title: The bone marrow microenvironment contributes to type I diabetes induced osteoblast death.
abstract: Type I diabetes increases an individual's risk for bone loss and fracture, predominantly through suppression of osteoblast activity (bone formation). During diabetes onset, levels of blood glucose and pro-inflammatory cytokines (including tumor necrosis factor α (TNFα)) increased. At the same time, levels of osteoblast markers are rapidly decreased and stay decreased chronically (i.e., 40 days later) at which point bone loss is clearly evident. We hypothesized that early bone marrow inflammation can promote osteoblast death and hence reduced osteoblast markers. Indeed, examination of type I diabetic mouse bones demonstrates a greater than twofold increase in osteoblast TUNEL staining and increased expression of pro-apoptotic factors. Osteoblast death was amplified in both pharmacologic and spontaneous diabetic mouse models. Given the known signaling and inter-relationships between marrow cells and osteoblasts, we examined the role of diabetic marrow in causing the osteoblast death. Co-culture studies demonstrate that compared to control marrow cells, diabetic bone marrow cells increase osteoblast (MC3T3 and bone marrow derived) caspase 3 activity and the ratio of Bax/Bcl-2 expression. Mouse blood glucose levels positively correlated with bone marrow induced osteoblast death and negatively correlated with osteocalcin expression in bone, suggesting a relationship between type I diabetes, bone marrow and osteoblast death. TNF expression was elevated in diabetic marrow (but not co-cultured osteoblasts); therefore, we treated co-cultures with TNFα neutralizing antibodies. The antibody protected osteoblasts from bone marrow induced death. Taken together, our findings implicate the bone marrow microenvironment and TNFα in mediating osteoblast death and contributing to type I diabetic bone loss.
authors.affiliation: Department of Physiology, Biomedical Imaging Research Center, Michigan State University, East Lansing, Michigan 48824, USA.
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: Coe
authors.forename: Regina
authors.initials: R
authors.lastname: Irwin
authors.forename: Dennean
authors.initials: D
authors.lastname: Lippner
authors.forename: Laura R
authors.initials: LR
authors.lastname: McCabe
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000473:pathology*; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D014409:Tumor Necrosis Factor-alpha