title: Sclerostin antibody treatment improves fracture outcomes in a Type I diabetic mouse model.
abstract: Type 1 diabetes mellitus (T1DM) patients have osteopenia and impaired fracture healing due to decreased osteoblast activity. Further, no adequate treatments are currently available that can restore impaired healing in T1DM; hence a significant need exists to investigate new therapeutics for treatment of orthopedic complications. Sclerostin (SOST), a WNT antagonist, negatively regulates bone formation, and SostAb is a potent bone anabolic agent. To determine whether SOST antibody (SostAb) treatment improves fracture healing in streptozotocin (STZ) induced T1DM mice, we administered SostAb twice weekly for up to 21days post-fracture, and examined bone quality and callus outcomes at 21days and 42days post-fracture (11 and 14weeks of age, respectively). Here we show that SostAb treatment improves bone parameters; these improvements persist after cessation of antibody treatment. Markers of osteoblast differentiation such as Runx2, collagen I, osteocalcin, and DMP1 were reduced, while an abundant number of SP7/osterix-positive early osteoblasts were observed on the bone surface of STZ calluses. These results suggest that STZ calluses have poor osteogenesis resulting from failure of osteoblasts to fully differentiate and produce mineralized matrix, which produces a less mineralized callus. SostAb treatment enhanced fracture healing in both normal and STZ groups, and in STZ+SostAb mice, also reversed the lower mineralization seen in STZ calluses. Micro-CT analysis of calluses revealed improved bone parameters with SostAb treatment, and the mineralized bone was comparable to Controls. Additionally, we found sclerostin levels to be elevated in STZ mice and β-catenin activity to be reduced. Consistent with its function as a WNT antagonist, SostAb treatment enhanced β-catenin activity, but also increased the levels of SOST in the callus and in circulation. Our results indicate that SostAb treatment rescues the impaired osteogenesis seen in the STZ induced T1DM fracture model by facilitating osteoblast differentiation and mineralization of bone.
authors.affiliation: Biology and Biotechnology Division, Lawrence Livermore National Laboratory, 7000 East Avenue, L-452, Livermore, CA 94550, USA; School of Natural Sciences, University of California, Merced, Merced, CA, USA.
authors.forename: Cristal S
authors.initials: CS
authors.lastname: Yee
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY, USA.
authors.forename: LiQin
authors.initials: L
authors.lastname: Xie
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hatsell
authors.affiliation: Biology and Biotechnology Division, Lawrence Livermore National Laboratory, 7000 East Avenue, L-452, Livermore, CA 94550, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Hum
authors.affiliation: School of Natural Sciences, University of California, Merced, Merced, CA, USA.
authors.forename: Deepa
authors.initials: D
authors.lastname: Murugesh
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY, USA.
authors.forename: Aris N
authors.initials: AN
authors.lastname: Economides
authors.affiliation: Biology and Biotechnology Division, Lawrence Livermore National Laboratory, 7000 East Avenue, L-452, Livermore, CA 94550, USA; School of Natural Sciences, University of California, Merced, Merced, CA, USA.
authors.forename: Gabriela G
authors.initials: GG
authors.lastname: Loots
authors.affiliation: School of Natural Sciences, University of California, Merced, Merced, CA, USA. Electronic address: collette2@llnl.gov.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Collette
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D017102:Fracture Healing / Q000187:drug effects* / Q000502:physiology; D050723:Fractures, Bone / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D006023:Glycoproteins / Q000494:pharmacology / Q000627:therapeutic use*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016896:Treatment Outcome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse
keywords: Fracture repair; Osteoblast differentiation; STZ; Sclerostin; Sclerostin antibody; Streptozotocin; Type I diabetes