Dr. Clohisy et al., Osteoprotegerin inhibits tumor-induced osteoclastogenesis and bone tumor growth in osteopetrotic mice, J ORTHOP R, 18(6), 2000, pp. 967-976
Osteoprotegerin and osteoprotegerin ligand have recently been identified as
novel proteins that inhibit and stimulate, respectively, osteoclast format
ion. 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 osteoclastogene
sis and grow in femora of osteoclast-deficient mice (op/op). Osteoprotegeri
n treatment decreased the number of osteoclasts by 90% (p < 0.0007) at site
s of tumor in a dose-dependent manner and decreased bone tumor area by grea
ter than 90% (p < 0.003). The mechanisms through which osteoprotegerin decr
eased osteoclast formation in tumor-bearing animals included (a) an osteopr
otegerin-mediated, systemic reduction in the number of splenic and bone mar
row-residing osteoclast precursor cells, (b) a decrease in the number of os
teoclast precursor cells at sites of tumor as detected by cathepsin K and r
eceptor activator of NF kappaB mRNA expression, and (c) a decrease in osteo
protegerin ligand mRNA at sites of tumor. These findings suggest that osteo
protegerin treatment, in addition to having direct antagonistic effects on
endogenous osteoprotegerin ligand, decreases the number of osteoclast precu
rsors and reduces production of osteoprotegerin ligand at sites of osteolyt
ic tumor.