Soluble RANKL Induces High Bone Turnover and Decreases Bone Volume, Density, and Strength in Mice
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Receptor activator for nuclear factor-κ B ligand (RANKL) is an essential mediator of osteoclastogenesis. We hypothesized that administration of soluble RANKL to mice would result in high turnover and deleterious effects on both cortical and trabecular bone. For 10 days, 10-week-old C57BL/6J female mice (n = 12/group) were given twice-daily subcutaneous injections of human recombinant RANKL (0.4 or 2 mg/kg/day) or inert vehicle (VEH). Bone turnover was greatly accelerated by RANKL, as evidenced by the 49–84% greater levels of serum TRAP-5b (bone resorption marker) and 300–400% greater levels of serum alkaline phosphatase (bone formation marker). RANKL resulted in significantly greater endocortical bone erosion surface (79–83%) and periosteal bone formation rate (64–87%) vs. VEH. Microcomputed tomographic (microCT) analysis of the proximal tibia indicated a reduction in trabecular volume fraction (–84%) for both doses of RANKL. Cortical bone geometry and strength were also negatively influenced by RANKL. MicroCT analysis of the femoral diaphysis indicated significantly lower cortical bone volume (−10% to –13%) and greater cortical porosity (8–9%) relative to VEH. Biomechanical testing of the femur diaphysis revealed significantly lower maximum bending load (−19% to –25%) vs. VEH. Bone strength remained correlated with bone mass, independent of RANKL stimulation of bone turnover. These findings are consistent with the hypothesis that soluble RANKL could be an important etiologic factor in pathologic bone loss. RANKL also has potential utility as a model for studying the consequences of high bone turnover on bone quality and strength in animals.
KeywordsRANKL Bone strength Turnover Microcomputed tomography Osteoporosis
This work was supported by the National Space Biomedical Research Institute through NASA NCC 9–58, Amgen, Inc., and BioServe Space Technologies (through NASA NCC8–242). The editorial and formatting assistance of Jenny Bourne is greatly appreciated. Thanks also to Steven Adamu (Amgen, Inc.) for assistance in measuring biochemical markers and Michael Lemus for help with microCT analysis.
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