Hyperglycemia inhibits osteoblastogenesis of rat bone marrow stromal cells via activation of the Notch2 signaling pathway

Abstract

Background: Bone fragility and related fractures are increasingly being recognized as an important diabetic complication. Mesenchymal progenitors often serve as an important source of bone formation and regeneration. In the present study, we have evaluated the effects of diabetes on osteoblastogenesis of mesenchymal progenitors. Methods: Primary bone marrow stromal cells (BMSCs) were isolated from control and streptozotocin-induced diabetic rats. These cells were evaluated for the effects of in vivo hyperglycemia on the survival and function of mesenchymal progenitors. We concomitantly investigated the effects of different concentrations of glucose, osmolality, and advanced glycation end product (AGE) on osteogenic differentiation and matrix mineralization of rat bone marrow mesenchymal stem cells (RMSC-bm). The relationship between the expression levels of Notch proteins and the corresponding ALP levels was also examined. Results: Our results revealed that in vivo hyperglycemia increased cell proliferation rate but decreased osteogenic differentiation and matrix mineralization of primary rat BMSCs. In vitro high glucose treatment, instead of high AGE treatment, induced a dose-dependent inhibition of osteoblastogenesis of RMSC-bm cells. Activation of the Notch2 signaling pathway, instead of the Notch1 or osmotic response pathways, was associated with these diabetic effects on osteoblastogenesis of mesenchymal progenitors. Conclusions: Hyperglycemia might inhibit osteoblastogenesis of mesenchymal progenitors via activation of the Notch2 signaling pathway.

Impact of Type 2 Diabetes Mellitus on Human Bone Marrow Stromal Cell Number and Phenotypic Characteristics

“…It was here hypothesized that T2DM impacts the bone marrow MSC (osteoblastic precursor) population, with potential implications for bone homeostasis in humans. This is in line with what has been observed in other complications associated with DM (reviewed in [29]) and in rodent models of T2DM [10,12]. Osteopathic comorbidities associated with T2DM include an increase in BMD [7], increased fracture risk [6,11] and delayed fracture repair [30].…”

“…That MSCs are osteoblastic precursors in vivo [11] prioritises this cell type for investigation into whether T2DM can impact their ability to function appropriately in supporting bone homeostasis. Studies investigating this hypothesis have primarily taken place in exaggerated rodent models of T2DM and demonstrate reduced osteoblastogenesis (potentially via Notch2 signalling) and fewer osteoblast progenitors within the MSC population [10,12].…”

Impact of Diabetes Mellitus on Bone Health

“…A recent study utilising rat bone-marrow derived (BM-)MSCs has suggested that hyperglycemia activates the Notch2 signaling pathway, which was negatively correlated with ALP expression levels. This inhibited osteo-blastogenesis [152]. Additionally, hyperglycemia has been shown to increase production of sclerostin, which induces adipogenesis by inhibiting WNT signaling in human BM-MSCs [153].…”

Current Knowledge Regarding the Interaction Between Oral Bone Metabolic Disorders and Diabetes Mellitus

“…Hyperglycemia has a direct toxic effect on osteoblasts, inhibiting their differentiation. It also has a negative impact on the production of bone matrix and its components (97,98). However, the osmotic diuresis caused by hyperglycemia also results in a substantial loss of calcium, magnesium, and phosphorus from the body, resulting in lower circulating concentrations and mineral imbalances (99).…”