokines
  • DKK1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • noggin protein