1. Sclerostin antibody treatment improves fracture outcomes in a Type I diabetic mouse model
- Author
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Nicholas R. Hum, Deepa Murugesh, Sarah J. Hatsell, N M Collette, Cristal S. Yee, Aris N. Economides, LiQin Xie, and Gabriela G. Loots
- Subjects
0301 basic medicine ,Male ,endocrine system diseases ,Physiology ,Endocrinology, Diabetes and Metabolism ,Inbred C57BL ,Medical and Health Sciences ,Fractures, Bone ,chemistry.chemical_compound ,Mice ,Engineering ,STZ ,Fracture Healing ,Pediatric ,biology ,Osteoblast differentiation ,Streptozotocin ,Diabetes ,Adaptor Proteins ,Osteoblast ,Biological Sciences ,RUNX2 ,medicine.anatomical_structure ,Treatment Outcome ,5.1 Pharmaceuticals ,Osteocalcin ,Intercellular Signaling Peptides and Proteins ,Development of treatments and therapeutic interventions ,medicine.drug ,Type 1 ,medicine.medical_specialty ,Histology ,Sclerostin ,Sclerostin antibody ,Bone healing ,Autoimmune Disease ,Article ,Antibodies ,03 medical and health sciences ,Endocrinology & Metabolism ,Internal medicine ,medicine ,Diabetes Mellitus ,Type I diabetes ,Animals ,Bone ,Metabolic and endocrine ,Adaptor Proteins, Signal Transducing ,Glycoproteins ,Fracture repair ,business.industry ,Signal Transducing ,nutritional and metabolic diseases ,medicine.disease ,DMP1 ,Mice, Inbred C57BL ,Osteopenia ,Diabetes Mellitus, Type 1 ,030104 developmental biology ,Endocrinology ,chemistry ,Musculoskeletal ,biology.protein ,Osteoporosis ,business ,Fractures - 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.
- Published
- 2016
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