Sclerostin antibody inhibits skeletal deterioration due to reduced mechanical loading

Abstract

Sclerostin, a product of the SOST gene produced mainly by osteocytes, is a potent negative regulator of bone formation that appears to be responsive to mechanical loading, with SOST expression increasing following mechanical unloading. We tested the ability of a murine sclerostin antibody (SclAbII) to prevent bone loss in adult mice subjected to hindlimb unloading (HLU) via tail suspension for 21 days. Mice (n = 11–17/group) were assigned to control (CON, normal weight bearing) or HLU and injected with either SclAbII (subcutaneously, 25 mg/kg) or vehicle (VEH) twice weekly. SclAbII completely inhibited the bone deterioration due to disuse, and induced bone formation such that bone properties in HLU-SclAbII were at or above values of CON-VEH mice. For example, hindlimb bone mineral density (BMD) decreased –9.2%±1.0% in HLU-VEH, whereas it increased 4.2%±0.7%, 13.1%±1.0%, and 30.6%±3.0% in CON-VEH, HLU-SclAbII, and CON-SclAbII, respectively (p < 0.0001). Trabecular bone volume, assessed by micro–computed tomography (μCT) imaging of the distal femur, was lower in HLU-VEH versus CON-VEH (p < 0.05), and was 2- to 3-fold higher in SclAbII groups versus VEH (p < 0.001). Midshaft femoral strength, assessed by three-point bending, and distal femoral strength, assessed by micro–finite element analysis (μFEA), were significantly higher in SclAbII versus VEH-groups in both loading conditions. Serum sclerostin was higher in HLU-VEH (134±5 pg/mL) compared to CON-VEH (116±6 pg/mL, p < 0.05). Serum osteocalcin was decreased by hindlimb suspension and increased by SclAbII treatment. Interestingly, the anabolic effects of sclerostin inhibition on some bone outcomes appeared to be enhanced by normal mechanical loading. Altogether, these results confirm the ability of SclAbII to abrogate disuse-induced bone loss and demonstrate that sclerostin antibody treatment increases bone mass by increasing bone formation in both normally loaded and underloaded environments.

The Wnt Inhibitor Sclerostin Is Up-regulated by Mechanical Unloading in Osteocytes in Vitro

“…Prior studies in rodents have reported increases in SOST/ sclerostin in bone tissue (10) and in circulating sclerostin (19) during unloading. In addition, increased circulating serum sclerostin levels with a concurrent reduction of PTH levels have been reported in the context of disuse-induced bone loss in rodents (55) and humans (17).…”

“…SOST/sclerostin expression increases with mechanical unloading (10,17) and decreases with loading (10). In addition, SOST knock-out mice are resistant to disuse-induced bone loss (18), and mice treated with sclerostin antibody show an anabolic response in the hind limb unloaded model (19). Furthermore, serum sclerostin is significantly increased during prolonged (90-day) bed rest in healthy volunteers (17), in obese patients undergoing weight loss (20), and acutely in postmenopausal stroke patients (21).…”

Predicting mouse vertebra strength with micro-computed tomography-derived finite element analysis

“…This failure criterion was found to predict failure force values that were strongly correlated with experimental failure forces of cadaveric radii 18 and is commonly used in mFEA studies of mouse bone. 29,30 The FE models had between 676 000 and 989 000 elements with 901 000 to 1 253 000 nodes requiring a wall-clock time between 23 min and 48 min to solve and perform all post-processing on an HP BL870c system with two quad-core GHz Intel Itanium processors and 32 GB of RAM per blade server. To verify that the mesh density associated with 12 mm isotropic voxels did not inadvertently affect the predictive ability of the analyses, each element in FE models was divided into eight elements (6.0 Â 6.0 Â 6.0 mm 3 ), and the mFEA models were re-run with an inhomogeneous material definition (described in the next section).…”

“…24 Moreover, mFEA of excised bones is non-destructive allowing for subsequent histological analysis. Although a number of studies involving rodents have used mFEA to determine the effect of drug treatment on bone strength, [25][26][27][28][29][30] there is little evidence in the literature establishing that mFEA can accurately predict the mechanical properties of rodent bone, and especially murine bones. Of the few studies comparing FEA predictions to experimental measurements of strength in rodent tissues, long bones were tested with limited examination of material definitions.…”

Sclerostin is essential for alveolar bone loss in occlusal hypofunction

“…Sclerostin is emerging as a promising therapeutic target in bone disease therapy (43). Various animal studies demonstrated that the sclerostin antibody was effective in preventing unloading-induced osteoporosis (44,45). Thus, it can be hypothesized that anti-sclerostin treatment may be able to protect against occlusal hypofunction-induced alveolar bone loss, and its application in dental prosthetic rehabilitation may be promising.…”