Targeted Deletion of the Sclerostin Gene in Mice Results in Increased Bone Formation and Bone Strength

Abstract

ABSTRACT:Introduction: Sclerosteosis is a rare high bone mass genetic disorder in humans caused by inactivating mutations in SOST, the gene encoding sclerostin. Based on these data, sclerostin has emerged as a key negative regulator of bone mass. We generated SOST knockout (KO) mice to gain a more detailed understanding of the effects of sclerostin deficiency on bone. Materials and Methods: Gene targeting was used to inactivate SOST and generate a line of SOST KO mice. Radiography, densitometry, CT, histomorphometry, and mechanical testing were used to characterize the impact of sclerostin deficiency on bone in male and female mice. Comparisons were made between same sex KO and wildtype (WT) mice. Results:The results for male and female SOST KO mice were similar, with differences only in the magnitude of some effects. SOST KO mice had increased radiodensity throughout the skeleton, with general skeletal morphology being normal in appearance. DXA analysis of lumbar vertebrae and whole leg showed that there was a significant increase in BMD (>50%) at both sites. CT analysis of femur showed that bone volume was significantly increased in both the trabecular and cortical compartments. Histomorphometry of trabecular bone revealed a significant increase in osteoblast surface and no significant change in osteoclast surface in SOST KO mice. The bone formation rate in SOST KO mice was significantly increased for trabecular bone (>9-fold) at the distal femur, as well as for the endocortical and periosteal surfaces of the femur midshaft. Mechanical testing of lumbar vertebrae and femur showed that bone strength was significantly increased at both sites in SOST KO mice. Conclusions: SOST KO mice have a high bone mass phenotype characterized by marked increases in BMD, bone volume, bone formation, and bone strength. These results show that sclerostin is a key negative regulator of a powerful, evolutionarily conserved bone formation pathway that acts on both trabecular and cortical bone.

Sclerostin: A gem from the genome leads to bone-building antibodies

“…(73,74) Despite the clear increase in osteoblast-mediated bone formation found in this OVX rat study, osteoclast surface was decreased, pointing toward an absence of the coupling that typically exists between osteoblasts and osteoclasts during bone remodeling. This apparent lack of coupling was also reported for SOST knockout mice (18) and is consistent with the very limited (one patient) histomorphometric data available for sclerosteosis. (75) Currently, it is unclear whether the reduction in osteoclast surface resulting from antibody-mediated sclerostin inhibition is from a direct impact on osteoclasts or secondary to the marked increase in bone-forming surface.…”

“…(18) Analysis of bones from these mice revealed that bone formation was markedly increased on each of the key skeletal surfaces where new bone is normally formed (surface of trabecular bone and internal and external surfaces of cortical bone). Consistent with the increases in bone formation and bone mass, robust increases in bone strength also were found in these animals.…”

Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones

“…(15,16) Sclerostin knockout mice have greater bone mass and bone strength owing to increased bone formation. (17) Although the mechanism by which sclerostin negatively regulates bone formation is an area of continuing investigation, one body of research supports the hypothesis that sclerostin binds to LRP5/6 to inhibit Wnt/bcatenin signaling, (18) thus impairing osteoblast differentiation and function. Sclerostin antibodies (Scl-Abs) have been shown to neutralize the inhibitory effects of sclerostin on Wnt/b-catenin signaling in vitro (19,20) and to have significant bone anabolic activity in various species in vivo.…”

Does Sclerostin Depletion Stimulate Fracture Healing in a Mouse Model?

“…Sclerosteosis is a rare, autosomal-recessive disease causing high bone mass in affected humans; thickened bone and a hyperostotic bony skeleton characterize these patients, which is caused by a mutation in the sclerostin gene (SOST), leading to sclerostin depletion [2,28]. This finding has led researchers to study the effect of sclerostin depletion on the osteogenic process in animal and human models [15,16,22]. In the genetically altered mouse model in which sclerostin was completely knocked out, it was found that their bones have greater mass and strength owing to increased bone formation [15].…”

“…This finding has led researchers to study the effect of sclerostin depletion on the osteogenic process in animal and human models [15,16,22]. In the genetically altered mouse model in which sclerostin was completely knocked out, it was found that their bones have greater mass and strength owing to increased bone formation [15]. These studies guided researchers to deplete sclerostin through administration of sclerostin antibodies.…”