Streptozotocin, Type I Diabetes Severity and Bone |
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Authors: | Katherine Motyl Laura R McCabe |
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Institution: | (1) Departments of Physiology and Radiology, Biomedical Imaging Research Center, Michigan State University, 2201 Biomedical Physical Science Bldg., East Lansing, MI 48824, USA; |
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Abstract: | As many as 50% of adults with type I (T1) diabetes exhibit bone loss and are at increased risk for fractures. Therapeutic
development to prevent bone loss and/or restore lost bone in T1 diabetic patients requires knowledge of the molecular mechanisms
accounting for the bone pathology. Because cell culture models alone cannot fully address the systemic/metabolic complexity
of T1 diabetes, animal models are critical. A variety of models exist including spontaneous and pharmacologically induced
T1 diabetic rodents. In this paper, we discuss the streptozotocin (STZ)-induced T1 diabetic mouse model and examine dose-dependent
effects on disease severity and bone. Five daily injections of either 40 or 60 mg/kg STZ induce bone pathologies similar to
spontaneously diabetic mouse and rat models and to human T1 diabetic bone pathology. Specifically, bone volume, mineral apposition
rate, and osteocalcin serum and tibia messenger RNA levels are decreased. In contrast, bone marrow adiposity and aP2 expression
are increased with either dose. However, high-dose STZ caused a more rapid elevation of blood glucose levels and a greater
magnitude of change in body mass, fat pad mass, and bone gene expression (osteocalcin, aP2). An increase in cathepsin K and
in the ratio of RANKL/OPG was noted in high-dose STZ mice, suggesting the possibility that severe diabetes could increase
osteoclast activity, something not seen with lower doses. This may contribute to some of the disparity between existing studies
regarding the role of osteoclasts in diabetic bone pathology. Examination of kidney and liver toxicity indicate that the high
STZ dose causes some liver inflammation. In summary, the multiple low-dose STZ mouse model exhibits a similar bone phenotype
to spontaneous models, has low toxicity, and serves as a useful tool for examining mechanisms of T1 diabetic bone loss. |
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