Growth-Inhibitory Effect of a High Glucose Concentration on Osteoblast-like Cells

Terada, Makoto; Inaba, Masaaki; Yano, Yoshihisa; Hasuma, Tadayoshi; Nishizawà, Yoshiki; Morii, Hirotoshi; Otani, Shuzo

doi:10.1016/s8756-3282(97)00220-2

Cited by 171 publications

(114 citation statements)

References 26 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Wittrant

Gorin

Woodruff

et al. 2008

Bone

146

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Diabetes is a chronic disease associated with hyperglycemia and altered bone metabolism that may lead to complications including osteopenia, increased risk of fracture and osteoporosis. Hyperglycemia has been implicated in the pathogenesis of diabetic bone disease; however, the biologic effect of glucose on osteoclastogenesis is unclear. In the present study, we examined the effect of high D(+)glucose (D-Glc) and L(−)glucose (L-Glc; osmotic control) on RANKL-induced osteoclastogenesis using RAW264.7 cells and Bone Marrow Macrophages (BMM) as models. Cells were exposed to sustained high glucose levels to mimic diabetic conditions. Osteoclast formation was analyzed using tartrate resistant acid phosphatase (TRACP) assay, expression of calcitonin receptor (CTR) and cathepsin K mRNAs, and cultures were examined for reactive oxygen species (ROS) using dichlorodihydrofluorescein diacetate (DCF-DA) fluorescence, caspase-3 and Nuclear Factor kappaB (NF-κB) activity. Cellular function was assessed using a migration assay. Results show, for the first time, that high D-Glc inhibits osteoclast formation, ROS production, caspase-3 activity and migration in response to RANKL through a metabolic pathway. Our findings also suggest that high D-Glc may alter RANKL-induced osteoclast formation by inhibiting redox-sensitive NF-κB activity through an anti-oxidative mechanism. This study increases our understanding of the role of glucose in diabetes-associated bone disease. Our data suggest that high glucose levels may alter bone turnover by decreasing osteoclast differentiation and function in diabetes and provide new insight into the biologic effects of glucose on osteoclastogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Wittrant

Gorin

Woodruff

et al. 2008

Bone

146

View full text Add to dashboard Cite

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“…Several studies have demonstrated that type-2 diabetic osteoporosis is associated with depression of osteoblastic activities, resulting in a decrease in bone formation (Inaba et al 1999, Takizawa et al 2003. In in vitro studies, elevated extracellular glucose has been shown to change osteoblast phenotype by inhibiting osteocalcin expression (Inaba et al 1995, Terada et al 1998, Zayzafoon et al 2002. Irreversible advanced glycosylation end-products (AGEs) are generated by even sporadic elevations in blood glucose and appear to act through specific receptors (RAGEs) to increase the levels of inflammatory cytokines (tumor necrosis factor-α and interleukin-6), which have been shown to negatively affect the balance of bone formation/resorption.…”

Section: Discussionmentioning

confidence: 99%

A novel rat model for the study of deficits in bone formation in type-2 diabetes

et al. 2007

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Background There is evidence to suggest that impairment in bone formation and/or turnover is associated with the metabolic abnormalities characteristic of type-2 diabetes mellitus. However, bone regeneration/repair in type-2 diabetes has not been modeled. Using Zucker Diabetic Fatty (ZDF) rats (a model of type-2 diabetes) for tibial distraction osteogenesis (DO), we hypothesized that bone formation within the distraction gap would be impaired.Animals and methods Rats were examined for body weight, glycosuria, and glycosemia to confirm the diabetic condition during the study. The rats received placement of the external fixators and osteotomies on the left tibia. Distraction was initiated the following day at 0.2 mm twice a day and continued for 14 days. The lengthened tibiae were harvested and distraction gaps were examined radiographically and histologically.Results We found significant reduction in new bone formation in the distraction gaps of the ZDF rats, both radiographically and histologically, compared to lean rats. We found a decrease in a marker of cellular proliferation in the distraction gaps and increased adipose volume in adjacent bone marrow of the ZDF rats.Interpretation Our findings suggest that this model might be used to study the contributions of leptin resistance, insulin resistance and/or hyperglycemia to impaired osteoblastogenesis in vivo.

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“…On one hand, hyperinsulinemia and relatively high BMI are protective against bone loss in type 2 diabetes mellitus. On the other, increased calciuria and decreased osteoblastic function due to hyperglycemia may lead to deterioration of bone mass (Terada et al 1998). Considering the likelihood that patients with type 2 diabetes mellitus may potentially be at a somewhat higher risk of developing osteoporosis, treatment with TZDs could increase this risk further.…”

Section: Figurementioning

confidence: 99%

Rosiglitazone impacts negatively on bone by promoting osteoblast/osteocyte apoptosis

Sorocéanu

Miao²,

Xiu-juan³

et al. 2004

Journal of Endocrinology

178

103

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Thiazolidinediones (TZDs) increase peripheral tissue insulin sensitivity in patients with type 2 diabetes mellitus by activating the nuclear receptor peroxisome proliferatoractivated receptor (PPAR ). In bone marrow stromal cell cultures and in vivo, activation of PPAR by high doses (20 mg/kg/day) of TZDs has been reported to alter stem cell differentiation by promoting commitment of progenitor cells to the adipocytic lineage while inhibiting osteoblastogenesis. Here, we have examined the in vivo effects of low-dose rosiglitazone (3 mg/kg/day) on bone, administered to mice by gavage for 90 days. Rosiglitazone-treated mice had increased weight when compared with controls, with no significant alterations in serum levels of glucose, calcium or parathyroid hormone (PTH). Bone mineral density (BMD) at the lumbar vertebrae (L1-L4), ilium/sacrum, and total body was diminished by rosiglitazone treatment. Histologically, bone was characterized by decreased trabecular bone volume and increased marrow space with no significant change in bone marrow adipocity. Decreased osteoblast number and activity due to increased apoptotic death of osteoblasts and osteocytes was apparent while osteoclast parameters and serum levels of osteocalcin, alkaline phosphatase activity, and leptin were unaltered by rosiglitazone treatment. Therefore, the imbalance in bone remodeling that follows rosiglitazone administration arises from increased apoptotic death of osteogenic cells and diminished bone formation leading to the observed decrease in trabecular bone volume and BMD. These novel in vivo effects of TZDs on bone are of clinical relevance as patients with type 2 diabetes mellitus and other insulin resistant states treated with these agents may potentially be at increased risk of osteoporosis.

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Growth-Inhibitory Effect of a High Glucose Concentration on Osteoblast-like Cells

Cited by 171 publications

References 26 publications

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

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

A novel rat model for the study of deficits in bone formation in type-2 diabetes

Rosiglitazone impacts negatively on bone by promoting osteoblast/osteocyte apoptosis

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