Analysis of tooth development of osteoprotegerin- deficient mice

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Osteopetrosis is an inherited disorder characterized by an increase in bone mass due to reduced bone resorption. It has been reported that the osteoclast deficiency in osteopetrotic op/op mice is due to a mutation in the coding region of the M-CSF gene. Using op/op mice, we explored roles of osteoclasts in ectopic bone formation induced by bone morphogenetic protein (BMP). Collagen sponge disks containing human recombinant BMP-2 were implanted into the dorsal muscle pouches in op/op and wild-type mice for 3 weeks. Bisphosphonate (risedronate) was injected into op/op and wild-type mice every day for 3 weeks. Bone mineral density of each ossicle was measured by single energy x-ray absorptiometry. Quantitative histomorphometric analysis was also performed. Bone mineral density of BMP-induced ectopic bone in op/op mice was about 3-fold higher than that in wild-type mice. Histological examination revealed that BMP induced higher calcified trabecular bone formation in op/op mice than in wild … More -type mice. Interestingly, the periphery of ectopic bones formed in op/op mice showed extremely rough surface, whereas that in wild-type mice showed smooth ones. Bisphosphonate treatment further enhanced ectopic bone formation in op/op mice. We previously reported that serum levels of RANKL were markedly elevated in osteoprotegerin (OPG)-deficient mice, but were unaffected by bisphosphonate administration. Unexpectedly, serum levels of RANKL in op/op mice were as high as those in OPG-deficient mice, whereas those in wild-type mice were under detectable levels in the RANKL assay. Treatment of op/op mice with bisphosphonate treatment sharply decreased the elevated levels of serum RANKL. These results suggest that BMP-induced ectopic bone formation is accurately enhanced in the absence of osteoclasts, and osteoclasts are involved in normal bone morphogenesis. Our results also suggest that bisphosphonates may be directly involved in bone formation without inhibition of osteoclastic bone resorption. Further studies will elucidate the mechanism of bisphosphonate action in BMP-induced bone formation in osteoclast-deficient mice Less