Reduced intramembranous bone healing in experimentally-induced diabetes mellitus
Date
2001
DOI
Authors
Santana, Ronaldo
Version
OA Version
Citation
Abstract
Despite its well characterized abnormalities in sugar and lipid metabolism, relatively little is known about the effect of diabetes on bone healing, bone formation, and osteoblast function. Thus, the effect of multiple low dose streptozotocin-induced diabetes on bone healing and bone formation was determined for the first time utilizing standardized craniotomy defects made in Balbc/byJ mice, followed by computer assisted quantitative histomorphometric analyses of stained histoIogical sections. Defects (1 mm, 1.6 mm, and 2.1 mm diameter) made in diabetic animals healed approximately 50% of the degree of healing found in defects made in control non-diabetic animals, determined by both bone bridging and bone area measurements (P[less than]0.05) after two weeks of healing.
The hypothesis that advanced glycation end products (AGE's) contribute to the observed inhibited diabetic bone healing was evaluated first by assessing for the increased presence of the receptor for advanced glycation end products (RAGE) by immunohistochemistry in healing diabetic craniotomy defects (1 mm diameter). Second, the effect on craniotomy defect healing in normal animals of application of a known AGE and RAGE ligand was determined. Thus, [N epsilon]-(carboxymethyl)lysine modified mouse serum albumin (CML-MSA) was applied to 1 mm craniotomy defects over a two week period in normal animals via surgically implanted osmotic minipumps. Results indicated that in diabetic lesions RAGE was expressed at high levels in the periosteum, dura mater and granulation tissue filling the bone defects at 10 days of healing, whereas RAGE expression was significantly lower in corresponding control lesions. CML-MSA application studies in non-diabetic animals indicate that bone healing (linear/area measurements) was reduced by 48/63 % and 63/42 % in lesions treated with 0.85 mg and 0.085 mg CML-MSA, respectively, compared to control animals treated with non-modified mouse serum albumin (P[less than]0.05). Taken together, these studies support the notion that AGE/RAGE interactions may contribute to inhibited bone healing in Type I diabetes.
The hypothesis that diminished bone healing in diabetes could be related to diminished osteoblast differentiation and/or osteoblast function was evaluated by localapplication of factors that stimulate osteoblast differentiation and/or osteoblast function to craniotomy defects in diabetic and control non-diabetic animals, followed by quantitative histomorphometric analyses. Factors chosen were rhBMP-2 and rhFGF-2. For rhFGF-2, a delivery vehicle was first developed for in vivo application utilizing a polylactide polymer. Results demonstrated stimulation of bone healing in diabetic animals resulting in bone bridging at least comparable to untreated bone defects in normal animals, suggesting that both factors were effective in rescuing the deleterious effects of diabetes on bone healing. Histomorphometric measurements of surface area of new bone formation support that although rhBMP-2 and rhFGF-2 each restored bone healing and stimulated regeneration, defects in non-diabetic animals exhibited more total mineralized bone. It is concluded that rhBMP-2 and rhFGF-2 may be of value in therapeutic regimens for osteopenic conditions associated with Type l diabetes mellitus, but that other factors or application protocols may further enhance normal bone healing.
Description
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Dissertation (DSc) --Boston University Goldman School of Dental Medicine, 2001 (Department of Periodontology and Oral Biology).
Includes bibliographic references: leaves 201-226.
Dissertation (DSc) --Boston University Goldman School of Dental Medicine, 2001 (Department of Periodontology and Oral Biology).
Includes bibliographic references: leaves 201-226.
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This work is protected by copyright. Downloading is restricted to the BU community. If you are the author of this work and would like to make it publicly available, please contact open-help@bu.edu.