Sclerostin-neutralizing Antibody Research Articles

Sclerostin is the product of the SOST gene. Loss-of-function mutations in the SOST gene result in a high-bone-mass phenotype, demonstrating that sclerostin is a negative regulator of bone mass. Primarily expressed by osteocytes in bone, sclerostin is reported to bind the LRP5/6 receptor, thereby antagonizing canonical Wnt signaling and negatively regulating bone formation. We therefore investigated whether systemic administration of a sclerostin-neutralizing antibody would increase the regeneration of traumatized metaphyseal bone in rats. Young male rats had a screw inserted in the proximal tibia and were divided into six groups given 25 mg/kg of sclerostin antibody or control twice a week subcutaneously for 2 or 4 weeks. In four groups, the screws were tested for pull-out strength. At the time of euthanasia, a similar screw also was inserted in the contralateral tibia and pull-out tested immediately. Sclerostin antibody significantly increased the pull-out force by almost 50% compared with controls after 2 and 4 weeks. Also, the screws inserted at the time of euthanasia showed increased pull-out force. Micro-computed tomography (µCT) of the remaining two groups showed that the antibody led to a 30% increase in bone volume fraction in a region surrounding the screw. There also was a general increase in trabecular thickness in cancellous bone. Thus, as measured by the amount of bone and its mechanical resistance, the sclerostin antibody increased bone formation during metaphyseal repair but also in untraumatized bone.

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