Abstract
Although bone regeneration is typically a reliable process, type 2 diabetes is associated with impaired or delayed healing processes. In addition, angiogenesis, a crucial step in bone regeneration, is often altered in the diabetic state. In this study, different stages of bone regeneration were characterized in an unicortical bone defect model comparing transgenic type 2 diabetic (db-/db-) and wild type (WT) mice in vivo. We investigated angiogenesis, callus formation and bone remodeling at early, intermediate and late time points by means of histomorphometry as well as protein level analyses. In order to enhance bone regeneration, defects were locally treated with recombinant FGF-9 or VEGFA. Histomorphometry of aniline blue stained sections indicated that bone regeneration is significantly decreased in db-/db- as opposed to WT mice at intermediate (5 days post operation) and late stages (7 days post operation) of bone regeneration. Moreover, immunohistochemical analysis revealed significantly decreased levels of RUNX-2, PCNA, Osteocalcin and PECAM-1 in db-/db- defects. In addition, osteoclastogenesis is impaired in db-/db- indicating altered bone remodeling. These results indicate significant impairments in angiogenesis and osteogenesis in type 2 diabetic bones. Importantly, angiogenesis, osteogenesis and bone remodeling could be reconstituted by application of recombinant FGF-9 and, in part, by VEGFA application. In conclusion, our study demonstrates that type 2 diabetes affects angiogenesis, osteogenesis and subsequently bone remodeling, which in turn leads to decreased bone regeneration. These effects could be reversed by local application of FGF-9 and to a lesser degree VEGFA. These data could serve as a basis for future therapeutic applications aiming at improving bone regeneration in the type 2 diabetic patient population.
Highlights
IntroductionBone regeneration is an efficient process that occurs without scar formation
In physiological conditions, bone regeneration is an efficient process that occurs without scar formation
Bone formation remained significantly decreased 7dpO in db-/db- mice by 80% compared to wild type (WT) mice
Summary
Bone regeneration is an efficient process that occurs without scar formation. It is generally accepted that diabetes impairs and/or delays fracture healing [2]. 90%) are suffering from type 2 diabetes mellitus. Both type 1 and type 2 diabetes mellitus patients appear to have an increased fracture risk [4,5]. Detrimental effects on bone fracture healing have been described in diabetic patients [6,7]. Loder et al showed that diabetic patients without neuropathy have a 1.6 fold delay in fracture healing [7]. There is a high demand in a growing and aging population for further research to develop novel strategies in treating diabetes associated bony defects and impaired bone regeneration
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