Abstract
Osteoprotegerin and osteoprotegerin ligand have recently been identified as novel proteins that inhibit and stimulate, respectively, osteoclast formation. We examined the possibility that osteoprotegerin would inhibit cancer-induced osteoclastogenesis and cancer growth in bone. An experimental model was used in which osteolytic tumors are known to stimulate osteoclastogenesis and grow in femora of osteoclast-deficient mice (op/op). Osteoprotegerin treatment decreased the number of osteoclasts by 90% (p < 0.0007) at sites of tumor in a dose-dependent manner and decreased bone tumor area by greater than 90% (p < 0.003). The mechanisms through which osteoprotegerin decreased osteoclast formation in tumor-bearing animals included (a) an osteoprotegerin-mediated, systemic reduction in the number of splenic and bone marrow-residing osteoclast precursor cells, (b) a decrease in the number of osteoclast precursor cells at sites of tumor as detected by cathepsin K and receptor activator of NFkappaB mRNA expression, and (c) a decrease in osteoprotegerin ligand mRNA at sites of tumor. These findings suggest that osteoprotegerin treatment, in addition to having direct antagonistic effects on endogenous osteoprotegerin ligand, decreases the number of osteoclast precursors and reduces production of osteoprotegerin ligand at sites of osteolytic tumor.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Bone Neoplasms / complications
-
Bone Neoplasms / drug therapy*
-
Bone Neoplasms / physiopathology
-
Carrier Proteins / genetics
-
Disease Models, Animal
-
Dose-Response Relationship, Drug
-
Femur / drug effects
-
Femur / pathology
-
Femur / surgery
-
Gene Expression Regulation, Neoplastic / drug effects
-
Gene Expression Regulation, Neoplastic / physiology
-
Glycoproteins / pharmacology*
-
Macrophage Colony-Stimulating Factor / genetics
-
Membrane Glycoproteins / genetics
-
Mice
-
Mice, Inbred Strains
-
Osteoclasts / cytology
-
Osteoclasts / drug effects*
-
Osteoclasts / metabolism
-
Osteolysis / drug therapy*
-
Osteolysis / etiology
-
Osteolysis / physiopathology
-
Osteopetrosis / pathology
-
Osteopetrosis / physiopathology
-
Osteoprotegerin
-
Parathyroid Hormone-Related Protein
-
Proteins / genetics
-
RANK Ligand
-
RNA, Messenger / drug effects
-
RNA, Messenger / metabolism
-
Receptor Activator of Nuclear Factor-kappa B
-
Receptors, Cytoplasmic and Nuclear
-
Receptors, Tumor Necrosis Factor
-
Stem Cells / cytology
-
Stem Cells / drug effects
-
Stem Cells / metabolism
-
Stromal Cells / cytology
-
Stromal Cells / drug effects
-
Stromal Cells / metabolism
-
Tumor Cells, Cultured / drug effects
-
Tumor Cells, Cultured / pathology
-
Tumor Cells, Cultured / transplantation
Substances
-
Carrier Proteins
-
Glycoproteins
-
Membrane Glycoproteins
-
Osteoprotegerin
-
Parathyroid Hormone-Related Protein
-
Proteins
-
RANK Ligand
-
RNA, Messenger
-
Receptor Activator of Nuclear Factor-kappa B
-
Receptors, Cytoplasmic and Nuclear
-
Receptors, Tumor Necrosis Factor
-
Tnfrsf11a protein, mouse
-
Tnfrsf11b protein, mouse
-
Tnfsf11 protein, mouse
-
Macrophage Colony-Stimulating Factor