Elevated glucose acts directly on osteocytes to increase sclerostin expression in diabetes

Abstract

Bone quality in diabetic patients is compromised, leading to weaker bones and increased fracture risk. However, the mechanism by which this occurs in diabetic bone remains to be fully elucidated. We hypothesized that elevated glucose and glucose variation would affect the function of osteocytes, essential regulators of bone homeostasis and quality. To first test this hypothesis, we used the IDG-SW3 osteocyte-like cell line to examine the effects of glucose levels on osteocyte function and viability in vitro. We confirmed our in vitro findings using the in vivo streptozotocin-induced (STZ) diabetic rat model and ex-vivo cultured osteocytes from these rats. IDG-SW3 cells cultured under high glucose conditions displayed significantly increased Sost mRNA(100-fold) and sclerostin protein, a negative regulator of bone formation(5000-fold), compared to cells in control media. mRNA expression of osteoblast markers such as Osx, Ocn and Col1a1 was unaffected by glucose. Factors associated with osteoclast activation were affected by glucose, with Rankl being upregulated by low glucose. Opg was also transiently upregulated by high glucose in mature IDG-SW3 cells. Induction of diabetes in Sprague-Dawley rats via a single dose of STZ (70 mg/kg) resulted in elevated maximum glucose and increased variability compared to control animals (670/796 vs. 102/142 mg/dL). This was accompanied by increased Sost/sclerostin expression in the osteocytes of these animals. These results show that glucose levels directly regulate osteocyte function through sclerostin expression and suggest a potential mechanism for the negative impact of diabetes on bone quality.

The Impact of Antiosteoporotic Drugs on Glucose Metabolism and Fracture Risk in Diabetes: Good or Bad News?

“…Moreover, T2DM subjects have higher sclerostin levels than patients with T1DM [ 28 , 29 , 30 , 31 ], although this does not seem to be correlated with the risk of T2DM onset [ 27 ]. Preclinical findings also suggest that high glucose levels can directly increase the sclerostin expression leading to a negative impact on bone quality in DM [ 32 ]. Recent clinical data have confirmed that subjects with T2DM have higher bone gene expression of SOST, suggesting that impaired WNT signaling may be one of the key factors impairing bone metabolism in diabetic patients [ 33 ].…”

Lack of PTEN in osteocytes increases circulating phosphate concentrations by decreasing intact fibroblast growth factor 23 levels

“…In support of this notion, the presence of insulin receptors in UMR106-01 cells, not in immature osteoblastic UMR201-10B cells, was previously reported 32 . Similarly, insulin receptor expression was detected in the osteocyte-like cell line IDG-SW3 33 . Despite these findings, in vivo evidence for the expression of insulin receptors in osteocytes is limited.…”

Mechanisms of altered bone remodeling in children with type 1 diabetes

“…The important role of both molecules has also been demonstrated in a mouse model, showing that a bispecific antibody targeting sclerostin and DKK-1 supports bone mass accrual and fracture repair, exerting a greater effect compared to monotherapies[ 71 ]. In type 1 diabetic rats, an increased SOST mRNA and sclerostin expression has been observed[ 72 ]. Clinical studies and Homeostatic Model Assessment for Insulin Resistance have shown an inverse correlation between sclerostin and insulin levels, suggesting that sclerostin could modulate glucose homeostasis[ 73 ].…”