A Role for Advanced Glycation End Products in Diminished Bone Healing in Type 1 Diabetes

Santana, Ronaldo B.; Xu, Lei; Chase, Hermik Babakhanlou; Amar, Salomon; Graves, Dana T.; Trackman, Philip C.

doi:10.2337/diabetes.52.6.1502

Cited by 219 publications

(216 citation statements)

References 54 publications

(46 reference statements)

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“…CML-collagen was prepared by chemical modification of acid soluble bovine skin collagen (Sigma), as previously described (23,38). Briefly, 50 μg of collagen was dissolved 1 mM HCl followed by incubation in sodium cyanoborohydride and glyoxylic acid in PBS.…”

Section: Cml-collagenmentioning

confidence: 99%

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Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways

Alikhani

Boyd

et al. 2007

Bone

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319

220

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We have previously shown that diabetes significantly enhances apoptosis of osteoblastic cells in vivo and that the enhanced apoptosis contributes to diabetes impaired new bone formation. A potential mechanism is enhanced apoptosis stimulated by advanced glycation endproducts (AGEs). To investigate this further, an advanced glycation product, carboxymethyl lysine modified collagen (CML-collagen) was injected in vivo and stimulated a 5 fold increase in calvarial periosteal cell apoptosis compared to unmodified collagen. It also induced apoptosis in primary cultures of human or neonatal rat osteoblastic cells or MC-3T3-E1 cells in vitro. Moreover, the apoptotic effect was largely mediated through RAGE receptor. CML-collagen increased p38 and JNK activity 3.2 and 4.4 fold, respectively. Inhibition of p38 and JNK reduced CML-collagen stimulated apoptosis by 45% and 59% and by 90% when used together (P<0.05). The predominant apoptotic pathway induced by CML-collagen involved caspase-8 activation of caspase-3 and was independent of NF-κB activation. When osteoblastic cells were exposed to a long-term low dose incubation with CMLcollagen there was a higher degree of apoptosis compared to short term incubation. In more differentiated osteoblastic cultures apoptosis was enhanced even further. These results indicate that advanced glycation endproducts, which accumulate in diabetic and aged individuals may promote apoptosis of osteoblastic cells and contribute to deficient bone formation.

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Section: Cml-collagenmentioning

confidence: 99%

“…AGEs may exert a negative effect on bone by interfering with osteoblast differentiation and the production of matrix proteins such as collagen and osteocalcin (13,33,38,54). It has recently been reported that AGEs stimulate apoptosis of human mesenchymal stem cells which could limit the formation of adipose tissue, cartilage and bone (25).…”

Section: Introductionmentioning

confidence: 99%

Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways

Alikhani

Boyd

et al. 2007

Bone

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319

220

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“…CML-collagen-CML-collagen was prepared by chemical modification of acid-soluble bovine skin collagen (Sigma), as described previously (21,42). Briefly, 50 mg of collagen was dissolved in 25 ml of 1 mM HCl freshly made in sterile water and incubated at 37°C with occasional mixing.…”

Section: Methodsmentioning

confidence: 99%

“…These include diabetes-associated cataract formation, nephropathy, retinopathy, neuropathy, and periodontal disease (15)(16)(17)(18)(19)(20). AGEs also impair osseous wound healing (21).…”

mentioning

confidence: 99%

Advanced Glycation End Products Enhance Expression of Pro-apoptotic Genes and Stimulate Fibroblast Apoptosis through Cytoplasmic and Mitochondrial Pathways

Alikhani

Boyd

et al. 2005

Journal of Biological Chemistry

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121

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Both aging and diabetes are characterized by the formation of advanced glycation end products (AGEs). Both exhibit other similarities including deficits in wound healing that are associated with higher rates of fibroblast apoptosis. In order to investigate a potential mechanism for enhanced fibroblast apoptosis in diabetes and aged individuals, experiments were carried out to determine whether the predominant advanced glycation end product in skin, N-⑀-(carboxymethyl) lysine (CML)-collagen, could induce fibroblast apoptosis. In vivo experiments established that CML-collagen but not unmodified collagen induced fibroblast apoptosis and that apoptosis was dependent upon caspase-3, -8, and -9 activity. In vitro experiments demonstrated that CMLcollagen but not control collagen induced a time-and dose-dependent increase in fibroblast apoptosis. By use of blocking antibodies, apoptosis was shown to be mediated through receptor for AGE signaling. AGE-induced apoptosis was largely dependent on the effector caspase, caspase-3, which was activated through both cytoplasmic (caspase-8-dependent) and mitochondrial (caspase-9) pathways. CML-collagen had a global effect of enhancing mRNA levels of pro-apoptotic genes that included several classes of molecules including ligands, receptors, adaptor molecules, mitochondrial proteins, and others. However, the pattern of expression was not identical to the pattern of apoptotic genes induced by tumor necrosis factor ␣.

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“…1) (Santana et al 2003). Defects were created in anesthetized mice with shaved heads and a midline incision with a carbide cylinder square bur (Meisinger cat#BA-2021-010) under normal saline irrigation.…”

Section: Methodsmentioning

confidence: 99%

Diabetes-induced fibrotic matrix inhibits intramembranous bone healing

Khosravi

Trackman

2014

J. Cell Commun. Signal.

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Diabetes diminishes bone healing and ossification. Reduced bone formation in intramembranous ossification is known, yet t he mechanism(s) behind impaired intramembranous bone healing are unclear. Here we report the formation of a fibrotic matrix during healing of intramembranous calvarial bone defects that appears to exclude new bone growth. Our histological analyses of 7-day and 14-day calvaria bone healing tissue in chemically-induced diabetic mice and non-diabetic mice showed the accumulation of a non-mineralized fibrotic matrix, likely as a consequence of unresolved hematomas under diabetic conditions. Elevated mRNA and enzyme activity levels of lysyl oxidase on day 7 in diabetic bone healing tissues also supports that the formation of a fibrotic matrix occurs in these tissues. Based on these findings, we propose that elevated fibroblast proliferation and formation of a non-mineralized fibrotic extracellular matrix in diabetes contributes to deficient intramembranous bone healing in diabetes. A greater understanding of this process has relevance to managing dental procedures in diabetics in which successful outcomes depend on intramembranous bone formation.

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A Role for Advanced Glycation End Products in Diminished Bone Healing in Type 1 Diabetes

Cited by 219 publications

References 54 publications

Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways

Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways

Advanced Glycation End Products Enhance Expression of Pro-apoptotic Genes and Stimulate Fibroblast Apoptosis through Cytoplasmic and Mitochondrial Pathways

Diabetes-induced fibrotic matrix inhibits intramembranous bone healing

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