A chimeric form of osteoprotegerin inhibits hypercalcemia and bone resorption induced by IL-1beta, TNF-alpha, PTH, PTHrP, and 1, 25(OH)2D3.
Osteoprotegerin (OPG) is a secreted protein that inhibits osteoclast formation and activity and appears to be a critical regulator of bone mass and metabolism. In the current study, mice were challenged with various cytokines and hormones (interleukin-1beta, tumor necrosis factor-alpha, parathyroid hormone, parathyroid hormone-related protein, and 1alpha,25-dihydroxyvitamin D3) that are known to increase bone resorption and cause hypercalcemia and treated concurrently with either a recombinant chimeric Fc fusion form of human OPG, with enhanced biological activity (cOPG) (2.5 mg/kg/day) or vehicle. Mice receiving these bone-resorbing factors became hypercalcemic by day 3 after commencing treatment and had increased bone resorption as evidenced by elevated osteoclast numbers on day 5. Concurrent cOPG treatment prevented hypercalcemia (p < 0.05) and maintained osteoclast numbers in the normal range (p < 0.001). The demonstration that cOPG can inhibit bone resorption suggests that this molecule may be useful in the treatment of diseases including hyperparathyroidism, humoral hypercalcemia of malignancy, osteoporosis, and inflammatory bone disease, which are characterized, in part, by increases in osteoclastic bone resorption.
Morony
S
S
Department of Pathology, Amgen, Thousand Oaks, California 91320-1789, USA.
Capparelli
C
C
Lee
R
R
Shimamoto
G
G
Boone
T
T
Lacey
D L
DL
Dunstan
C R
CR
D000818:Animals; D001862:Bone Resorption; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects; D002117:Calcitriol / Q000494:pharmacology*; D002118:Calcium / Q000097:blood; D002452:Cell Count / Q000187:drug effects; D006023:Glycoproteins / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006934:Hypercalcemia / Q000517:prevention & control*; D007375:Interleukin-1 / Q000494:pharmacology*; D007536:Isomerism; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects; D053244:Osteoprotegerin; D010281:Parathyroid Hormone / Q000097:blood / Q000494:pharmacology*; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins / Q000494:pharmacology*; D011859:Radiography; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015431:Weight Loss / Q000187:drug effects
D006023:Glycoproteins; D007375:Interleukin-1; D053244:Osteoprotegerin; C470121:PTHLH protein, human; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse; D014409:Tumor Necrosis Factor-alpha; D002117:Calcitriol; D002118:Calcium