Osteoprotegerin prevents and reverses hypercalcemia in a murine model of humoral hypercalcemia of malignancy.
Osteoprotegerin (OPG), a novel, secreted tumor necrosis factor receptor family member that inhibits osteoclast formation and activity was examined for its activity in a syngeneic tumor model of humoral hypercalcemia of malignancy. Normal mice bearing Colon-26 tumors develop increases in both parathyroid hormone-related protein (PTHrP) expression and plasma PTHrP, marked hypercalcemia, and increased bone resorption. OPG, given either at the onset of hypercalcemia or after it had occurred, blocked tumor-induced increases in bone resorption and hypercalcemia and rapidly normalized blood ionized calcium. In tumor-bearing mice, OPG treatments reduced osteoclast activity from approximately 2-fold above normal into the subphysiological range but had no effects on tumor size, tumor-induced cachexia, or PTHrP levels. The potent effects of OPG in this humoral hypercalcemia of malignancy model suggest a potential therapeutic role for OPG in the prevention and treatment of this disorder.
Capparelli
C
C
Department of Pathology, Amgen Inc., Thousand Oaks, California 91320-1789, USA.
Kostenuik
P J
PJ
Morony
S
S
Starnes
C
C
Weimann
B
B
Van
G
G
Scully
S
S
Qi
M
M
Lacey
D L
DL
Dunstan
C R
CR
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006023:Glycoproteins / Q000627:therapeutic use*; D006934:Hypercalcemia / Q000188:drug therapy / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects; D053244:Osteoprotegerin; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*
D006023:Glycoproteins; D053244:Osteoprotegerin; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506031:Tnfrsf11b protein, mouse