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- Document type:
- Journal Article; Research Support, Non-U.S. Gov't; Article
- Author(s):
- Freude, T; Braun, KF; Haug, A; Pscherer, S; Stöckle, U; Nüssler, AK; Ehnert, S
- Title:
- Hyperinsulinemia reduces osteoblast activity in vitro via upregulation of TGF-?.
- Abstract:
- Affecting more than 230,000,000 patients, diabetes mellitus is one of the most frequent metabolic disorders in developed countries. Among other complications, diabetic patients have an increased fracture risk and show delayed fracture healing. During the disease progression, these patients' blood glucose and insulin levels vary significantly. Thus, the aim of this study was to analyze the effects of glucose and insulin on primary human osteoblasts. Although, in the presence of insulin and glucose, proliferation of osteoblasts was increased (1.2- to 1.7-fold), their alkaline phosphatase activity and, consequently, production of mineralized matrix were significantly reduced down to 55 % as compared to control cells (p < 0.001). Interestingly, the observed effects were mainly due to stimulation with insulin. Increase in glucose did not alter osteoblasts' function significantly but further enhanced the effects of insulin. Expression of active and total transforming growth factor beta (TGF-?) was increased by glucose and insulin. Stimulation with both glucose and insulin induced gene expression changes (e.g., osteocalcin, Runx2, Satb2, or Stat1) comparable to treatment with recombinant TGF-?(1), further indicating osteoblasts' dysfunction. Inhibition of TGF-? signaling completely abolished the negative effects of glucose and insulin. In summary, glucose and insulin treatment causes osteoblast dysfunction, which is accompanied by an increased TGF-? expression. Blocking TGF-? signaling abrogates the functional loss observed in glucose- and insulin-treated osteoblasts, thus identifying TGF-? as a key regulator. Therefore, increased TGF-? expression during diabetes may be a feasible pathogenic mechanism underlying poor bone formation in uncontrolled diabetes mellitus.
- Journal title abbreviation:
- J Mol Med
- Year:
- 2012
- Journal volume:
- 90
- Journal issue:
- 11
- Pages contribution:
- 1257-66
- Fulltext / DOI:
- doi:10.1007/s00109-012-0948-2
- Pubmed ID:
- http://view.ncbi.nlm.nih.gov/pubmed/22926010
- Print-ISSN:
- 0946-2716
- TUM Institution:
- Klinik und Poliklinik für Unfallchirurgie
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