Osteoprotegerin administration reduces femural bone loss in ovariectomized mice via impairment of osteoclast...

Osteoprotegerin (OPG) is a novel osteoblast-derived secreted member of the tumour necrosis factor receptor superfamily that inhibits osteoclastogenesis. We examined the effects of OPG administration on the distribution, ultrastructure and vacuolar-type H+-ATPase expression of osteoclasts and resulting trabecular bone loss in the femurs of ovariectomized (OVX) mice. Two-month-old female ddY mice were allocated to the following groups: (1) pretreatment base-line controls; (2) untreated sham-operated controls; (3) untreated OVX; and (4) OPG-administered OVX mice. Postoperatively, OPG (0.3 mg kg(-1) day(-1)) was intraperitoneally administered daily to OVX mice for 7 days. On postoperative day 7, all mice were sacrificed, and the dissected femurs were examined by means of light and immunoelectron microscopy and quantitative backscattered-electron image analysis. Backscattered-electron examination revealed that trabecular bone area/unit medullary area in untreated OVX mice was significantly lower than that of base-line control and sham-operated control mice. Compared with untreated OVX mice, OPG administration to OVX mice significantly increased trabecular bone area, which was similar to that of sham-operated control mice. Surprisingly, the number of TRAP-positive osteoclasts along the trabecular bone surfaces in OPG-administered OVX mice was not significantly decreased compared with that of sham-operated control and untreated OVX mice. Ultrastructurally, OPG administration caused disappearance of ruffled borders in most osteoclasts, but induced neither necrotic nor apoptotic changes. In addition, the expression of vacuolar-type H+-ATPase in osteoclasts was decreased by OPG administration. Our results suggest that low-dose OPG administration significantly reduces trabecular bone loss in OVX mice via impairment of the structure and bone resorbing activity of osteoclasts.