Tumor necrosis factor enhances parathyroid hormone-related protein- induced hypercalcemia and bone resorption without inhibiting: Bone formation in vivo

Harry L. Uy, Gregory R. Mundy, Brendan F. Boyce, Beryl M. Story, Colin R. Dunstan, Juan Juan Yin, G. David Roodman, Theresa Guise

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Humoral hypercaleemia of malignancy results from the effects of tumor- produced factors on bone, kidney, and intestine that disrupt normal calcium homeostasis. Although parathyroid hormone-related protein (PTHrP) is a major mediator of the syndrome, tumors also produce other hypercalcemic factors, such as tumor necrosis factor (TNF), which may modulate the effects of PTHrP. It has been postulated that TNF may counteract the stimulatory effects of PTHrP on bone formation. To examine the effects of TNF on PTHrP-induced changes in calcium and bone metabolism, a murine tumor model of hyperealcemia was used. Nude mice were inoculated with Chinese hamster ovarian (CHO) cells expressing human TNF (CHO/TNF) or nontransfected CHO cells (CHO/-) and further treated with injections of human PTHrP(1-34) or vehicle. The effects of TNF, PTHrP, and the combination of the two factors on blood ionized calcium, osteoclast recruitment, and bone histomorphometry were evaluated. Mice bearing CHO/TNF tumors that were injected with PTHrP had significantly higher calcium concentrations, increased committed osteoclast progenitors, and mature osteoclasts as well as enhanced bone resorption compared with mice bearing CHO/TNF tumors injected with vehicle or those bearing CHO/- tumors injected with PTHrP or vehicle. A 2-fold increase in new woven bone formed in the calvaria at sites of previous bone resorption was observed in CHO/TNF mice treated with PTHrP. Bone formation rates in the vertebrae were similar in both CHO/- and CHO/TNF mice treated with PTHrP. These data demonstrate that the hypercalcemic effects of PTHrP are enhanced by TNF and that this effect is due to the increased production of committed osteoclast precursors with a subsequent increase in osteoclastic bone resorption. Furthermore, PTHrP caused a coupled increase in osteoelastic bone resorption and new bone formation that was not inhibited by TNF. These findings highlight the complex interactions that may occur between tumor-produced factors on bone that result in malignancy-associated hypercalcemia and suggest that TNF may not be responsible for the decreased bone formation seen in some patients with this condition.

Original languageEnglish (US)
Pages (from-to)3194-3199
Number of pages6
JournalCancer Research
Volume57
Issue number15
StatePublished - 1997
Externally publishedYes

Fingerprint

Parathyroid Hormone-Related Protein
Hypercalcemia
Bone Resorption
Osteogenesis
Cricetulus
Tumor Necrosis Factor-alpha
Osteoclasts
Neoplasms
Bone and Bones
Calcium
Skull
Nude Mice
Intestines
Spine
Homeostasis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Tumor necrosis factor enhances parathyroid hormone-related protein- induced hypercalcemia and bone resorption without inhibiting : Bone formation in vivo. / Uy, Harry L.; Mundy, Gregory R.; Boyce, Brendan F.; Story, Beryl M.; Dunstan, Colin R.; Yin, Juan Juan; Roodman, G. David; Guise, Theresa.

In: Cancer Research, Vol. 57, No. 15, 1997, p. 3194-3199.

Research output: Contribution to journalArticle

Uy, Harry L. ; Mundy, Gregory R. ; Boyce, Brendan F. ; Story, Beryl M. ; Dunstan, Colin R. ; Yin, Juan Juan ; Roodman, G. David ; Guise, Theresa. / Tumor necrosis factor enhances parathyroid hormone-related protein- induced hypercalcemia and bone resorption without inhibiting : Bone formation in vivo. In: Cancer Research. 1997 ; Vol. 57, No. 15. pp. 3194-3199.
@article{c41669debb334c2788e4e645f33483b2,
title = "Tumor necrosis factor enhances parathyroid hormone-related protein- induced hypercalcemia and bone resorption without inhibiting: Bone formation in vivo",
abstract = "Humoral hypercaleemia of malignancy results from the effects of tumor- produced factors on bone, kidney, and intestine that disrupt normal calcium homeostasis. Although parathyroid hormone-related protein (PTHrP) is a major mediator of the syndrome, tumors also produce other hypercalcemic factors, such as tumor necrosis factor (TNF), which may modulate the effects of PTHrP. It has been postulated that TNF may counteract the stimulatory effects of PTHrP on bone formation. To examine the effects of TNF on PTHrP-induced changes in calcium and bone metabolism, a murine tumor model of hyperealcemia was used. Nude mice were inoculated with Chinese hamster ovarian (CHO) cells expressing human TNF (CHO/TNF) or nontransfected CHO cells (CHO/-) and further treated with injections of human PTHrP(1-34) or vehicle. The effects of TNF, PTHrP, and the combination of the two factors on blood ionized calcium, osteoclast recruitment, and bone histomorphometry were evaluated. Mice bearing CHO/TNF tumors that were injected with PTHrP had significantly higher calcium concentrations, increased committed osteoclast progenitors, and mature osteoclasts as well as enhanced bone resorption compared with mice bearing CHO/TNF tumors injected with vehicle or those bearing CHO/- tumors injected with PTHrP or vehicle. A 2-fold increase in new woven bone formed in the calvaria at sites of previous bone resorption was observed in CHO/TNF mice treated with PTHrP. Bone formation rates in the vertebrae were similar in both CHO/- and CHO/TNF mice treated with PTHrP. These data demonstrate that the hypercalcemic effects of PTHrP are enhanced by TNF and that this effect is due to the increased production of committed osteoclast precursors with a subsequent increase in osteoclastic bone resorption. Furthermore, PTHrP caused a coupled increase in osteoelastic bone resorption and new bone formation that was not inhibited by TNF. These findings highlight the complex interactions that may occur between tumor-produced factors on bone that result in malignancy-associated hypercalcemia and suggest that TNF may not be responsible for the decreased bone formation seen in some patients with this condition.",
author = "Uy, {Harry L.} and Mundy, {Gregory R.} and Boyce, {Brendan F.} and Story, {Beryl M.} and Dunstan, {Colin R.} and Yin, {Juan Juan} and Roodman, {G. David} and Theresa Guise",
year = "1997",
language = "English (US)",
volume = "57",
pages = "3194--3199",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "15",

}

TY - JOUR

T1 - Tumor necrosis factor enhances parathyroid hormone-related protein- induced hypercalcemia and bone resorption without inhibiting

T2 - Bone formation in vivo

AU - Uy, Harry L.

AU - Mundy, Gregory R.

AU - Boyce, Brendan F.

AU - Story, Beryl M.

AU - Dunstan, Colin R.

AU - Yin, Juan Juan

AU - Roodman, G. David

AU - Guise, Theresa

PY - 1997

Y1 - 1997

N2 - Humoral hypercaleemia of malignancy results from the effects of tumor- produced factors on bone, kidney, and intestine that disrupt normal calcium homeostasis. Although parathyroid hormone-related protein (PTHrP) is a major mediator of the syndrome, tumors also produce other hypercalcemic factors, such as tumor necrosis factor (TNF), which may modulate the effects of PTHrP. It has been postulated that TNF may counteract the stimulatory effects of PTHrP on bone formation. To examine the effects of TNF on PTHrP-induced changes in calcium and bone metabolism, a murine tumor model of hyperealcemia was used. Nude mice were inoculated with Chinese hamster ovarian (CHO) cells expressing human TNF (CHO/TNF) or nontransfected CHO cells (CHO/-) and further treated with injections of human PTHrP(1-34) or vehicle. The effects of TNF, PTHrP, and the combination of the two factors on blood ionized calcium, osteoclast recruitment, and bone histomorphometry were evaluated. Mice bearing CHO/TNF tumors that were injected with PTHrP had significantly higher calcium concentrations, increased committed osteoclast progenitors, and mature osteoclasts as well as enhanced bone resorption compared with mice bearing CHO/TNF tumors injected with vehicle or those bearing CHO/- tumors injected with PTHrP or vehicle. A 2-fold increase in new woven bone formed in the calvaria at sites of previous bone resorption was observed in CHO/TNF mice treated with PTHrP. Bone formation rates in the vertebrae were similar in both CHO/- and CHO/TNF mice treated with PTHrP. These data demonstrate that the hypercalcemic effects of PTHrP are enhanced by TNF and that this effect is due to the increased production of committed osteoclast precursors with a subsequent increase in osteoclastic bone resorption. Furthermore, PTHrP caused a coupled increase in osteoelastic bone resorption and new bone formation that was not inhibited by TNF. These findings highlight the complex interactions that may occur between tumor-produced factors on bone that result in malignancy-associated hypercalcemia and suggest that TNF may not be responsible for the decreased bone formation seen in some patients with this condition.

AB - Humoral hypercaleemia of malignancy results from the effects of tumor- produced factors on bone, kidney, and intestine that disrupt normal calcium homeostasis. Although parathyroid hormone-related protein (PTHrP) is a major mediator of the syndrome, tumors also produce other hypercalcemic factors, such as tumor necrosis factor (TNF), which may modulate the effects of PTHrP. It has been postulated that TNF may counteract the stimulatory effects of PTHrP on bone formation. To examine the effects of TNF on PTHrP-induced changes in calcium and bone metabolism, a murine tumor model of hyperealcemia was used. Nude mice were inoculated with Chinese hamster ovarian (CHO) cells expressing human TNF (CHO/TNF) or nontransfected CHO cells (CHO/-) and further treated with injections of human PTHrP(1-34) or vehicle. The effects of TNF, PTHrP, and the combination of the two factors on blood ionized calcium, osteoclast recruitment, and bone histomorphometry were evaluated. Mice bearing CHO/TNF tumors that were injected with PTHrP had significantly higher calcium concentrations, increased committed osteoclast progenitors, and mature osteoclasts as well as enhanced bone resorption compared with mice bearing CHO/TNF tumors injected with vehicle or those bearing CHO/- tumors injected with PTHrP or vehicle. A 2-fold increase in new woven bone formed in the calvaria at sites of previous bone resorption was observed in CHO/TNF mice treated with PTHrP. Bone formation rates in the vertebrae were similar in both CHO/- and CHO/TNF mice treated with PTHrP. These data demonstrate that the hypercalcemic effects of PTHrP are enhanced by TNF and that this effect is due to the increased production of committed osteoclast precursors with a subsequent increase in osteoclastic bone resorption. Furthermore, PTHrP caused a coupled increase in osteoelastic bone resorption and new bone formation that was not inhibited by TNF. These findings highlight the complex interactions that may occur between tumor-produced factors on bone that result in malignancy-associated hypercalcemia and suggest that TNF may not be responsible for the decreased bone formation seen in some patients with this condition.

UR - http://www.scopus.com/inward/record.url?scp=0030843582&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030843582&partnerID=8YFLogxK

M3 - Article

C2 - 9242449

AN - SCOPUS:0030843582

VL - 57

SP - 3194

EP - 3199

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 15

ER -