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

A Role for Advanced Glycation End Products in Diminished Bone Healing in Type 1 Diabetes Ronaldo B. Santana 1 , Lei Xu 1 , Hermik Babakhanlou Chase 1 , Salomon Amar 1 2 , Dana T. Graves 1 2 and Philip C. Trackman 1 2 1 Boston University Goldman School of Dental Medicine, Division of Oral Biology, Boston, Massachusetts 2 Boston University School of Medicine, Biochemistry, Boston, Massachusetts Abstract The effect of type 1 diabetes on bone healing and bone formation in standardized craniotomy defects created in BALB/cByJ mice was determined. The hypothesis that advanced glycation end products (AGEs) contribute to diminished bone healing in diabetes was evaluated by assessing for the presence of the receptor for advanced glycation end products (RAGE) by immunohistochemistry in healing craniotomy defects in diabetic animals. The effect of local application of a known RAGE protein ligand, N ε -(carboxymethyl)lysine (CML)−mouse serum albumin (MSA), on craniotomy defect healing in normal animals was then assessed and compared to the effects of control MSA. Finally, evidence in support of the expression of RAGE mRNA and protein in osteoblastic cells was obtained. The results indicated that craniotomy defects in diabetic animals healed ∼40% of the degree to which they healed in nondiabetic animals ( P < 0.05). RAGE was expressed at higher levels in healing bone tissues in diabetic compared to control animals. Further studies in nondiabetic animals indicated that bone healing was reduced by 63 and 42% in lesions treated with 900 and 90 μg CML-MSA, respectively, compared to in animals treated with MSA alone ( P < 0.05). Evidence for the expression of RAGE was obtained in mouse and rat osteoblastic cultures. These results support the contribution of AGEs to diminished bone healing in type 1 diabetes, possibly mediated by RAGE. Footnotes Address correspondence and reprint requests to Dr. Philip C. Trackman, Boston University Goldman School of Dental Medicine, Department of Periodontology and Oral Biology, 100 East Newton St., Rm. G-07, Boston, MA 02118. E-mail: trackman{at}bu.edu . Received for publication 6 August 2002 and accepted in revised form 18 February 2003. AGE, advanced glycation end product; CML, N ε -(carboxymethyl)lysine; MSA, mouse serum albumin; RAGE, AGE receptor; STZ, streptozotocin. DIABETES