Streptozotocin, Type I Diabetes Severity and Bone

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

Biological repair of the degenerated intervertebral disc by the injection of growth factors

The homeostasis of intervertebral disc (IVD) tissues is accomplished through a complex and precise coordination of a variety of substances, including cytokines, growth factors, enzymes and enzyme inhibitors. Recent biological therapeutic strategies for disc degeneration have included attempts to up-regulate the production of key matrix proteins or to down-regulate the catabolic events induced by pro-inflammatory cytokines. Several approaches to deliver these therapeutic biologic agents have been proposed and tested in a preclinical setting. One of the most advanced biological therapeutic approaches to regenerate or repair a degenerated disc is the injection of a recombinant growth factor. Abundant evidence for the efficacy of growth factor injection therapy for the treatment of IVD degeneration can be found in preclinical animal studies. Recent data obtained from animal studies on changes in cytokine expression following growth factor injection illustrate the great potential for patients with chronic discogenic low back pain. The first clinical trial for growth factor injection has been initiated and the results of that study may prove the usefulness of growth factor injection for treating the symptoms of patients with degenerative disc diseases. The focus of this review article is the effects of an in vivo injection of growth factors on the biological repair of the degenerated intervertebral disc in animal models. The effects of growth factor injection on the symptoms of patients with low back pain, the therapeutic target of growth factor injection and the limitations of the efficacy of growth factor therapy are also reviewed. Further quantitative studies on the effect of growth factor injection on pain generation and the long term effects on the endplate and cell survival after an injection using large animals are needed. An international academic-industrial consortium addressing these aims, such as was achieved for osteoarthritis (The Osteoarthritis Initiative), may further the development of biological therapies for degenerative disc diseases