Canine Prostate Stimulates Osteoblast Function Using the Endothelin Receptors

Bruce E. LeRoy, Rani S. Sellers, Thomas J. Rosol

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


BACKGROUND. Bone metastases are common in humans and dogs with late-stage prostate cancer. A unique feature of prostate cancer metastases is new bone formation at metastatic sites ("osteoblastic metastases"). Many carcinomas that metastasize to bone cause bone destruction, not new bone formation. The mechanisms by which prostate cancer induces bone formation at sites of bone metastasis are not well understood. We hypothesized that stimulation of osteoblasts by prostate tissue at metastatic sites was due to the paracrine actions of growth factors produced by prostate epithelial cells. METHODS. We have previously shown that normal canine prostate tissue induced new bone formation when implanted adjacent to the calvarium of nude mice. To complement this in vivo model, we developed an in vitro system of prostate-stimulated osteoblast function to investigate mechanisms of prostate-induced new bone formation. RESULTS. We found that treatment of cultured rat calvaria for 24 hr with proteins from normal dog prostate stimulated alkaline phosphatase activity in a dose-dependent manner 4-6 fold compared to controls. Stimulation began approximately 8 hr after treatment, and was diminished after 72 hr. Calvaria treated with homogenates of normal dog salivary gland, kidney, bladder, and muscle did not increase ALP activity. Pretreatment of the calvaria for 1 hr with endothelin antagonists, but not anti-parathyroid hormone-related protein (PTHrP) antibody or indomethacin, abrogated the stimulation of ALP. CONCLUSIONS. Our results indicated that osteoblast activation by canine prostate occurs via an endothelin-dependent mechanism, and that PTHrP or prostaglandin synthase-mediated pathways are likely not involved. This is a reliable, reproducible assay for determining the roles of molecules important in the activation of osteoblasts by the prostate.

Original languageEnglish (US)
Pages (from-to)148-156
Number of pages9
Issue number2
StatePublished - May 1 2004
Externally publishedYes


  • Alkaline phosphatase
  • Calvarium
  • Dog
  • Endothelin receptor antagonist
  • Osteoblast
  • Prostate

ASJC Scopus subject areas

  • Oncology
  • Urology


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