Chronic hyperglycemia modulates osteoblast gene expression through osmotic and non‐osmotic pathways

Abstract

Insulin dependent diabetes mellitus (IDDM; type I) is a chronic disease stemming from little or no insulin production and elevated blood glucose levels. IDDM is associated with osteoporosis and increased fracture rates. The mechanisms underlying IDDM associated bone loss are not known. Previously we demonstrated that osteoblasts exhibit a response to acute (1 and 24 h) hyperglycemia and hyperosmolality. Here we examined the influence of chronic hyperglycemia (30 mM) and its associated hyperosmolality on osteoblast phenotype. Our findings demonstrate that osteoblasts respond to chronic hyperglycemia through modulated gene expression. Specifically, chronic hyperglycemia increases alkaline phosphatase activity and expression and decreases osteocalcin, MMP-13, VEGF and GAPDH expression. Of these genes, only MMP-13 mRNA levels exhibit a similar suppression in response to hyperosmotic conditions (mannitol treatment). Acute hyperglycemia for a 48-h period was also capable of inducing alkaline phosphatase and suppressing osteocalcin, MMP-13, VEGF, and GAPDH expression in differentiated osteoblasts. This suggests that acute responses in differentiated cells are maintained chronically. In addition, hyperglycemic and hyperosmotic conditions increased PPARgamma2 expression, although this increase reached significance only in 21 days chronic glucose treated cultures. Given that osteocalcin is suppressed and PPARgamma2 expression is increased in type I diabetic mouse model bones, these findings suggest that diabetes-associated hyperglycemia may modulate osteoblast gene expression, function and bone formation and thereby contribute to type I diabetic bone loss.

High d(+)glucose concentration inhibits RANKL-induced osteoclastogenesis

“…It is also unclear whether hyperglycemia has a role in maintaining normal bone mass in some cases of diabetes, and may protect against bone loss during early stages of the disease [9]. Although the role of glucose in osteoblast differentiation and mineralization has been examined [10][11][12][13][14], little is known regarding its effect on osteoclast differentiation and function. Our findings indicate that high D-Glc inhibits osteoclastogenesis, likely by preventing the formation of pre-osteoclast cells capable of fusing into multinucleated osteoclasts.…”

“…Hyperglycemia has been implicated in the pathogenesis of diabetic bone disease and, decreased activity of osteoblasts under diabetic conditions has been reported in both animal models and humans [9,10]. In vitro, incubation of cultured osteoblast-like cells with high glucose inhibits mineralization, Insulinlike Growth Factor-I (IGF-I)-stimulated growth and modulates osteoblast gene expression [11][12][13][14]. Studies are conflicting as to whether osteoclastogenesis is altered in diabetes [6].…”

MECHANISMS IN ENDOCRINOLOGY: Mechanisms and evaluation of bone fragility in type 1 diabetes mellitus

“…Given the fact that a lot of in vitro data (80,100) suggest that hyperglycaemia and hyperlipidaemia are toxic to osteoblasts, and at least some clinical reports (18,19,20) have confirmed a relationship between glycaemic control and fracture incidence, it is our contention that every effort should be made to optimise metabolic control in patients with T1DM at risk of fracture; this is especially relevant to T1DM in the young. Optimization of the insulin treatment remains a major point for normalization of glycaemia, prevention of diabetic complications and even prevention of bone health.…”

“…Hyperglycaemia is known to suppress osteoblastic differentiation and signalling, potentially resulting in impaired bone formation (80,100). Chronic hyperglycaemia may also result in the non-enzymatic glycosylation of proteins (e.g.…”

Mouse Strain Dependent and Independent Effects of Type 1 Diabetic Bone Pathology

“…Human and animal models of T1D display diminished bone mineral apposition rate (MAR), bone mineral density (BMD) and bone mineral content (BMC) [3,4]. Potential contributors to the pathogenesis of T1D bone loss include disturbed glucose metabolism [5,6] systemic and bone marrow inflammation [7][8][9], changes in lipid metabolism [10][11][12], and changes in systematic hormones [13] (Figure 1). Bone marrow adiposity, which can promote bone oss1, may play less of a role in T1D osteoporosis [1,14,15], but is a key marker of the diabetic bone pathology in mice.…”