Abstract. insulin-dependent diabetes mellitus (iddm) is known to be associated with an increased risk of osteopenia. However, the cellular and molecular mechanisms for iddminduced alterations of the bone are not well understood. the effects of iddm on bone metabolism were investigated using rats rendered diabetic by an injection of streptozotocin (StZ). after 4 weeks, the diabetic rats exhibited bone loss, low levels of osteocalcin, insulin-like growth factor-i (iGf-i) and bone alkaline phosphatase (alP) activity with normal levels of bone tartrate-resistant acid phosphatase (traP) and cathepsin K activity, and urinary excretion of deoxypyridinoline (dpd). Histological analysis showed a decrease in the number of osteoblasts with a normal number of osteoclasts in the metaphysis of the proximal tibia. the decreased expression of alP, osteoclacin and collagen mrna was associated with a decrease in the expression of runt-related transcription factor 2 (runx2), osterix and distal-less homeobox 5 (dlx5) and an unaltered expression of bone morphogenic protein-2 (BmP2). the protein levels of runx2, phosphorylated glycogen synthase kinase 3β (GSK3β), active β-catenin and β-catenin decreased. the activation of akt was inhibited. the mrna and protein levels of sclerosteosis (Sost) and dickkopf 1 (dkk1), inhibitors of Wnt signaling, increased. the mrna expression of iGf-i and the iGf-i receptor (iGf-ir) was suppressed. these changes observed in the bone of diabetic rats were reversed by treatment with insulin, but not by normalization of the circulating iGf-i levels by treatment with iGf-i. These results suggest that insulin-deficiency in IDDM decreases osteoblastogenesis associated with inhibition of Wnt signaling through the increased expression of Sost and dkk1 and the inhibition of akt activation.
Introductioninsulin-dependent diabetes mellitus (iddm, type i diabetes) is known to be associated with decreased bone mass, osteoporosis, and increased fracture rates (1-3). Streptozotocin (StZ)-induced diabetes in rats is a well-recognized model for iddm (4,5). in these rats, bone histology and biochemical markers of bone formation and resorption indicate decreased osteoblastic activity with normal (5), decreased (6,7), or increased (8-10) osteoclastic activity. although these observational studies have provided consistent findings regarding deficits in bone integrity attributable to the diabetic state, little is known about the specific cellular and molecular mechanisms underlying the changes in bone metabolism in iddm.Bone formation is a tightly regulated process characterized by a sequence of events starting with the commitment of osteoprogenitor cells, and their differentiation into pre-osteoblasts and then into mature osteoblasts, which express high levels of alkaline phosphatase (alP), osteocalcin and collagen. osteoblast commitment, differentiation, and function are all governed by several transcription factors, resulting in the expression of phenotypic genes and in the acquisition of the osteoblast phenotype (11). the...
