Sclerostin antibody treatment improves fracture outcomes in a Type I diabetic mouse model.

Autor: Yee CS; 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., Xie L; Regeneron Pharmaceuticals, Tarrytown, NY, USA., Hatsell S; Regeneron Pharmaceuticals, Tarrytown, NY, USA., Hum N; Biology and Biotechnology Division, Lawrence Livermore National Laboratory, 7000 East Avenue, L-452, Livermore, CA 94550, USA., Murugesh D; School of Natural Sciences, University of California, Merced, Merced, CA, USA., Economides AN; Regeneron Pharmaceuticals, Tarrytown, NY, USA., Loots GG; 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., Collette NM; School of Natural Sciences, University of California, Merced, Merced, CA, USA. Electronic address: collette2@llnl.gov.
Jazyk: angličtina
Zdroj: Bone [Bone] 2016 Jan; Vol. 82, pp. 122-34. Date of Electronic Publication: 2015 May 05.
DOI: 10.1016/j.bone.2015.04.048
Abstrakt: 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.
(Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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