title: 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.
authors.affiliation: Harvard-Massachusetts Institute of Technology (MIT) Division of Health Sciences and Technology (HST), Bioastronautics Program, Cambridge, MA, USA.
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Spatz
authors.forename: Rachel
authors.initials: R
authors.lastname: Ellman
authors.forename: Alison M
authors.initials: AM
authors.lastname: Cloutier
authors.forename: Leeann
authors.initials: L
authors.lastname: Louis
authors.forename: Miranda
authors.initials: M
authors.lastname: van Vliet
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Suva
authors.forename: Denise
authors.initials: D
authors.lastname: Dwyer
authors.forename: Marina
authors.initials: M
authors.lastname: Stolina
authors.forename: Hua Zhu
authors.initials: HZ
authors.lastname: Ke
authors.forename: Mary L
authors.initials: ML
authors.lastname: Bouxsein
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D001696:Biomechanical Phenomena / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D020342:Finite Element Analysis; D006023:Glycoproteins / Q000097:blood / Q000276:immunology*; D019417:Hindlimb Suspension; D036341:Intercellular Signaling Peptides and Proteins; D008810:Mice, Inbred C57BL; D009132:Muscles / Q000187:drug effects / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D016474:Weight-Bearing / Q000502:physiology; D055114:X-Ray Microtomography
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D015415:Biomarkers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse