Abstract
Patients with diabetes suffer from poor fracture healing. Molecular reasons are not fully understood and our previous gene expression microarray analyses of regenerating bones from mice with type 2 diabetes (db−/db−) revealed accelerated activation of pathways concerning matrix metalloproteases (MMPs). Thus, we picked out the pathological MMP acceleration as a target for profound gene expression analyses and additional therapeutic intervention in the present study. In the first part, gene expression of ECM degrading proteinases and inhibitors was investigated three and seven days postoperatively. Mmp3, Mmp9, Mmp13 and gene expression of MMP inhibitor Timp2 was significantly higher in regenerating bone fractures of db−/db− compared to wild type animals. Timp1 and metalloproteinase AdamTS4 showed no differences. In the second part, we locally applied a single dose (1 µL of 5 µM solution) of the broad-spectrum molecular MMP inhibitor Marimastat on tibial defects in db−/db−. We performed immunohistochemical and histological stainings seven days post operation. Impaired bone healing, collagen content, angiogenesis, and osteoclast invasion in db−/db− were restored significantly by application of Marimastat compared to PBS controls (n = 7/group). Hence, local intervention of bone defects by the molecular MMP inhibitor Marimastat might be an alternative therapeutic intervention for bone healing in diabetes.
Highlights
Patients with diabetes (PwD) without metabolically stable blood glucose complain of disturbed bone homeostasis, increased risk of fracture occurrence, and poor healing after fractures [1,2,3,4,5,6]
Several genes related to matrix metalloproteases (MMPs) were selected in order to analyze gene expression by Quantitative Real-Time PCR (qRT-PCR) in more detail
Expression of Mmp3 and Mmp13 was significantly elevated in general, whereas up-regulation in bones of db− /db− was significantly higher compared to wt bones (Figure 2)
Summary
Patients with diabetes (PwD) without metabolically stable blood glucose (hyperglycemia) complain of disturbed bone homeostasis, increased risk of fracture occurrence, and poor healing after fractures [1,2,3,4,5,6]. 90% of PwD have type 2 diabetes [7]; it exhibits hyperglycemia due to insulin resistance [8]. Of US adults and that an additional nearly 35% of adults are estimated to have increased blood glucose that may develop to type 2 diabetes without intervention, an ever increasing health and economic burden is looming [9]. In former studies, we exhibited a reduction in regeneration of tibial bone, osteogenic differentiation, and osteoclastic activity in mouse models of type 2 diabetes (db− /db− ) [10,11]
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