Lung tumor cells inhibit bone mineralization and osteoblast activity

Taylor E. Berent, Jessica M. Dorschner, Theodore A. Craig, Matthew M Drake, Jennifer J Westendorf, Rajiv Kumar

Research output: Contribution to journalArticle

Abstract

Patients with non-small cell lung cancer (NSLC) often develop skeletal complications and fractures. To understand mechanisms of bone loss, we developed a murine model of non-metastatic NSLC. Decreased bone mineral density, trabecular thickness and mineralization, without an increase in bone resorption, were observed in vivo in mice injected with Lewis lung adenocarcinoma (LLC1) cells in the absence of tumor cell metastases. A decrease in trabecular bone mineral density was observed in mice injected with cell-free LLC1 CM. Plasma osteoblast biomarkers and PTH-related peptide (PTHrP) were reduced, and parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, calcium and phosphate concentrations were normal in tumor-bearing mice. LLC1 cell conditioned medium (CM) inhibited alkaline phosphatase activity, osteoblast mineralization, and expression of Alpl and Ocn/Bglap mRNA in MC3T3 osteoblast cultures, whereas non-CM or CM from NIH/3T3 fibroblasts did not induce similar changes. LLC1 CM reduced Wnt3a-stimulated Tcf/Lef reporter plasmid activity and Wnt5A, Tcf1 and Lef1 mRNA expression in MC3T3 cells. Although concentrations of the Wnt inhibitor, DKK2, were increased in LLC1 CM compared to non-CM, depletion of DKK2 from LLC1 CM did not completely restore Wnt3a activity in MC3T3 cultures, and recombinant DKK2 failed to inhibit osteoblast mineralization. The data indicate that in a model of lung adenocarcinoma without bone metastases, tumor cells elaborate a secreted factor(s) that reduces bone mass, bone formation and osteoblast Wnt signaling without increases in bone resorption or calcium-regulating hormone concentrations. The factor(s) mediating this inhibition of osteoblast mineralization require further characterization.

Original languageEnglish (US)
JournalBiochemical and Biophysical Research Communications
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Physiologic Calcification
Osteoblasts
Conditioned Culture Medium
Tumors
Bone
Cells
Lung
Neoplasms
Bone Resorption
Bone and Bones
Non-Small Cell Lung Carcinoma
Bone Density
Cell culture
Neoplasm Metastasis
Minerals
Parathyroid Hormone-Related Protein
Messenger RNA
Bearings (structural)
Parathyroid Hormone
Osteogenesis

Keywords

  • Bone loss
  • Cancer
  • LLC1
  • NSLC
  • Wnt-signaling

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Lung tumor cells inhibit bone mineralization and osteoblast activity. / Berent, Taylor E.; Dorschner, Jessica M.; Craig, Theodore A.; Drake, Matthew M; Westendorf, Jennifer J; Kumar, Rajiv.

In: Biochemical and Biophysical Research Communications, 01.01.2019.

Research output: Contribution to journalArticle

@article{a6c78652ff0c47eebd8965a19da5dca1,
title = "Lung tumor cells inhibit bone mineralization and osteoblast activity",
abstract = "Patients with non-small cell lung cancer (NSLC) often develop skeletal complications and fractures. To understand mechanisms of bone loss, we developed a murine model of non-metastatic NSLC. Decreased bone mineral density, trabecular thickness and mineralization, without an increase in bone resorption, were observed in vivo in mice injected with Lewis lung adenocarcinoma (LLC1) cells in the absence of tumor cell metastases. A decrease in trabecular bone mineral density was observed in mice injected with cell-free LLC1 CM. Plasma osteoblast biomarkers and PTH-related peptide (PTHrP) were reduced, and parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, calcium and phosphate concentrations were normal in tumor-bearing mice. LLC1 cell conditioned medium (CM) inhibited alkaline phosphatase activity, osteoblast mineralization, and expression of Alpl and Ocn/Bglap mRNA in MC3T3 osteoblast cultures, whereas non-CM or CM from NIH/3T3 fibroblasts did not induce similar changes. LLC1 CM reduced Wnt3a-stimulated Tcf/Lef reporter plasmid activity and Wnt5A, Tcf1 and Lef1 mRNA expression in MC3T3 cells. Although concentrations of the Wnt inhibitor, DKK2, were increased in LLC1 CM compared to non-CM, depletion of DKK2 from LLC1 CM did not completely restore Wnt3a activity in MC3T3 cultures, and recombinant DKK2 failed to inhibit osteoblast mineralization. The data indicate that in a model of lung adenocarcinoma without bone metastases, tumor cells elaborate a secreted factor(s) that reduces bone mass, bone formation and osteoblast Wnt signaling without increases in bone resorption or calcium-regulating hormone concentrations. The factor(s) mediating this inhibition of osteoblast mineralization require further characterization.",
keywords = "Bone loss, Cancer, LLC1, NSLC, Wnt-signaling",
author = "Berent, {Taylor E.} and Dorschner, {Jessica M.} and Craig, {Theodore A.} and Drake, {Matthew M} and Westendorf, {Jennifer J} and Rajiv Kumar",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.bbrc.2019.09.045",
language = "English (US)",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Lung tumor cells inhibit bone mineralization and osteoblast activity

AU - Berent, Taylor E.

AU - Dorschner, Jessica M.

AU - Craig, Theodore A.

AU - Drake, Matthew M

AU - Westendorf, Jennifer J

AU - Kumar, Rajiv

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Patients with non-small cell lung cancer (NSLC) often develop skeletal complications and fractures. To understand mechanisms of bone loss, we developed a murine model of non-metastatic NSLC. Decreased bone mineral density, trabecular thickness and mineralization, without an increase in bone resorption, were observed in vivo in mice injected with Lewis lung adenocarcinoma (LLC1) cells in the absence of tumor cell metastases. A decrease in trabecular bone mineral density was observed in mice injected with cell-free LLC1 CM. Plasma osteoblast biomarkers and PTH-related peptide (PTHrP) were reduced, and parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, calcium and phosphate concentrations were normal in tumor-bearing mice. LLC1 cell conditioned medium (CM) inhibited alkaline phosphatase activity, osteoblast mineralization, and expression of Alpl and Ocn/Bglap mRNA in MC3T3 osteoblast cultures, whereas non-CM or CM from NIH/3T3 fibroblasts did not induce similar changes. LLC1 CM reduced Wnt3a-stimulated Tcf/Lef reporter plasmid activity and Wnt5A, Tcf1 and Lef1 mRNA expression in MC3T3 cells. Although concentrations of the Wnt inhibitor, DKK2, were increased in LLC1 CM compared to non-CM, depletion of DKK2 from LLC1 CM did not completely restore Wnt3a activity in MC3T3 cultures, and recombinant DKK2 failed to inhibit osteoblast mineralization. The data indicate that in a model of lung adenocarcinoma without bone metastases, tumor cells elaborate a secreted factor(s) that reduces bone mass, bone formation and osteoblast Wnt signaling without increases in bone resorption or calcium-regulating hormone concentrations. The factor(s) mediating this inhibition of osteoblast mineralization require further characterization.

AB - Patients with non-small cell lung cancer (NSLC) often develop skeletal complications and fractures. To understand mechanisms of bone loss, we developed a murine model of non-metastatic NSLC. Decreased bone mineral density, trabecular thickness and mineralization, without an increase in bone resorption, were observed in vivo in mice injected with Lewis lung adenocarcinoma (LLC1) cells in the absence of tumor cell metastases. A decrease in trabecular bone mineral density was observed in mice injected with cell-free LLC1 CM. Plasma osteoblast biomarkers and PTH-related peptide (PTHrP) were reduced, and parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, calcium and phosphate concentrations were normal in tumor-bearing mice. LLC1 cell conditioned medium (CM) inhibited alkaline phosphatase activity, osteoblast mineralization, and expression of Alpl and Ocn/Bglap mRNA in MC3T3 osteoblast cultures, whereas non-CM or CM from NIH/3T3 fibroblasts did not induce similar changes. LLC1 CM reduced Wnt3a-stimulated Tcf/Lef reporter plasmid activity and Wnt5A, Tcf1 and Lef1 mRNA expression in MC3T3 cells. Although concentrations of the Wnt inhibitor, DKK2, were increased in LLC1 CM compared to non-CM, depletion of DKK2 from LLC1 CM did not completely restore Wnt3a activity in MC3T3 cultures, and recombinant DKK2 failed to inhibit osteoblast mineralization. The data indicate that in a model of lung adenocarcinoma without bone metastases, tumor cells elaborate a secreted factor(s) that reduces bone mass, bone formation and osteoblast Wnt signaling without increases in bone resorption or calcium-regulating hormone concentrations. The factor(s) mediating this inhibition of osteoblast mineralization require further characterization.

KW - Bone loss

KW - Cancer

KW - LLC1

KW - NSLC

KW - Wnt-signaling

UR - http://www.scopus.com/inward/record.url?scp=85072177765&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072177765&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2019.09.045

DO - 10.1016/j.bbrc.2019.09.045

M3 - Article

C2 - 31537378

AN - SCOPUS:85072177765

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

ER -