Sclerostin Antibody Treatment Stimulates Bone Formation to Normalize Bone Mass in Male Down Syndrome Mice

Abstract

Down syndrome (DS), characterized by trisomy of human chromosome 21, is associated with a variety of endocrine disorders as well as profound skeletal abnormalities. The low bone mass phenotype in DS is defined by low bone turnover due to decreased osteoclast and osteoblast activity, decreasing the utility of antiresorptive agents in people with DS. Sclerostin antibody (SclAb) is a therapeutic candidate currently being evaluated as a bone anabolic agent. Scl, the product of the sclerostin gene (SOST), inhibits bone formation through its inhibition of Wnt signaling. SclAb increases bone mass by suppressing the action of the endogenous inhibitor of bone formation, Scl. To examine the effects of SclAb on the DS bone phenotype, 8‐week‐old male wild‐type (WT) andTs65Dn DS mice were treated with 4 weekly iv injections of 100 mg/kg SclAb. Dual‐energy X‐ray absorptiometry (DXA), microCT, and dynamic histomorphometry analyses revealed that SclAb had a significant anabolic effect on both age‐matched WT littermate controls and Ts65Dn DS mice that was osteoblast mediated, without significant changes in osteoclast parameters. SclAb treatment significantly increased both cortical and trabecular bone mass at multiple sites; SclAb treatment resulted in the normalization of Ts65Dn bone mineral density (BMD) to WT levels in the proximal tibia, distal femur, and whole body. Ex vivo bone marrow cultures demonstrated that SclAb increased the recruitment of the mesenchymal progenitors into the osteoblast lineage, as indicated by increased alkaline phosphatase–positive colonies, with no effect on osteoclast differentiation. Together, in the setting of a murine model of DS and decreased bone turnover, SclAb had a potent anabolic effect. SclAb stimulated bone formation and increased osteoblastogenesis without affecting osteoclastogenesis or bone resorption. These data suggest that SclAb is a promising new therapy to improve bone mass and reduce fracture risk in the face of the low bone mass and turnover prevalent in the DS population. © 2017 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Sclerostin depletion induces inflammation in the bone marrow of mice

“…To test if acute depletion of SOST changed hematopoiesis, we performed studies in which SOST was depleted using sclerostinspecific antibodies (Scl-Ab), administered subcutaneously in 8-week-old mice in multiple doses for 6 weeks ( Figure 1A). Scl-Ab treatment resulted in increased trabecular volume BV/TV and midshaft cortical thickness, similar to that observed in the Sost -/mice ( Figure 1B, 1C and 1D) (41,42). However, the BM total cellularity was unchanged (data not shown).…”

Sclerostin Depletion Induces Inflammation in the Bone Marrow of Mice

“…To test if acute depletion of SOST changed hematopoiesis, we performed studies in which SOST was depleted using sclerostin-specific antibodies (Scl-Ab), administered subcutaneously in 8-week-old mice in multiple doses for 6 weeks (Figure 1A). Scl-Ab treatment resulted in increased trabecular volume/total volume (BV/TV) and midshaft cortical thickness, similar to that observed in the Sost −/− mice (Figure 1B-D) [34,39]. However, the BM total cellularity was unchanged (data not shown).…”

Reduction of SOST gene promotes bone formation through the Wnt/β‐catenin signalling pathway and compensates particle‐induced osteolysis

“…Previous studies have shown that sclerostin antibodies can be used to treat osteoporosis and skeletal abnormalities, increasing bone formation, bone mass and bone strength . Additionally, sclerostin antibodies have been reported to promote fracture callus formation and increase the stability of internal fixation .…”